Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial.

BACKGROUND: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings. METHODS: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task). RESULTS: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula. CONCLUSIONS: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements. TRIAL REGISTRATION NUMBER: NCT03679468.

Safety of anti-varicella zoster virus vaccination in patients with multiple sclerosis treated with natalizumab: A case series.

The vaccination with live attenuated vaccines is generally not recommended during natalizumab (NTZ), as it is included among immunosuppressive/immunomodulating therapies. Nevertheless, considering the lack of evidence of a non-Central Nervous System (CNS) immunosuppressive effect of NTZ, after a risk/benefit evaluation, we decided to vaccinate four multiple sclerosis (MS) patients (three with an indication to switch to ocrelizumab for high-risk Progressive Multifocal Leukoencephalopathy (PML) and one for pregnancy planning). No vaccine-related adverse events of any type nor varicella zoster virus (VZV) infections were observed. To the best of our knowledge, these case series represent the first description of the good safety profile of anti-VZV vaccination in MS patients during NTZ treatment.

Evaluating the central vein sign in paediatric-onset multiple sclerosis: A case series study.

The central vein sign (CVS) has been proposed as a biomarker of multiple sclerosis (MS). In adult-onset MS (AOMS), 40%-threshold of CVS positive (+) lesions demonstrated high accuracy for MS diagnosis. However, CVS+ lesions' performance has not been characterized in paediatric-onset (POMS) yet. We compared the CVS contribution to MS diagnosis in 10 POMS and 12 disease-duration-matched AOMS patients. Three POMS patients did not meet the 40%-threshold, while all AOMS patients were correctly diagnosed as having MS. The high proportion of periventricular confluent lesions, excluded from the CVS assessment, seemed to impair CVS sensitivity in POMS diagnosis.

Brain lesion microstructure in neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein disease.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) diagnosis are based on the presence of serological and magnetic resonance imaging (MRI) biomarkers. Diffusion tensor imaging (DTI), neurites orientation dispersion and density imaging (NODDI), and the Spherical Mean Technique (SMT) may be helpful to provide a microstructural characterization of the different types of white matter lesions and give an insight about their different pathological mechanisms. The aim of the study was to characterize microstructural differences between brain typical lesions (TLs) and nontypical lesions (nTLs). METHODS: A total of 17 NMOSD and MOGAD patients [9 Aquaporin4 (AQP4) + NMO, 2 seronegative-NMO, 6 MOGAD] underwent MRI scans on a 3 Tesla MAGNETON PRISMA. Diffusion parameters (fractional anisotropy; mean diffusivity [MD]; intracellular volume fraction [ICVF]; extra-neurite transverse diffusivity; and extra-neurite MD; neurite signal fraction) were obtained using DTI, NODDI, and SMT. Microstructural parameters within lesions were compared through a generalized linear model using age, sex, and total lesion volume as covariates. RESULTS: In NMOSD/MOGAD whole cohort (total lesions = 477), TLs showed increased MD and decreased ICVF compared to nTLs (p < .05), indicating higher inflammation and axonal loss. Similar results were found also in the AQP4 + NMO subgroup (decreased ICVF, p < .05). Furthermore, in NMOSD/MOGAD whole cohort and in AQP4 + NMO subgroup, TLs showed a trend toward higher EXRATRANS than nTLs, suggesting a more severe degree of demyelination within TLs. CONCLUSIONS: TLs and nTLs in NMOSD/MOGAD showed different diffusion MRI-derived microstructural features, with TLs showing a more severe degree of inflammation and fiber disruption with respect to nTLs.

Lesion phenotyping based on magnetic susceptibility in pediatric multiple sclerosis.

BACKGROUND AND PURPOSE: Pediatric multiple sclerosis (MS) displays different pathological features compared to adult MS, which can be studied in vivo by assessing tissue magnetic susceptibility with 3T-MRI. We aimed to assess different white matter lesions (WMLs) phenotypes in pediatric MS patients using quantitative susceptibility mapping (QSM) and susceptibility mapping weighted imaging (SMWI) over 12 months. METHODS: Eleven pediatric MS patients [female: 63.6%; mean ± standard deviation (SD) age and disease duration: 16.3 ± 2.2 and 2.4 ± 1.5; median (range) Expanded Disability Status Scale (EDSS) 1 (0-2)] underwent 3 Tesla-MRI exams and EDSS assessments at baseline and after 1 year. QSM and SMWI were obtained using 3-dimensional (3D)-segmented echo-planar-imaging with submillimetric spatial resolution. WMLs were classified according to their QSM appearance and SMWI was used to identify QSM hyperintensities ascribable to veins. Total brain volumes at baseline and follow-up were computed using high-resolution 3D T1-weighted images. RESULTS: Mean ± SD paramagnetic rim lesions (PRLs) prevalence was 7.0% ± 9.0. Fifty-four percent (6/11) of patients exhibited at least one PRL, with one patient exhibiting ≥ 4 PRLs. All patients showed QSM-iso-/hypo-intense lesions, which represented a mean ± SD of 65.8% ± 22.7 of total WMLs. QSM-hyperintense WMLs showed a positive correlation with total brain volume reduction at follow-up (r = 0.705; p =  .02). No lesion was classified as different between baseline and follow-up. CONCLUSION: Chronic compartmentalized inflammation seems to occur early in pediatric MS patients with short disease duration. A high prevalence of iso-/hypo-intense lesions was found, which could account for the higher remyelination potential in pediatric MS.

A comparison of natalizumab and ocrelizumab on disease progression in multiple sclerosis.

OBJECTIVE: No direct comparisons of the effect of natalizumab and ocrelizumab on progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) events are currently available. We aimed to compare the risk of achieving first 6 months confirmed PIRA and RAW events and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 in a cohort of naïve patients treated with natalizumab or ocrelizumab from the Italian Multiple Sclerosis Register. METHODS: Patients with a first visit within 1 year from onset, treated with natalizumab or ocrelizumab, and ≥3 visits were extracted. Pairwise propensity score-matched analyses were performed. Risk of reaching the first PIRA, RAW, and EDSS 4.0 and 6.0 events were estimated using multivariable Cox proportional hazards models. Kaplan-Meier curves were used to show cumulative probabilities of reaching outcomes. RESULTS: In total, 770 subjects were included (natalizumab = 568; ocrelizumab = 212) and the propensity score-matching retrieved 195 pairs. No RAW events were found in natalizumab group and only 1 was reported in ocrelizumab group. A first PIRA event was reached by 23 natalizumab and 25 ocrelizumab exposed patients; 7 natalizumab- and 10 ocrelizumab-treated patients obtained an irreversible EDSS 4.0, while 13 natalizumab- and 15 ocrelizumab-treated patients reached an irreversible EDSS 6.0. No differences between the two groups were found in the risk (HR, 95%CI) of reaching a first PIRA (1.04, 0.59-1.84; p = 0.88) event, an irreversible EDSS 4.0 (1.23, 0.57-2.66; p = 0.60) and 6.0 (0.93, 0.32-2.68; p = 0.89). INTERPRETATION: Both medications strongly suppress RAW events and, in the short term, the risk of achieving PIRA events, EDSS 4.0 and 6.0 milestones is not significantly different.

Overexpression of both CXC chemokine receptor 4 and vascular endothelial growth factor proteins predicts early distant relapse in stage II-III colorectal cancer patients.

PURPOSE: CXC chemokine receptor 4 (CXCR4) and vascular endothelial growth factor (VEGF) are implicated in the metastatic process of malignant tumors. However, no data are currently available on the biological relationship between these molecules in colorectal cancer. We studied whether CXCR4 and VEGF expression could predict relapse and evaluated in vitro the contribution of CXCR4 in promoting clonogenic growth, VEGF secretion, and intercellular adhesion molecule-1 (ICAM-1) expression of colorectal cancer cells. EXPERIMENTAL DESIGN: CXCR4 and VEGF were studied in colorectal cancer tissues and in Lovo, HT29, and SW620 colorectal cancer cell lines by immunohistochemistry. Correlations with baseline characteristics of patients and tumors were analyzed by chi2 test. VEGF secretion induced by CXCL12 was measured by ELISA. The effect of CXCL12 on ICAM-1 expression was evaluated by flow cytometry. Clonogenic growth induced by CXCL12 was determined by clonogenic assays. Functional effects induced by CXCL12 were prevented by the administration in vitro of AMD3100, a bicyclam noncompetitive antagonist of CXCR4. RESULTS: Seventy-two patients, seen between January 2003 and January 2004, were studied. CXCR4 was absent in 16 tumors (22.2%); it was expressed in < or = 50% of cells in 25 (34.7%) tumors and in >50% of cells in 31 (43.0%) tumors. VEGF was absent in 17 (23.6%) tumors; it was expressed in < or = 50% of cells in 16 (22.2%) tumors and in >50% of cells in 39 (54.2%) tumors. There was a significant association between CXCR4 expression and lymph nodal status (P = 0.0393). There were significant associations between VEGF and tumor invasion (P = 0.0386) and lymph nodal involvement (P = 0.0044). American Joint Committee on Cancer stage (P = 0.0016), VEGF expression (P = 0.0450), CXCR4 expression (P = 0.0428), and VEGF/CXCR4 expression (P = 0.0004) had a significant prognostic value for disease-free survival with univariate analysis. The predictive ability of the American Joint Committee on Cancer stage and of the concomitant and high expression of VEGF and CXCR4 was confirmed by multivariate analysis. Prognosis is particularly unfavorable for patients whose primary tumors express CXCR4 and VEGF in >50% of cells (median disease-free survival in relapsed patients, 5.8 months; hazard ratio of relapse, 8.23; 95% confidence interval, 7.24-14.29). In clonogenic assays, CXCL12 (20 ng/mL/d) significantly increased the number of clones in SW620, HT29, and Lovo cells at 7 and 14 days. Again, CXCL12 was able to stimulate VEGF secretion in SW620, HT29, and Lovo cells as well as up-regulated ICAM-1. These effects were prevented by the administration of AMD3100 (1 micromol/L). CONCLUSIONS: We have shown that concomitant and high expression of CXCR4 and VEGF is a strong and independent predictor of early distant relapse in colorectal cancer. CXCR4 triggers a plethora of phenomena, including stimulation of clonogenic growth, induction of VEGF release, and ICAM-1 up-regulation. These data support the inhibition of CXCR4 to prevent the development of colorectal cancer metastasis.

Has lung cancer in the elderly different characteristics at presentation?

Lung cancer is the first cause of cancer death for males aged > or =35 years, and the second for females aged between 35 and 70 years. Elderly patients seem to have the worst performance status (PS) and earlier stage of disease at diagnosis. We analyzed data concerning 1,035 patients with lung cancer referred to the National Cancer Institute of Naples. The variables considered in the analysis were: gender; type of cancer [small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)]; ECOG (Eastern Cooperative Oncology Group) PS, the stage of disease at diagnosis, the histological type, age at diagnosis. In order to better assess the relevance of age at diagnosis in lung cancer patients we categorized the age into two groups (young < or =70; old >70 years). The statistical analyses were performed using chi2 trend test with corresponding p-value and odds ratios (OR) for the examined variables, with a corresponding 95% confidence interval. These were derived using multiple logistic regression, fitted by the maximum likelihood method. For all the 1035 patients the risk between the age at diagnosis and the performance status was not statistically significant (OR=1.1, 95%CI 0.8-1.5). We repeated the same risk distinguishing the histological type and we analyzed the performance status for the SCLC (OR=1.0, 95%CI 0.4-2.5) and the stage at diagnosis (OR=1.0, 95%CI 0.4-3.0), without any significant difference. Our study showed that elderly patients with lung cancer do not seem to have different characteristics at presentation, particularly related to stage of disease, PS and histology, as compared to their younger counterpart. Other characteristics such as type and number of co-morbidities and organ function differ in the two groups of populations.