Simultaneous neoadjuvant radiochemotherapy with capecitabine and oxaliplatin for locally advanced rectal cancer: Treatment outcome outside clinical trials

Background: Phase II trials of neoadjuvant treatment in UICC-TNM stageII and III rectal cancer with capecitabine and oxaliplatin demonstrated favourable rates on tumour regression with acceptable toxicity. Patients and methods: Retrospective evaluation of 34 patients treated from 2005-2008 outside clinical trials (CTR) with neoadjuvant irradiation (45-50.4Gy) and simultaneous capecitabine 825mg/m2 b.i.d. on days 1-14 and 22-35 and oxaliplatin 50mg/m2 on days 1, 8, 22 and 29 (CAPOX). Twenty-six (77%) patients received one or two courses of capecitabine 1,000mg/m2 b.i.d. on days 1-14 and oxaliplatin 130mg/m2 on day 1 (XELOX) prior to simultaneous chemoradiotherapy. Results: UICC-TNM stage regression was observed in 60% (n = 20). Dworak's regression grades 3 and 4 were achieved in 18.2% (n = 6) and 15.1% (n = 5) of the patients. Sphincter-preserving surgery was performed in 53% (n = 8) of patients with a tumour of the lower rectum. Within the mean observation of 24 months, none of the patients relapsed locally, 1patient had progressive disease and 5patients (15%) relapsed distantly. Toxicity of grade 3 and 4 was mainly diarrhoea 18% (n = 6) and perianal pain 9% (n = 3). Nevertheless, severe cardiac events (n = 2), severe electrolyte disturbances (n = 2), and syncopes (n = 2) were observed as well. Conclusion: Treatment efficacy and common toxicity are similar to the reports of phaseI/II trials. However, several severe adverse events were observed in our cohort study. The predisposing factors for these events have yet to be studied and may have implications for the selection of patients outside CT

Cerebral blood perfusion changes in multiple sclerosis

The proximity of immune cell aggregations to the vasculature is a hallmark of multiple sclerosis. Furthermore, it is widely accepted that inflammation is able to modulate the microcirculation. Until recently, the detection of cerebral blood perfusion changes was technically challenging, and perfusion studies in multiple sclerosis patients yielded contradictory results. However, new developments in fast magnetic resonance imaging have enabled us to image the cerebral hemodynamics based on the dynamic tracking of a bolus of paramagnetic contrast agents (dynamic susceptibility contrast). This review discusses the technical principles, possible pitfalls, and potential for absolute quantification of cerebral blood volume and flow in a clinical setting. It also outlines recent findings on inflammation associated perfusion changes, which are inseparable from pathological considerations in multiple sclerosis

Does open space increase development?

Land-use change, spatial modeling, Land Economics/Use,

Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis

AbstractObjectiveWhite matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increases if WMV decreases and the cortical surface area remains constant.MethodsIn total, 95 participants were enrolled: 30 patients with early and advanced relapsing–remitting MS; 30 age-matched control subjects; 30 patients with Alzheimer's disease (AD) and 5 patients with clinically isolated syndrome (CIS).Results29/30 MS and 5/5 CIS patients showed lower WMV than expected from their intracranial volume (average reduction 13.0%, P<10−10), while the cortical surface area showed no significant differences compared with controls. The estimated WMV reductions were correlated with an increase in cortical curvature (R=0.62, P=0.000001). Discriminant analysis revealed that the curvature increase was highly specific for the MS and CIS groups (96.7% correct assignments between MS and control groups) and was significantly correlated with reduction of white matter fractional anisotropy, as determined by diffusion tensor imaging and the Expanded Disability Status Scale. As expected by the predominant gray and WM degeneration in AD, no systematic curvature increase was observed in AD.ConclusionWhole-brain-averaged cortical extrinsic curvature appears to be a specific and quantitative marker for a WMV–cortex disproportionality and allows us to assess “pure” WMA without being confounded by intracranial volume. WMA seems to be a characteristic symptom in early MS and can already occur in patients with CIS and should thus be considered in future MS research and clinical studies

Factors predisposing to humoral autoimmunity against brain-antigens in health and disease Analysis of 49 autoantibodies in over 7000 subjects

Background:Circulating autoantibodies (AB) against brain-antigens, often deemed pathological, receive increasing attention. We assessed predispositions and seroprevalence/characteristics of 49 AB in >7000 individuals.Methods:Exploratory cross-sectional cohort study, investigating deeply phenotyped neuropsychiatric patients and healthy individuals of GRAS Data Collection for presence/characteristics of 49 brain-directed serum-AB. Predispositions were evaluated through GWAS of NMDAR1-AB carriers, analyses of immune check-point genotypes, APOE4 status, neurotrauma. Chi-square, Fisher’s exact tests and logistic regression analyses were used.Results:Study of N=7025 subjects (55.8% male; 41±16 years) revealed N=1133 (16.13%) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR=1.018/year; 95% CI [1.015-1.022]) emerged, but no disease association, neither general nor with neuropsychiatric subgroups. Males had higher AB seroprevalence (OR=1.303; 95% CI [1.144-1.486]). Immunoglobulin class (N for IgM:462; IgA:487; IgG:477) and titers were similar. Abundant were NMDAR1-AB (7.7%). Low seroprevalence (1.25%-0.02%) was seen for most AB (e.g. amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65). Non-detectable were others. GWAS of NMDAR1-AB carriers revealed three genome-wide significant SNPs, two intergenic, one in TENM3, previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovered effects on humoral anti-brain autoimmunity (OR=1.55; 95% CI [1.058-2.271]) and disease likelihood (OR=1.43; 95% CI [1.032-1.985]). APOE4 carriers (∼19%) had lower seropositivity (OR=0.766; 95% CI [0.625-0.933]). Neurotrauma predisposed to NMDAR1-AB seroprevalence (IgM: OR=1.599; 95% CI [1.022-2.468]).Conclusions:Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Seroprevalence, immunoglobulin class, or titers do not predict disease