Impact of Endoscopic Ultrasonography on 18F-FDG-PET/CT Upfront Towards Patient Specific Esophageal Cancer Treatment.

INTRODUCTION: In patients with potentially resectable esophageal cancer (EC), the value of endoscopic ultrasonography (EUS) after fluorine-18 labeled fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG-PET/CT) is questionable. Retrospectively, we assessed the impact of EUS after PET/CT on the given treatment in EC patients. METHODS: During the period 2009-2015, 318 EC patients were staged as T1-4aN0-3M0 with hybrid 18F-FDG-PET/CT or 18F-FDG-PET with CT and EUS if applicable in a nonspecific order. We determined the impact of EUS on the given treatment in 279 patients who also were staged with EUS. EUS had clinical consequences if it changed curability, extent of radiation fields or lymph node resection (AJCC stations 2-5), and when the performed fine-needle aspiration (FNA) provided conclusive information of suspicious lymph node. RESULTS: EUS had an impact in 80 (28.7%) patients; it changed the radiation field in 63 (22.6%), curability in 5 (1.8%), lymphadenectomy in 48 (17.2%), and FNA was additional in 21 (7.5%). In patients treated with nCRT (n = 194), EUS influenced treatment in 53 (27.3%) patients; in 38 (19.6%) the radiation field changed, in 3 (1.5%) the curability, in 35 (18.0%) the lymphadenectomy, and in 17 (8.8%) FNA was additional. EUS influenced both the extent of radiation field and nodal resection in 31 (16.0%) nCRT patients. CONCLUSIONS: EUS had an impact on the given treatment in approximately 29%. In most patients, the magnitude of EUS found expression in the extent of radiotherapy target volume delineation to upper/high mediastinal lymph nodes.

Performance of the Swanton multiple sclerosis criteria for dissemination in space.

New diagnostic criteria for multiple sclerosis (MS) have been proposed by Swanton and co authors, but were not yet evaluated in patients suspected of MS, but diagnosed with another disease. The dissemination in space (DIS) criterion of these Swanton criteria was investigated in such a patient group and compared with the present McDonald criteria. We found that with the Swanton criteria for DIS, simplicity can be combined with some gain in sensitivity, without major loss of specificity.

Short-term adaptation to a simple motor task: a physiological process preserved in multiple sclerosis.

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.

A search for new MRI criteria for dissemination in space in subjects with a clinically isolated syndrome.

The International Panel on the Diagnosis of Multiple Sclerosis (MS) incorporated the Barkhof/Tintoré (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.

Reproducibility of fMRI in the clinical setting: implications for trial designs.

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.

Relating functional changes during hand movement to clinical parameters in patients with multiple sclerosis in a multi-centre fMRI study.

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.

Impairment of movement-associated brain deactivation in multiple sclerosis: further evidence for a functional pathology of interhemispheric neuronal inhibition.

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.

Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes.

OBJECTIVE: To assess the time course of brain atrophy and the difference across clinical subtypes in multiple sclerosis (MS). METHODS: 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). RESULTS: 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 (p < 0.001). 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. CONCLUSIONS: 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.

Can rate of brain atrophy in multiple sclerosis be explained by clinical and MRI characteristics?

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.

Diagnosing MS: recent guidelines and future goals focusing on magnetic resonance imaging.

Previous diagnostic guidelines for MS relied largely on clinical evidence and cerebrospinal fluid analysis. In 2001, guidelines were published that allowed partial substitution of the required clinical evidence by magnetic resonance imaging findings and defined primary progressive multiple sclerosis (PPMS). Recently, revised guidelines on MS diagnosis were published, mainly to improve definitions of dissemination in space (using spinal cord imaging) and in time (using T2 lesions), enabling a faster and more accurate MS diagnosis. Criteria for PPMS were also revised. Current research is concentrating on the definition of uniform clinical terms, to allow a more standardized diagnosis, and aims to simplify the criteria while improving diagnostic accuracy.