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Contains fulltext : 200332.pdf (Publisher’s version ) (Open Access) BACKGROUND: Nearly one third of patients undergoing neoadjuvant chemoradiotherapy (nCRT) for locally advanced esophageal cancer have a pathologic complete response (pCR) of the primary tumor upon histopathological evaluation of the resection specimen. The primary aim of this study is to develop a model that predicts the probability of pCR to nCRT in esophageal cancer, based on diffusion-weighted magnetic resonance imaging (DW-MRI), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and (18)F-fluorodeoxyglucose positron emission tomography with computed tomography ((18)F-FDG PET-CT). Accurate response prediction could lead to a patient-tailored approach with omission of surgery in the future in case of predicted pCR or additional neoadjuvant treatment in case of non-pCR. METHODS: The PRIDE study is a prospective, single arm, observational multicenter study designed to develop a multimodal prediction model for histopathological response to nCRT for esophageal cancer. A total of 200 patients with locally advanced esophageal cancer - of which at least 130 patients with adenocarcinoma and at least 61 patients with squamous cell carcinoma - scheduled to receive nCRT followed by esophagectomy will be included. The primary modalities to be incorporated in the prediction model are quantitative parameters derived from MRI and (18)F-FDG PET-CT scans, which will be acquired at fixed intervals before, during and after nCRT. Secondary modalities include blood samples for analysis of the presence of circulating tumor DNA (ctDNA) at 3 time-points (before, during and after nCRT), and an endoscopy with (random) bite-on-bite biopsies of the primary tumor site and other suspected lesions in the esophagus as well as an endoscopic ultrasonography (EUS) with fine needle aspiration of suspected lymph nodes after finishing nCRT. The main study endpoint is the performance of the model for pCR prediction. Secondary endpoints include progression-free and overall survival. DISCUSSION: If the multimodal PRIDE concept provides high predictive performance for pCR, the results of this study will play an important role in accurate identification of esophageal cancer patients with a pCR to nCRT. These patients might benefit from a patient-tailored approach with omission of surgery in the future. Vice versa, patients with non-pCR might benefit from additional neoadjuvant treatment, or ineffective therapy could be stopped. TRIAL REGISTRATION: The article reports on a health care intervention on human participants and was prospectively registered on March 22, 2018 under ClinicalTrials.gov Identifier: NCT03474341 .

We performed a prospective multi-centre study using functional magnetic resonance imaging (fMRI) to better characterize the relationships between clinical expression and brain function in patients with multiple sclerosis (MS) at eight European sites (56 MS patients and 60 age-matched, healthy controls). Patients showed greater task-related activation bilaterally in brain regions including the pre- and post-central, inferior and superior frontal, cingulate and superior temporal gyri and insula (P < 0.05, all statistics corrected for multiple comparisons). Both patients and healthy controls showed greater brain activation with increasing age in the ipsilateral pre-central and inferior frontal gyri (P < 0.05). Patients, but not controls, showed greater brain activation in the anterior cingulate gyrus and the bilateral ventral striatum (P < 0.05) with less hand dexterity. An interaction between functional activation changes in MS and age was found. This large fMRI study over a broadly selected MS patient population confirms that movement for patients demands significantly greater cognitive 'resource allocation' and suggests age-related differences in brain responses to the disease. These observations add to evidence that brain functional responses (including potentially adaptive brain plasticity) contribute to modulation of clinical expression of MS pathology and demonstrate the feasibility of a multi-site functional MRI study of MS.

Introduction Multiple sclerosis (MS) is characterized, besides focal lesions, by brain atrophy. The determinants of atrophy rates in individual patients are poorly understood. Aim This study investigated the predictive value of clinical and magnetic resonance imaging (MRI) factors, including short-term changes thereof, for concurrent and future atrophy evolution using Spearman’s rank correlations and stepwise multiple linear regression. Methods We retrospectively identified a group of 115 active, early relapsing-remitting (RR) patients relatively homogeneous in terms of disease course and MRI activity compared to a second group of 96 patients with broader spectrum of MS phenotypes and inactive scans. All patients had undergone three MRI investigations with interscan intervals of at least 12 and 24 months, respectively. Results In the RR patients, 23% of variance in concurrent atrophy rates (over the first interval) could be explained by the combination of baseline T2 lesion volume and change in EDSS score over the first interval, whereas only 6% in future atrophy rates (over the second interval) was explained. In the heterogeneous group, 20.2% of the variance in future atrophy rates could be explained, but slightly less in concurrent atrophy rates (16.2%). Conclusion We concluded that variance in brain atrophy rates can partially be explained by clinical and MRI measures of disease. Future atrophy rates in individual MS patients are difficult to predict even when including previous atrophy rates.

Background: Although essential in treatment decision making, clinical nodal (cN) staging in esophageal cancer (EC) remains difficult. We assessed the rate of nodal up- and downstaging and its prognostic value on 5-year disease-free survival (DFS) in EC patients treated with surgery-alone or with neoadjuvant chemoradiotherapy (nCRT). Methods: For this retrospective study, we included 395 EC patients who underwent a curative esophagectomy with or without nCRT between 2000 and 2015. The surgery-alone and nCRT group were matched on clinical T-stage (cT), cN-stage, and histopathological type using propensity score matching (n=270). Staging consisted of PET with CT, or PET/CT, and endoscopic ultrasonography (n = 235). We compared cN and pathological N-stage (pN) and scored correct, down- and upstaging. The prognostic value of nodal up- and downstaging and localization of node metastases on 5-year DFS were assessed with multivariate Cox regression analysis (factors with a P-value 25% nodal downstaging. This inaccuracy might impede assessment of true nodal response to nCRT, affording dubious decisions for a 'wait-and-see' strategy.

Om de overleving van patiënten met een lokaal gevorderd slokdarmcarcinoom te verbeteren worden patiënten behandeld met chemoradiotherapie alvorens geopereerd te worden. Echter, niet iedereen heeft baat bij deze neoadjuvante chemoradiotherapie (nCRT). Het doel van dit promotieonderzoek was om de selectie en behandeling van patiënten met slokdarmkanker te verbeteren en zo toe te werken naar een gepersonaliseerde behandeling. In dit proefschrift werd aangetoond dat endoechografie de behandeling in 29% van de patiënten beïnvloedde na stadiering met een 18F-FDG PET/CT-scan. Echter, zelfs na stadiëring met deze beeldvormende technieken bleek de beoordeling van lymfekliermetastasen vaak inaccuraat. Re-stadiëring na nCRT en vóór de slokdarmoperatie met CT-scans bleek nuttig, maar matig effectief, waarbij op basis van literatuuronderzoek een prominentere rol blijkt te zijn weggelegd voor 18F-FDG PET/CT-scans. In een gepersonaliseerde behandeling is naast een adequate stadiëring, een goede inschatting welke patiënt baat heeft bij nCRT onmisbaar. Hoewel uitbreiding van traditionele inclusiecriteria voor nCRT niet tot een toename van bijwerkingen en mortaliteit leidde, was de overleving wel significant lager. Daarnaast veranderde nCRT de prognostische waarde van een vrije circumferentiële resectie marge op de overleving. Patiënten met een pathologisch complete respons (pCR: 25-42%) zouden in de toekomst mogelijk voordeel hebben bij een ‘wait-and-see’ beleid. In dit proefschrift werd aangetoond dat textural features, verkregen uit PET/PET-CT-scans, waardevol zijn in de predictie van pCR. Tot slot bleek in een pilotstudie dat diffusie gewogen magnetic resonance imaging (DW-MRI) van additionele waarde was op de standaard 18F-FDG PET/CT-scan in de detectie van pCR.

Short-term adaptation indicates the attenuation of the functional MRI (fMRI) response during repeated task execution. It is considered to be a physiological process, but it is unknown whether short-term adaptation changes significantly in patients with brain disorders, such as multiple sclerosis (MS). In order to investigate short-term adaptation during a repeated right-hand tapping task in both controls and in patients with MS, we analyzed the fMRI data collected in a large cohort of controls and MS patients who were recruited into a multi-centre European fMRI study. Four fMRI runs were acquired for each of the 55 controls and 56 MS patients at baseline and 33 controls and 26 MS patients at 1-year follow-up. The externally cued (1 Hz) right hand tapping movement was limited to 3 cm amplitude by using at all sites (7 at baseline and 6 at follow-up) identically manufactured wooden frames. No significant differences in cerebral activation were found between sites. Furthermore, our results showed linear response adaptation (i.e. reduced activation) from run 1 to run 4 (over a 25 minute period) in the primary motor area (contralateral more than ipsilateral), in the supplementary motor area and in the primary sensory cortex, sensory-motor cortex and cerebellum, bilaterally. This linear activation decay was the same in both control and patient groups, did not change between baseline and 1-year follow-up and was not influenced by the modest disease progression observed over 1 year. These findings confirm that the short-term adaptation to a simple motor task is a physiological process which is preserved in MS.

Although the mechanisms underlying the accumulation of disability in primary progressive (PP) multiple sclerosis (MS) are still unclear, a major role seems to be played by `occult' tissue damage. We investigated whether conventional and magnetization transfer (MT) MRI may provide complementary information for the assessment of PPMS severity. Conventional and MT MRI scans from 226 PPMS patients and 84 healthy controls were collected for centralized analysis. The expanded disability status scale (EDSS) score was rated at the time of MRI acquisition. T2 lesion volume, normalized brain volume (NBV) and cervical cord cross-sectional area (CSA) were measured. Magnetization transfer ratio (MTR) histograms from whole brain tissue, normal-appearing white matter and grey matter (NAGM) were also obtained. Mean NBV, CSA and MTR histogram-derived metrics showed significant inter-centre heterogeneity. After correcting for the acquisition centre, pooled average MTR and histogram peak height values were different between PPMS patients and controls for all tissue classes ( P-values between 0.03 and 0.0001). More severe brain and cord atrophy and MT MRI-detectable NAGM damage were found in patients who required walking aids than in those who did not ( P-values: 0.03, 0.001 and 0.016). A composite score of NBV, CSA, whole brain and NAGM MTR histogram peak height z-scores was correlated with patients' EDSS ( r = 0.37, P 0.001). Magnetization transfer MRI might provide information complementary to that given by conventional MRI when assessing PPMS severity. Sequence-related variability of measurements makes the standardization of MT MRI acquisition essential for the design of multicentre studies. Multiple Sclerosis 2008; 14: 455—464. http://msj.sagepub.com

To assess the time course of brain atrophy and the difference across clinical subtypes in multiple sclerosis (MS).The percent brain volume change (PBVC) was computed on existing longitudinal (2 time points) T1-weighted MRI from untreated (trial and nontrial) patients with MS. Patients (n = 963) were classified as clinically isolated syndromes suggestive of MS (CIS, 16%), relapsing-remitting (RR, 60%), secondary progressive (SP, 15%), and primary progressive (9%) MS. The median length of follow-up was 14 months (range 12-68).There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003). However, this heterogeneity disappeared when data were corrected for the baseline normalized brain volume. When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group, due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p0.001). The estimation of the sample sizes required for demonstrating a reduction of brain atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the progressive forms of the disease.This first large study in untreated patients with multiple sclerosis (MS) with different disease subtypes shows that brain atrophy proceeds relentlessly throughout the course of MS, with a rate that seems largely independent of the MS subtype, when adjusting for baseline brain volume.

The International Panel on the Diagnosis of Multiple Sclerosis (MS) incorporated the Barkhof/Tintore (B/T) magnetic resonance criteria into their diagnostic scheme to provide evidence of dissemination in space of central nervous system lesions, a prerequisite for diagnosing MS in patients who present with clinically isolated syndromes (CIS). Although specific for MS, the B/T criteria were criticised for their low sensitivity and relative complexity in clinical use. We used lesion characteristics at onset from 349 CIS patients in logistic regression and recursive partitioning modelling in a search for simpler and more sensitive criteria, while maintaining current specificity. The resulting models, all based on the presence of periventricular and deep white matter lesions, performed roughly in agreement with the B/T criteria, but were unable to provide higher diagnostic accuracy based on information from a single scan. Apparently, findings from contrast-enhanced and follow-up magnetic resonance scans are needed to improve the diagnostic algorithm.

In this multicenter study, we used dynamic causal modeling to characterize the abnormalities of effective connectivity of the sensorimotor network in 61 patients with multiple sclerosis (MS) compared with 74 age‐matched healthy subjects. We also investigated the correlation of such abnormalities with findings derived from structural MRI. In a subgroup of subjects, diffusion tensor (DT) MRI metrics of the corpus callosum and the left corticospinal tract (CST) were also assessed. MS patients showed increased effective connectivity relative to controls between: (a) the left primary SMC and the left dorsal premotor cortex (PMd), (b) the left PMd and the supplementary motor areas (SMA), (c) the left secondary sensorimotor cortex (SII) and the SMA, (d) the right SII and the SMA, (e) the left SII and the right SII, and (f) the right SMC and the SMA. MS patients had relatively reduced effective connectivity between the left SMC and the right cerebellum. No interaction was found between disease group and center. Coefficients of altered connectivity were weakly correlated with brain T2 LV, but moderately correlated with DT MRI‐measured damage of the left CST. In conclusion, large multicenter fMRI studies of effective connectivity changes in diseased people are feasible and can facilitate studies with sample size large enough for robust outcomes. Increased effective connectivity in the patients for the simple motor task suggests local network modulation contributing to enhanced long‐distance effective connectivity in MS patients. This extends and generalizes previous evidence that enhancement of effective connectivity may provide an important compensatory mechanism in MS. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.

Purpose To investigate whether multiple sclerosis (MS) atrophy can be assessed by SIENA and SIENAX software using other image types from MS research protocols than T1-weighted images without contrast agent, which are not always available. Materials and Methods We selected 46 MS patients with identical magnetic resonance imaging (MRI) protocols at two timepoints. We calculated normalized brain volume (NBV) using SIENAX, and percentage brain volume change (PBVC) using SIENA, from T1-weighted images with and without contrast agent, T2-weighted images, and (calculated) pseudo-T1-weighted images. Relative agreement of the results was assessed using variance component estimation. Results Relative agreement with T1-weighted images without contrast agent was good for T1-weighted images with contrast agent (ICC = 0.86 for NBV, ICC = 0.77 for PBVC), and reasonably good for pseudo-T1 and T2-weighted images (T2: ICC = 0.72 for NBV, 0.58 for PBVC; pseudo-T1: ICC = 0.68 for NBV, 0.83 for PBVC). Conclusion Brain atrophy can be studied using SIENA and SIENAX if T1-weighted images without contrast agent are not available. T1-weighted images with contrast agent should be used if available. Otherwise, pseudo-T1 and T2-weighted images seem acceptable and accessible alternatives. The use of these other images will greatly improve research possibilities, especially regarding older datasets. J. Magn. Reson. Imaging 2008;28:559–565. © 2008 Wiley-Liss, Inc.

Motor control demands coordinated excitation and inhibition across distributed brain neuronal networks. Recent work has suggested that multiple sclerosis (MS) may be associated with impairments of neuronal inhibition as part of more general progressive impairments of connectivity. Here, we report results from a prospective, multi-centre fMRI study designed to characterise the changes in patients relative to healthy controls during a simple cued hand movement task. This study was conducted at eight European sites using 1.5 Tesla scanners. Brain deactivation during right hand movement was assessed in 56 right-handed patients with relapsing-remitting or secondary progressive MS without clinically evident hand impairment and in 60 age-matched, healthy subjects. The MS patients showed reduced task-associated deactivation relative to healthy controls in the pre- and postcentral gyri of the ipsilateral hemisphere in the region functionally specialised for hand movement control. We hypothesise that this impairment of deactivation is related to deficits of transcallosal connectivity and GABAergic neurotransmission occurring with the progression of pathology in the MS patients. This study has substantially extended previous observations with a well-powered, multicentre study. The clinical significance of these deactivation changes is still uncertain, but the functional anatomy of the affected region suggests that they could contribute to impairments of motor control.

With expanding potential clinical applications of functional magnetic resonance imaging (fMRI) it is important to test how reliable different measures of fMRI activation are between subjects and sessions and between centres. This study compared variability across 17 patients with multiple sclerosis (MS) and 22 age-matched healthy controls (HC) in 5 European centres performing an fMRI block design with hand tapping. We recruited subjects from sites using 1.5 T scanners from different manufacturers. 5 healthy volunteers also were studied at each of 4 of the centres. We found that reproducibility between runs and sessions for single individuals was consistently much greater than between individuals. There was greater run-to-run variability for MS patients than for HC. Measurements of maximum signal change (MSC) appeared to provide higher reproducibility within individuals and greater sensitivity to differences between individuals than region of interest (ROI) suprathreshold voxel counts. The variability in measurements between centres was not as great as that between individuals. Consistent with these observations, we estimated that power should not be reduced substantially with use of multi-, as opposed to single-, centre study designs with similar numbers of subjects. Multi-centre interventional studies in which fMRI is used as an outcome measure thus appear practical even when implemented in conventional clinical environments.

Purpose To investigate intercenter agreement of brain volume (change) measurement in multiple sclerosis (MS) using structural image evaluation using normalization of atrophy (SIENA) and the cross-sectional version of SIENA (SIENAX) with additional manual editing to correct for inadequate brain extraction. Materials and Methods Baseline and follow-up T1-weighted MR images of 20 MS patients were dispatched to five centers. Each center performed fully-automated and manually-edited analyses for SIENAX, yielding normalized brain volume (NBV), and SIENA, yielding percentage brain volume change (PBVC). Intercenter agreement was assessed with the concordance correlation coefficient (CCC). Results Intercenter agreement was perfect for fully automated NBV and PBVC (both CCC = 1.0), and remained substantial upon manual editing (CCC = 0.94 for NBV, CCC = 0.95 for PBVC). Mean NBV values for each center decreased significantly after manual editing (overall mean NBV = 1605.3 cm3vs. 1651.1 cm3without manual editing; t = –4.58, P < 0.001). Total variance in PBVC decreased significantly by a factor of 1.8 after manual editing (σ2 = 2.82 before, and σ2 = 1.54 after manual editing, P < 0.05). Conclusion Substantial intercenter agreement was found for manually-edited SIENAX and SIENA, suggesting that measurements from multiple centers may be pooled. Manual editing reduces overestimation of NBV, and is likely to increase statistical power for PBVC. J. Magn. Reson. Imaging 2007;26:881–885. © 2007 Wiley-Liss, Inc.

The McDonald International Panel accepted the Barkhof/Tintoré criteria for providing MRI evidence of dissemination in space to allow a diagnosis of multiple sclerosis in patients with clinically isolated syndromes (CIS). We applied these criteria in a large cohort of patients with CIS, representative of those seen in a general diagnostic setting, to assess their accuracy in predicting conversion to definite multiple sclerosis and to identify factors that affect this risk.In a collaborative study of seven centres, baseline MRI and clinical follow-up data for 532 patients with CIS were studied, with the development of a second clinical event used as the main outcome. All scans were scored for lesion counts and spatial lesion distribution to assess the fulfilment--ie, at least three out of four--of the Barkhof/Tintoré criteria. We used survival analysis and 2x2 tables to assess the test characteristics of the criteria at baseline.Overall conversion rate was 32.5% with a median survival time of 85.3 months. Fulfilment of the criteria at baseline showed, after a survival time of 2 years, a conversion rate of about 45% (95% CI 37-53) versus about 10% (6-16) in those with no asymptomatic lesions at baseline (p0.0001). For patients with a follow-up of at least 2 years, the fulfilment of the MRI criteria showed an accuracy of 68% (sensitivity 49%, specificity 79%) for predicting conversion and an increase in risk of nearly four times for conversion compared with those not fulfilling the criteria (odds ratio 3.7, 95% CI 2.3-5.9; p0.0001). Cox proportional hazards regression analysis accorded with this increased risk. No effects were recorded on the performance of the criteria by sex, presenting symptoms, or centre. Age at baseline did have a small but significant effect as predictor (hazard ratio 0.97, 0.95-0.99; p=0.002), but did not affect the prognostic value of the MRI criteria.MRI abnormalities have important prognostic value. The cut-off, based on the Barkhof/Tintoré criteria, as incorporated in the McDonald diagnostic scheme yields acceptable specificity, but could have lower sensitivity than previously reported.

The magnetization transfer ratio (MTR) is strongly related to the field strength (B1) of the saturation pulse. B1 variations therefore can result in significant MTR variations and can affect histogram analysis, particularly if data from a large volume of interest are included. A multicenter study was performed to determine the typical range of B1 errors and the corresponding MTR variations in brain tissue of healthy volunteers. Seven subjects were included at each center resulting in a total cohort of 28 subjects. Additionally, numerical simulations were done to study this relationship more generally for pulsed saturation. It could be demonstrated, both theoretically and empirically, that for typical B1 errors there is a linear relationship between B1 error and the corresponding MTR change. In addition, for proton density-weighted sequences, this relationship seems to be largely independent of the underlying relaxation properties. Mean B1 errors in the entire brain were typically in the range between -3% and -7%. Due to different coil characteristics, significant MTR differences between different scanners and sites were observed. Using a simple correction scheme that is based on a linear regression analysis between MTR and B1 data it was possible to reduce the intersubject variation by ∼50%. Furthermore, interscanner variation could be reduced such that no significant differences between scanners could be detected. The correction scheme may be useful when investigating MTR as an outcome measure in single or multicenter studies. Magn Reson Med 53:134–140, 2005. © 2004 Wiley-Liss, Inc.