Seasonal adherence to, and effectiveness of, subcutaneous interferon ß-1a administered by RebiSmart® in patients with relapsing multiple sclerosis: results of the 1-year, observational GEPAT-SMART study.

BACKGROUND: Little is known about whether tolerability and adherence to treatment can be influenced by weather and temperature conditions. The objective of this study was to assess monthly and seasonal adherence to and safety of sc IFN-ß1a (Rebif®, Merck) in relapsing-remitting multiple sclerosis (RRMS) patients using the RebiSmart® electronic autoinjector. METHODS: A multicentre, prospective observational study in Greece in adult RRMS patients with EDSS < 6, under Rebif®/RebiSmart® treatment for ≤6 weeks before enrollment. The primary endpoint was monthly, seasonal and annual adherence over 12 months (defined in text). Secondary endpoints included number of relapses, disability, adverse events. RESULTS: Sixty four patients enrolled and 47 completed all study visits (Per Protocol Set - PPS). Mean annual adherence was 97.93% ± 5.704 with no significant monthly or seasonal variations. Mean relapses in the pre- and post- treatment 12-months were 1.1 ± 0.47 and 0.2 ± 0.54 (p < 0.0001, PPS). 10 patients (22%) showed 3-month disability progression, 19 (40%) stabilization and 18 (38%) improvement. EDSS was not correlated to pre- (r = 0.024, p = 0.87) or post-treatment relapses (r = 0.022, p = 0.88). CONCLUSION: High adherence with no significant seasonal or weather variation was observed over 12 months. While the efficacy on relapses was consistent with published studies, we could not identify a relationship between relapses and disability. TRIAL REGISTRATION: Greek registry of non-interventional clinical trials ID: 200136 , date of registration: February 18th, 2013.

The role of postoperative radiotherapy in the management of patients with thymic tumors -- a retrospective study.

BACKGROUND: Thymomas are the most common tumor arising in the anterior mediastinum. Surgery is the cornerstone for the management of these tumors. The role of postoperative radiotherapy in Masaoka stage II thymomas remains controversial, but it is well established in the advanced stages. The aim of this study was to investigate the role of postoperative radiotherapy in the overall management of thymomas, and the evaluation of potential prognostic factors. PATIENTS AND METHODS: Between 1989 and 2007, 41 thymoma patients underwent surgery and 27 of them received radiotherapy with a curative intent. The Masaoka staging system was used. The histopathological records and specimens of patients were thoroughly reviewed. Clinical and radiological evaluations took place every 6 months. The mean patient follow-up was 69 months (range: 2-212). RESULTS: DFS (disease free survival), TS (total survival) and DSS (disease specific survival) differed significantly between stages and histological types (p<0.04). Stage I patients were managed only surgically, with none recurring or dying. Concerning stage II patients, TS was significantly longer in non-irradiated cases (10/21) (p=0.025). Stage III (n=8) and IV (n=8) patients underwent postoperative radiotherapy, with 4/8 of stage IV disease also receiving induction chemotherapy. Six out of 8 stage III-IV patients recurred (1 distant and 5 intrathoracic failure), out of whom 4 died due to disease progression despite further treatment (all type C histology). The mean DFS and TS for stage III patients were 49.2 and 50.3 months respectively, with the corresponding values for stage IV being 14.5 and 29.1 months. Patients with myasthenia had a favorable outcome and the ones with complete resection a significantly longer DFS (p=0.0003) and DSS (p=0.039). The Cox regression analysis showed that myasthenia and tumor size are important prognostic factors for DFS (p<0.05). CONCLUSION: Myasthenic patients have a more favorable prognosis. Radiotherapy can be omitted in totally resected stage I-II patients, whereas it is beneficial in more advanced stages.

Design and synthesis of a novel potent myelin basic protein epitope 87-99 cyclic analogue: enhanced stability and biological properties of mimics render them a potentially new class of immunomodulators.

A cyclic analogue, [cyclo(87-99)MBP(87)(-)(99)], of the human immunodominant MBP(87)(-)(99) epitope, was designed based on ROESY/NMR distance information and modeling data for linear epitope 87-99, taking into account T-cell (Phe(89), Lys(91), Pro(96)) and HLA (His(88), Phe(90), Ile(93)) contact side-chain information. The cyclic analogue was found to induce experimental allergic encephalomyelitis (EAE), to bind HLA-DR4, and to increase CD4 T-cell line proliferation, like that of the conformationally related linear MBP(87)(-)(99) epitope peptide. The mutant cyclic peptides, the cyclo(91-99)[Ala(96)]MBP(87)(-)(99) and the cyclo(87-99)[Arg(91)Ala(96)]MBP(87)(-)(99), reported previously for suppressing, to a varying degree, autoimmune encephalomyelitis in a rat animal model, were found in this study to possess the following immunomodulatory properties: (i) they suppressed the proliferation of a CD4 T-cell line raised from a multiple sclerosis patient, (ii) they scored the best in vitro TH2/TH1 cytokine ratio in peripheral blood mononuclear cell cultures derived from 13 multiple sclerosis patients, inducing IL-10 selectively, and (iii) they bound to HLA-DR4, first to be reported for cyclic MBP peptides. In addition, cyclic peptides were found to be more stable to lysosomal enzymes and Cathepsin B, D, and H, compared to their linear counterparts. Taken together, these data render cyclic mimics as putative drugs for treating multiple sclerosis and potentially other Th1-mediated autoimmune diseases.

Immunotherapy for multiple sclerosis: basic insights for new clinical strategies.

Multiple Sclerosis (MS) is a chronic inflammatory degenerative disease of the central nervous system (CNS), first described over 100 years ago. MS is a clinically heterogeneous disease with an increasing incidence over time, and a population prevalence that increases with distance from the equator. It is postulated that environmental factors such as diet and population-specific genetics, influence the distribution of MS. Diagnosis is based on established clinical criteria, aided by magnetic resonance imaging, evoked potential recordings and cerebrospinal fluid examination. Whichever the type of clinical manifestation, MS is considered an organ-specific autoimmune disease, characterized by T-cell and macrophage infiltrates, triggered by CNS-specific CD4 T-cells. The prominent autoimmune etiology of MS is considered to be the aberrant activation of IFN-gamma-producing Th1 cells that recognize self-peptides of the myelin sheath, such as myelin basic protein (MBP) and proteolipid protein (PLP). Current treatments for MS aim primarily to suppress T-cell-mediated immune responses, albeit non-specifically. Experimental approaches towards the therapeutic management of MS involve the use of peptide analogs of disease-associated myelin epitopes or vaccines, to help shift T helper cell responses from Type-1 (secreting pro-inflammatory cytokines) to Type-2 (secreting anti-inflammatory cytokines) or induce peripheral T-cell tolerance. Animal models of MS have been useful to dissect disease mechanisms and evaluate new therapies. Experimental clinical trials, although few, are valuable to assess new treatment regimens and clarify possible conceptual mistakes about the disease. This review attempts to link the current knowledge of MS pathogenesis with clinical and experimental protocols of immunotherapy for MS.

Action and object naming in schizophrenia.

Patients with schizophrenia demonstrate impaired action verbal fluency, but no study has examined verb-noun differences using picture naming. The present study compared object and action naming in 20 adult patients diagnosed with schizophrenia (DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, Text Revision; American Psychiatric Association, 2000) criteria, and 20 demographically matched healthy controls, using pictures. Overall, schizophrenic patients showed poorer naming than controls on all measures of object and action lexical semantic access and retrieval despite normal comprehension for action and object names. Results further indicated that action names were significantly more difficult to retrieve than object names in schizophrenic patients. The absence of dissociation in comprehension of action and object names but semantic errors in naming both classes suggests intact conceptual-semantic stores among middle-aged community-dwelling outpatients with schizophrenia but difficulties mapping semantics onto the lexicon. Action-naming impairments can arise from both semantic and postsemantic origins in schizophrenia. These results have implications for the neurobiology of language given the association between both schizophrenia and verb processing and frontal damage. Moreover, the issue being addressed is important for a cognitive characterization of schizophrenia and for an understanding of the representations of action and object names in the brain.

Leptin and its soluble receptor in plasma of patients suffering from remitting-relapsing multiple sclerosis (MS) In vitro effects of leptin on type-1 and type-2 cytokine secretion by peripheral blood mononuclear cells, T-cells and monocytes of MS patients.

Leptin is synthesized by adipocytes to regulate appetite. Leptin has also been implicated in the pathogenesis of multiple sclerosis (MS) leading to speculation about a beneficial effect of fasting to autoimmune patients. We measured plasma leptin and its soluble receptor (OB-Rs) in 52 MS patients and 50 controls. We also cultured MS and control peripheral blood mononuclear cells (PBMC), T-cells and monocytes +/- recombinant leptin (rleptin), to assess leptin's direct effect on pro- and anti-inflammatory cytokine secretion. We found similar leptin and OB-Rs plasma levels between patients and controls. Untreated patients in the acute phase or in remission, or patients treated with methylprednisolone, had lower leptin levels than patients in the acute phase or in remission receiving IFN-beta. OB-Rs levels were low in patients refractory to IFN-beta but higher in patients receiving methylprednisolone or patients in remission receiving IFN-beta. PBMC from untreated patients in the acute phase, secreted spontaneously IFN-gamma, TNF-alpha and IL-10. IFN-gamma was contributed by T-cells, TNF-alpha and IL-10 primarily by monocytes and to a lesser extent by T-cells. The overall effect of rleptin on PBMC was a net increase in IL-10 production and a net reduction in IFN-gamma production. These results do not warrant a beneficial effect of fasting to MS patients.