Number Of Previous Relapses Research Articles

Impact of rituximab treatment regime on time to relapse in aquaporin-4 antibody positive neuromyelitis optica spectrum disorder

BackgroundAquaporin-4 (AQP4) antibody associated neuromyelitis optica (NMOSD) requires long-term immunosuppression. Rituximab is increasingly used worldwide, however the optimal regime is not established. MethodsWe retrospectively examined different rituximab regimens in AQP4-NMOSD. Standard monotherapy (SM; 6 monthly infusions), SM plus oral steroids (SM+S), extended interval dosing (EID; guided by CD19 repopulation) and EID with oral steroids (EID+S) were compared. The primary outcome was time to first clinical relapse. Potential confounders including age, gender, number of previous relapses, and onset phenotype were included. Results77 patients were included: 67 females, median onset age 35.6, median DSS at rituximab initiation 5.0. 39 were on SM+S, 20 SM, 6 EID, and 12 EID+S. 25/77 patients relapsed during a median follow-up of 44.0 months. No significant difference in time to first relapse was observed between any rituximab regimen. Pooled analyses to compare regimens that use standard monotherapy (SM and SM+S) against those that use extended interval dosing (EID and EID+S) showed no significant difference. Pooled analysis of regimens using steroids with those not using steroids also showed no significant difference. Adjusted Cox proportional hazard model revealed no significant difference between rituximab regimens or influence of demographic factors. 9 significant adverse events were recorded, 5 in the SM group and 4 in SM+S. ConclusionsThis study provides some basis for further exploring EID as a viable option for long term treatment of AQP4-NMOSD. This may improve patient experience and consolidate use of hospital resources.

Impact of Consolidative Unrelated Cord Blood Transplantation on Clinical Outcomes of Patients With Relapsed/Refractory Acute B Lymphoblastic Leukemia Entering Remission Following CD19 Chimeric Antigen Receptor T Cells.

BackgroundWhile chimeric antigen receptor (CAR)-T cell therapy is becoming widely used in hematological malignancies with remarkable remission rate, their high recurrence remains an obstacle to overcome. The role of consolidative transplantation following CAR-T cell-mediated remission remains controversial. We conducted a retrospective study to explore whether bridging to unrelated cord blood transplantation (UCBT) could improve the prognosis of patients entering remission after CAR-T therapy with different characteristics through subgroup analyses.MethodsWe reviewed 53 patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) successfully infused with CD19 CAR-T cells and achieved complete remission (CR). In this study, 25 patients received consolidative UCBT (UCBT group) and 28 patients did not accept any intervention until relapse (non-UCBT group). Subgroup analysis on prognosis was then performed according to gender, age, number of previous relapses, tumor burden, presence of poor prognostic markers, and structure of CAR.ResultsCompared with the non-UCBT group, patients who underwent consolidative UCBT had better median event-free survival (EFS; 12.3 months vs. 6.2 months; P = 0.035) and relapse-free survival (RFS; 22.3 months vs. 7.2 months; P = 0.046), while no significant difference was found in overall survival (OS; 30.8 months vs. 15.3 months; P = 0.118). Subsequent multivariate analysis revealed that bridging to UCBT was a protective factor for RFS (P = 0.048) but had no significant effect on EFS (P = 0.205) or OS (P = 0.541). In the subgroup analysis, UCBT has an added benefit in patients with specific characteristics. Patients who experienced ≥2 relapses or with sustained non-remission (NR) showed better RFS (P = 0.025) after UCBT. Better EFS was seen in patients with poor prognostic markers (P = 0.027). In the subgroup with pre-infusion minimal residual disease (MRD) ≥5% or with extramedullary disease (EMD), UCBT significantly prolonged EFS (P = 0.009), RFS (P = 0.017), and OS (P = 0.026). Patients with occurrence of acute graft-versus-host disease (aGVHD) appeared to have a longer duration of remission (P = 0.007).ConclusionConsolidative UCBT can, to some extent, improve clinical outcomes of patients with R/R B-ALL entering remission following CD19 CAR-T therapy, especially in patients with more recurrences before treatment, patients with poor prognostic markers, and patients with a higher tumor burden. The occurrence of aGVHD after UCBT was associated with better RFS.

The Greek Hybrid Version of the Assertive Community Treatment Model: A Perspective View between Challenges and Limitations

The Assertive Community Treatment (ACT) model of care has been long considered to be effective in the management of patients with severe mental illness (SMI) in most Western countries. The implementation of the original ACT model may be particularly challenging in rural and remote communities with small and dispersed populations and lack of adequate mental health services. Rural programs may have to adapt the model and modify the ACT fidelity standards to accommodate these limitations, and this is the rationale for the introduction of more flexible, hybrid ACT models. In rural Greece, the so called Mobile Mental Health Units (MMHUs) are well-established community mental health services. For patients with SMI that have difficulties engaging with treatment services, the new hybrid ACT model has been recently launched. The objective of this manuscript is to present the recently launched hybrid ACT model in rural areas in Greece and to explore the challenges and limitations in its implementation from the experience of a team of mental health professionals with ACT experience. Referral criteria have not been strictly set, but the number of previous relapses and hospitalizations is taken under consideration, as well as the history of poor treatment adherence and disengagement from mental health services. The main limitation in the implementation of the hybrid ACT service is that it has been introduced in several areas in the absence of a pre-existing community mental health service. This may impact referrals and limit focus on the difficult cases of patients with SMI, thus making the evaluation of the model inapplicable.

Predicting time to relapse in patients with schizophrenia according to patients\u2019 relapse history: a historical cohort study using real-world data in Sweden

BackgroundFor patients with schizophrenia, relapse is a recurring feature of disease progression, often resulting in substantial negative impacts for the individual. Although a patient’s relapse history (specifically the number of prior relapses) has been identified as a strong risk factor for future relapse, this relationship has not yet been meticulously quantified. The objective of this study was to use real-world data from Sweden to quantify the relationship of time to relapse in schizophrenia with a patient’s history of prior relapses.MethodsData from the Swedish National Patient Register and Swedish Prescribed Drug Register were used to study relapse in patients with schizophrenia with a first diagnosis recorded from 2006–2015, using proxy definitions of relapse. The primary proxy defined relapse as a psychiatric hospitalisation of ≥7 days’ duration. Hazard ratios (HRs) were calculated for risk of each subsequent relapse, and Aalen-Johansen estimators were used to estimate time to next relapse.Results2,994 patients were included, and 5,820 relapse episodes were identified using the primary proxy. As the number of previous relapses increased, there was a general trend of decreasing estimated time between relapses. Within 1.52 years of follow-up, 50% of patients with no history of relapse were estimated to have suffered their first relapse episode. 50% of patients with one prior relapse were estimated to have a second relapse within 1.23 years (HR: 1.84 [1.71–1.99]) and time to next relapse further decreased to 0.89 years (HR: 2.77 [2.53–3.03]) and 0.22 years (HR: 18.65 [15.42–22.56]) for 50% of patients with two or ten prior relapses, respectively. Supplementary analyses using different inclusion/exclusion criteria for the study population and redefined proxies of relapse reflected the pattern observed with the primary analyses of a higher number of prior relapses linked with increased risk of/reduced estimated time to the next relapse.ConclusionsThe results suggested a trend of accelerating disease progression in schizophrenia, each relapse episode predisposing an individual to the next within a shorter time period. These results emphasise the importance of providing early, effective, and tolerable treatments that better meet a patient’s individual needs.

Olfactory Dysfunction in Patients With Relapsing-Remitting Multiple Sclerosis Treated With Disease-Modifying Therapies.

Olfactory dysfunction evaluated with time-consuming tests was more common in patients with multiple sclerosis (MS) than in controls and correlated with neurological deficit. The aim of the present study was to compare olfactory function between patients with relapsing-remitting MS (RRMS) and controls with short and simple screening tool-the Sniffin' Sticks Identification Test (SSIT)-and search for its association with clinical and radiological features of the disease. The study included 30 controls and 30 patients with RRMS treated with disease-modifying therapies-injectables (interferon β or glatiramer acetate, N = 18) and oral drugs (dimethyl fumarate or fingolimod, N = 12). Hyposmia was defined as a score of 6 points or fewer in the SSIT olfactory test. The data concerning number of previous relapses, disability in Expanded Disability Status Scale (EDSS), and recent brain magnetic resonance imaging (MRI) scan were collected. Moreover, thalamic volume and third ventricle width were recorded in every patient. Additionally, cognition and fatigue in patients were evaluated 24 months after olfactory assessment with the Symbol Digit Modalities Test (SDMT) and Fatigue Scale for Motor and Cognitive Functions (FSMC), respectively. Patients with RRMS had a higher risk of hyposmia than controls (66.7% vs 36.7%, OR = 1.82, 95% CI, 1.10-3.67, P = .02). Neither inflammatory (number of previous relapses or new brain MRI lesions) nor neurodegenerative (EDSS, SDMT, and FSMC scores; thalamic volume; third ventricle width) MS features did not correlate with SSIT score (P > .05). In patients treated with oral drugs, olfactory dysfunction correlated with FSMC cognitive subscale (r = -0.90, P = .006). Olfactory dysfunction is nearly twice as common in RRMS as in controls and correlates with fatigue level in patients treated with dimethyl fumarate or fingolimod.

Framework for personalized prediction of treatment response in relapsing remitting multiple sclerosis

BackgroundPersonalized healthcare promises to successfully advance the treatment of heterogeneous neurological disorders such as relapsing remitting multiple sclerosis by addressing the caveats of traditional healthcare. This study presents a framework for personalized prediction of treatment response based on real-world data from the NeuroTransData network.MethodsA framework for personalized prediction of response to various treatments currently available for relapsing remitting multiple sclerosis patients was proposed. Two indicators of therapy effectiveness were used: number of relapses, and confirmed disability progression. The following steps were performed: (1) Data preprocessing and selection of predictors according to quality and inclusion criteria; (2) Implementation of hierarchical Bayesian generalized linear models for estimating treatment response; (3) Validation of the resulting predictive models based on several performance measures and routines, together with additional analyses that focus on evaluating the usability in clinical practice, such as comparing predicted treatment response with the empirically observed course of multiple sclerosis for different adherence profiles.ResultsThe results revealed that the predictive models provide robust and accurate predictions and generalize to new patients and clinical sites. Three different out-of-sample validation schemes (10-fold cross-validation, leave-one-site-out cross-validation, and excluding a test set) were employed to assess generalizability based on three different statistical performance measures (mean squared error, Harrell’s concordance statistic, and negative log-likelihood). Sensitivity to different choices of the priors, to the characteristics of the underlying patient population, and to the sample size, was assessed. Finally, it was shown that model predictions are clinically meaningful.ConclusionsApplying personalized predictive models in relapsing remitting multiple sclerosis patients is still new territory that is rapidly evolving and has many challenges. The proposed framework addresses the following challenges: robustness and accuracy of the predictions, generalizability to new patients and clinical sites and comparability of the predicted effectiveness of different therapies. The methodological and clinical soundness of the results builds the basis for a future support of patients and doctors when the current treatment is not generating the desired effect and they are considering a therapy switch.Graphical abstract(A) The framework is developed using quality-proven real-world data of patients with relapsing remitting multiple sclerosis. Patients have heterogeneous individual characteristics and diverse disease profiles, indicated for example by variations in frequency of relapses and degree of disability. Longitudinal characteristics regarding disease history (e.g. number of previous relapses in the last 12 months) are extracted at the time of an intended therapy switch, i.e. at time point “Today” (left). All clinical parameters are captured in a standardized way (right). (B) The model predicts the course of the disease based on the observed data (panel A), and is able to account for the impact of various available therapies on chosen clinical endpoints. The resulting ranking of therapies has a dependency on patient characteristics, illustrated here by a different highest ranked therapy depending on the number of relapse in the previous 12 months. (C) The model is evaluated for various generalization properties. Compared to performance on the training set (gray) it is able to predict for new patients not part of the training set (red).Top: Prediction for new patients. Middle: Prediction for new clinical sites. Bottom: Prediction for different time windows. (D) In order to assess the clinical impact of the model, disease activity is compared between patients treated with the highest ranked therapy and those treated with any of the other therapies. Patients adhering to the highest ranked therapy are associated with a better disease outcome when compared to those who did not.

Initiation of first disease-modifying treatment for multiple sclerosis patients in the Czech republic from 2013 to 2016: Data from the national registry ReMuS

Background: Proper management of multiple sclerosis (MS) requires feedback from clinical practice via registries. Objective: To introduce the Czech national multiple sclerosis registry, ReMuS, and explore the availability and use of disease-modifying drugs (DMD). Methods: The analysis focused on patients who started their first DMD, either with first-line or second-line medication and was based on reimbursement criteria set by Czech regulators. Baseline information was used to predict relapses after DMD initiation and to compare patients that started DMD in different years. Results: A total of 3,328 patients started DMD treatment for MS between 2013 and 2016; 3,203 on first-line and 125 on second-line medication. The proportion of patients starting on second-line drugs increased from 1.8% in 2013 to 4.7% in 2016. The occurrence of a relapse within one year of DMD initiation was significantly related to (1) the Expanded Disability Status Scale (EDSS) score immediately prior to starting DMD and (2) the number of previous relapses. Both parameters were significantly lower in patients starting in later years of the explored interval. Conclusion: Data from the ReMuS registry highlights improvements made in the management of MS in the Czech Republic. However, a relatively low percentage of patients started treatment using second-line drugs, in contrast to trends in other countries.

Assessment of psychosocial factors associated with relapse in patients with alcohol dependence: a retrospective observational study

Background: Alcohol in beverage form is among the most widely used psychoactive drugs in the world. Nonetheless, its complex pharmacologic actions, including panoply of psychoactive effects, have led societies throughout the world to surround alcoholic beverages with a variety of rules and regulations governing their use. Despite these efforts at control, excessive drinking, with its adverse effects are widespread. Methods: It was a one year retrospective observational study. The sample consisted of fifty patients of alcohol dependence who following treatment for their condition had remained in a remitted state for at least four weeks, and had at least one relapse. The eligible patients fulfilling inclusion and exclusion criteria and giving written informed consent were enrolled into the study. Results: Average time from treatment to lapse was 76.40±17.35 days, while time taken from treatment to relapse was 138.40±31.38 days. Average mean severity of alcohol dependence questionnaire score was 9.49±3.89, the total score of relapse precipitant inventory was 15.94±3.86, and the average value of coping behaviour inventory total score was 1.04±0.19. On the presumptive stressful life events scale the total stress score was 200.84±17.78. The self-efficacy scale (SES) of the patients, the average SES total scores was 60.10±8.77. Conclusions: Clinical parameters like number of previous relapses and positive family history of substance use emerged as significant determinants of relapse related psychosocial factors and appeared to be of greater importance in determining relapse.

Fecal Calprotectin is an Accurate Tool and Correlated to Seo Index in Prediction of Relapse in Iranian Patients With Ulcerative Colitis

Background:The natural clinical course of Ulcerative Colitis (UC) is characterized by episodes of relapse and remission. Fecal Calprotectin (FC) is a relatively new marker of intestinal inflammation and is an available, non-expensive tool for predicting relapse of quiescent UC. The Seo colitis activity index is a clinical index for assessment of the severity of UC.Objectives:The present study aimed to evaluate the accuracy of FC and the Seo colitis activity index and their correlation in prediction of UC exacerbation.Patients and Methods:In this prospective cohort study, 157 patients with clinical and endoscopic diagnosis of UC selected randomly from 1273 registered patients in Fars province’s IBD registry center in Shiraz, Iran, were followed from October 2012 to October 2013 for 12 months or shorter, if they had a relapse. Two patients left the study before completion and one patient had relapse because of discontinuation of drugs. The participants' clinical and serum factors were evaluated every three months. Furthermore, stool samples were collected at the beginning of study and every three months and FC concentration (commercially available enzyme linked immunoassay) and the Seo Index were assessed. Then univariate analysis, multiple variable logistic regression, Receiver Operating Characteristics (ROC) curve analysis, and Pearson’s correlation test (r) were used for statistical analysis of data.Results:According to the results, 74 patients (48.1%) relapsed during the follow-up (33 men and 41 women). Mean ± SD of FC was 862.82 ± 655.97 μg/g and 163.19 ± 215.85 μg/g in relapsing and non-relapsing patients, respectively (P < 0.001). Multiple logistic regression analysis revealed that age, number of previous relapses, FC and the Seo index were significant predictors of relapse. ROC curve analysis of FC level and Seo activity index for prediction of relapse demonstrated area under the curve of 0.882 (P < 0.001) and 0.92 1(P < 0.001), respectively. Besides, FC level of 341 μg/g was identified as the cut-off point with 11.2% and 79.7% relapse rate below and above this point, respectively. Additionally, Pearson correlation coefficient (r) between FC and the Seo index was significant in prediction of relapse (r = 0.63, P < 0.001).Conclusions:As a simple and noninvasive marker, FC is highly accurate and significantly correlated to the Seo activity index in prediction of relapse in the course of quiescent UC in Iranian patients.

Stabilisation des patients schizophrènes en post-aigu : de l’hôpital à la cité

Schizophrenia is a debilitating disease that usually begins in young adulthood, at a time when a person would usually make the transition to independent living, but it can occur at any age. The symptoms and behaviour associated with psychosis and schizophrenia have a distressing impact on the individual, and the family. The course of schizophrenia varies considerably. Although most patients will recover, some will have persisting difficulties or remain vulnerable to future episodes. Therefore, stabilisation of patients in acute phases and avoidance of relapse are major objectives of management throughout the course of this disease. The purpose of this article is to clarify the stabilisation, to study the contributing factors and strategies to implement to achieve stability, through a literature review and key guidelines. Thus, the patient is stabilised when productive symptoms and behavioural problems have decreased. So, the stable phase represents a prolonged period of treatment and rehabilitation during which symptoms are under adequate control and the focus is on improving functioning and recovery. Important predictive criteria of stabilisation include: positive symptoms, the number of previous relapses, cooperation with the patient and family, good adherence to treatment and the use of long acting injectable second-generation antipsychotics. After an acute relapse, the careful organization of the discharge and the development of a proposed ambulatory care in tailored care structures will help consolidate stabilisation and obtain remission. Accepting the idea of continuing treatment is a complex decision in which the psychiatrist plays a central role beside patients and their families. The course of integrated actions on modifiable risk factors such as psychosocial support, addictive comorbidities, identification of prodromes, active information for the therapeutic education of patients and families and access to care will also be supported. This would improve the functional abilities of patients, their social adaptation and particularly their quality of life.

Efficacy and Safety Profile of Long Term Exposure to Lenalidomide in Relapsed Multiple Myeloma.

Abstract 2964 Background. Lenalidomide is an oral IMiD®, immunomodulatory compound, approved for use in combination with dexamethasone (Len/Dex) in patients with RRMM who have received one prior therapy. Len/Dex is indicated until evidence of disease progression at the best-tolerated dose of both Len and Dex (Dimopoulos et al. Leukemia 2011). However, the tolerability profile of long term exposure to Len/Dex is not well described, and evidence that long term exposure to Len/Dex would improve on the response rate and survival has yet to be determined. We sought to determine the efficacy and safety profile of long term exposure to Len/Dex in RRMM pts in a multicentre study. Method. We retrospectively reviewed the medical records of 50 RRMM pts treated with Len/Dex and remaining on Len for ≥2 years with a special focus on pts receiving Len for ≥3 years. All pts included had complete follow up records. Results. The median (range min-max) age was 58 years (39–79) with 30% (n=15) > 65 years (elderly MM), the sex ratio M/F was 1.2, 49% (n=24) ISS 2 and 3, 12% (n=6) severe renal insufficiency (CrCl The response rate (ORR, ≥PR) was 96% (n=48), including 37 (74%) patients with ≥VGPR, similar across age categories. Interestingly, the ORR and ≥VGPR were similar irrespective of whether patients have stopped Len/Dex in our study. The ORR was also similar across number of previous relapses, but the ≥VGPR rate was lower in patients at third relapse and beyond, (50%; p=ns). The ORR and ≥VGPR rate was 93% and 77% in patients exposed to Len ≥3 years, similar to the whole cohort. The median time to first response and best response were 2 (1–5) months and 4.5 (2–9) months, respectively. Overall, 9 (18%) patients stopped treatment due to toxicity, 9 (18%) progression of MM, and 1 (0.5%) patient decision. With a median follow up of 4 years, the median (95%CI) TTP was not reached, the estimated 4-yr TTP was 51.5%. There was no imbalance in the incidence of toxicity based on age, number of previous relapses, and patients exposed to Len ≥3 years did not discontinue more often due to toxicity, 14% versus 19% for those receiving Len The hematological safety profile was similar across age categories, number of previous relapses, and patients exposed to Len ≥ 3 years; overall, 8 (16%) patients experienced grade 3–4 neutropenia, 6% thrombopenia, and 6% anemia. Ten (20%) patients experienced a thromboembolic event (VTE), all of them of venous type. Two patients had previous history of VTE, but none of them experienced VTE on Len/Dex, likely related to adequate VTE prophylaxis. The median time to first occurrence was 5 (1;28) months, although 4/10 occurred in patients with ≥3 years on Len. All VTE occurred while on VTE prophylaxis except for 1 patient, 5 on aspirin, 2 on prophylactic doses of LMWH, and 2 on VKA (target INR 2–3). The incidence rate of second primary malignancy (SPM) was 3 (6%) (larynx, lung, and MDS). The SPMs occurred at a median time of 4 years from start of Len, while Len was already stopped in 2/3 patients, the latter stopped len at time SPM was diagnosed. Interestingly, none of the patients with more than 3 years exposure on Len had SPM. Conclusions. The current study provides estimates of responses, TTP and safety in a series of MM pts with long-term exposure to Len-based regimen at relapse. 62% of patients remained on Len beyond 3 years reflecting the efficacy and good safety profile of Len in relapsed MM, irrespective of age and number of prior therapies. Furthermore, no excess of long term side effects, including SPM, was observed with a prolonged long follow-up in this study. Disclosures: Robinson:Celgene: Employment. Miljkovic:Celgene: Employment. Morel:Celgene: Employment. Boccacio:Celgene: Employment. Facon:millenium: Membership on an entity9s Board of Directors or advisory committees; janssen: Membership on an entity9s Board of Directors or advisory committees; celgene: Membership on an entity9s Board of Directors or advisory committees; onyx: Membership on an entity9s Board of Directors or advisory committees. Hulin:celgene: Honoraria, Membership on an entity9s Board of Directors or advisory committees; janssen: Membership on an entity9s Board of Directors or advisory committees. Leleu:Onyx: Honoraria, Speakers Bureau; Sanofi: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau.

Alemtuzumab versus interferon beta-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes

Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia. In this study, we further analysed the CAMMS223 data with the aim of determining whether demographic and baseline disease-related characteristics affect the beneficial effects of alemtuzumab. Additionally, we aimed to describe a new outcome measure in multiple sclerosis research: sustained reduction in disability. 334 treatment-naive patients with active, early RRMS were randomly assigned in a 1:1:1 ratio to receive interferon beta-1a (44 μg subcutaneously three times per week), or 24 mg per day or 12 mg per day alemtuzumab intravenously for 2 or 3 annual cycles. We analysed freedom from clinical disease activity (CDA; defined as no relapses and no sustained accumulation of disability) and occurrence of sustained reduction in disability (SRD; a ≥1 point decrease on the EDSS sustained for 6 consecutive months for patients with a baseline EDSS ≥2), and analysed efficacy outcomes for subgroups based on age, sex, geographic region, MRI-T1 brain volume, MRI-T2 lesion volume, disease duration, number of previous relapses within 2 years, and EDSS. 322 patients were analysed. 161 of 215 patients treated with alemtuzumab were free of CDA at 36 months (Kaplan-Meier estimate 71·8%, 95% CI 63·1-78·8%) compared with 52 of 107 patients treated with interferon beta-1a (42·6%, 32·4-52·4%; hazard ratio [HR]=0·31, 0·20-0·46; p<0·0001). For the 199 patients with a baseline EDSS score greater than or equal to 2, SRD was more likely (HR=2·61, 1·54-4·43; p=0·0004) among patients treated with alemtuzumab (66 of 133 patients, Kaplan-Meier estimate 51·6%, 95% CI 43·2-60·7%) than patients treated with interferon beta-1a (15 of 66 patients, 27·2%, 17·2-41·4%). All disability and relapse outcomes showed evidence of beneficial effects of alemtuzumab compared with interferon beta-1a across all analysed patient subsets, and no subgroup of patients consistently responded better than others to alemtuzumab. Alemtuzumab reduced disease activity compared with interferon beta-1a in most of the analysed subgroups. Significantly greater numbers of patients experienced sustained improvement in disability after treatment with alemtuzumab than interferon beta-1a. The efficacy offered by alemtuzumab is a substantial advance in the treatment of multiple sclerosis. Genzyme and Bayer Schering Pharma.

Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis

On the basis of various clinical and MRI measurements, the phase 3 Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study in patients with relapsing-remitting multiple sclerosis (RRMS) showed that short-course oral treatment with cladribine at cumulative doses of 3·5 and 5·25 mg/kg over 96 weeks was more effective than placebo. Achieving sustained freedom from disease activity is becoming a viable treatment goal in RRMS; we therefore aimed to assess the effects of cladribine on this composite outcome measure by doing a post-hoc analysis of data from the CLARITY study. Freedom from disease activity is composed of three components that are commonly used individually as endpoints in clinical trials; it is defined as the patient having no relapse, no 3-month sustained change in expanded disability status scale (EDSS) score, and no new MRI lesions (no T1 gadolinium-enhancing or active T2 lesions) over a specified period. We assessed the effect of two doses of cladribine tablets versus placebo on the proportion of patients who were free from disease activity based on the individual components, all pair-wise combinations, and the composite of the three components (freedom from disease activity). Freedom from disease activity was analysed at 24, 48, and 96 weeks, and in subgroups of patients stratified according to baseline demographic and disease characteristics (age, disease duration, previous treatment with disease-modifying therapy, T1 gadolinium-enhancing lesion number, T2 lesion volume, EDSS score, number of previous relapses, and highly active disease). Of the 1326 patients randomly assigned to treatment in the CLARITY study, 1192 were assessable for freedom from disease activity at 96 weeks. Over 24 weeks, 266 (67%) of 395 patients in the cladribine 3·5 mg/kg group and 283 (70%) of 406 in the cladribine 5·25 mg/kg group were free from disease activity, versus 145 (39%) of 373 in the placebo group (odds ratio [OR] 3·31, 95% CI 2·46-4·46 for the 3·5 mg/kg group; and 3·68, 2·73-4·97 for the 5·25 mg/kg group; both p<0·0001). Over 48 weeks, 208 (54%) of 384 patients in the cladribine 3·5 mg/kg group and 222 (56%) of 396 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 86 (24%) of 360 patients in the placebo group (OR 3·80, 2·77-5·22 for the 3·5 mg/kg group; 4·13, 3·02-5·66 for the 5·25 mg/kg group; both p<0·0001). Over 96 weeks, 178 (44%) of 402 patients in the cladribine 3·5 mg/kg group and 189 (46%) of 411 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 60 (16%) of 379 patients in the placebo group (OR 4·28, 3·05-6·02 for the 3·5 mg/kg group; 4·62, 3·29-6·48 for the 5·25 mg/kg group; both p<0·0001). The effects of cladribine tablets on freedom from disease activity were significant across all patient subgroups. Treatment with cladribine tablets significantly increased the proportion of patients with sustained freedom from disease activity over 96 weeks compared with placebo. Sustained freedom from disease activity could become an important measure of therapeutic response in RRMS. Merck Serono SA-Geneva, Switzerland; an affiliate of Merck, Darmstadt, Germany.

BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors

BackgroundThe prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU), one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare.MethodsWe performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m2 BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS), tumor burden, pretreatment with temozolomide (TMZ), type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model.ResultsThe median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15), median overall survival 22 weeks (95% CI: 18-27). The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression). No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off).ConclusionIn summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are available.

¿Implica el T0 en la pieza de cistectomía encontrarse libre de tumor a largo plazo?

Introduction and objectives The aim of this study was to evaluate the progress of patients with a pT0 radical cystectomy specimen in order to know what factors are helpful in deciding when the bladder can be preserved. Material and methods We reviewed 153 cases of radical cystectomies performed due to bladder tumours without neoadjuvant therapy between 1995 and 2005 and with a minimum of three years of follow-up. Stage pT0 patients were selected. We considered age at time of diagnosis, sex, pathological stage and grade of the tumour at the time of transurethral resection (TUR), number of resections, surgical factors, tumour characteristics (multifocal, papillary or solid), progression-free survival, cancer-specific survival and cause of death. We ran a univariate analysis of the different factors studied along with disease progression. Results 12.8% of cystectomy specimens were pT0N0. Progression occurred in 35% between 6 months and 4 years after the cystectomy. Cancer-specific survival was 75%. Five patients died within an average of 18 months. The cause of death for all of them was tumour progression with distant metastasis . Statistical studies in the univariate analysis were only related to progression and the number of prior TURs, which is probably due to the number of cases, but the tumour multifocality, grade and stage were noteworthy. 15% of the pT0 patients had a papillary phenotype and 33% of them died. Of those with a non-papillary phenotype, 23.5% died. Conclusions A stage pT0N0 cystectomy specimen does not define this surgery as curative, and these cases require the same follow-up as for the rest of the patients. It is of particular interest that out of all of our cases, there was no local recurrence, but there was distant metastasis. This leads us to believe that these patients could have benefitted from systemic chemotherapy with no need for radical surgery. In our study, the number of previous relapses was the only prognostic factor with statistical significance.

Can immune parameters predict short-term symptomatic outcome of treatment in mood disorder out-patients? A review of the literature

healthy control group. Methods: The present study was part of the DELTA study, a randomised trial on the effectiveness of a preventive cognitive behavioral module in rMDD patients with at least two depressive episodes in the past. At baseline level mean morning cortisol and DHEA-S, mean evening cortisol and DHEA-S, mean morning and evening cortisol/DHEA-S ratio and mean morning–evening difference for both cortisol and DHEA-S were determined, in 127 patients. Steroid levels will be compared with those of an age and gender matched control group (n=75), free from medical illness, life time psychiatric disorders and life time psychiatric disorders in first degree relatives. Results: Data are currently analysed. Differences in steroid levels between the rMDD and the control group will be calculated. In rMDDassociationswill be calculated between steroid levels and the number of previous relapses, the use of antidepressants, gender and age. Discussion: This is the first large scale study in rMDD comparing the levels of salivary cortisol, DHEA-S and the cortisol/DHEA-S ratio, with the levels from an age and gender matched healthy control group. We will discuss the nature and severity of the steroid abnormalities found in rMDD and the implications for further study upon the prediction of clinical outcome.

Evaluation of cephalexin intermittent therapy (weekend therapy) in the control of recurrent idiopathic pyoderma in dogs: a randomized, double‐blinded, placebo‐controlled study

The purpose of this study was to evaluate the efficacy of cephalexin intermittent therapy 2 days a week (weekend therapy) in the prevention of relapses of recurrent idiopathic superficial or deep pyoderma in dogs. Twenty‐eight dogs were entered into the study. A diagnosis of chronic idiopathic pyoderma was made based on: (1) history, including at least two previous relapses cured in the 12 months before inclusion; (2) clinical signs of pyoderma without underlying skin disease based on clinical presentation; and (3) appropriate diagnostic tests (compatible cytological examination and bacterial culture). In phase 1 of the study, dogs were treated with cephalexin (15 mg/kg twice daily) if sensitivity testing was compatible until 2 weeks after cure, for a minimum of 4 weeks and a maximum of 2 and 4 months for superficial and deep pyoderma, respectively. In phase 2, the cured dogs were then randomly and blindly allocated into two groups: Group 1 received cephalexin (15 mg/kg twice daily) on Saturdays and Sundays for 1 year, and Group 2 received a placebo in the same way. Dogs were examined every 3–4 weeks during phase 1 and every 2 months during phase 2, except in case of relapse justifying an earlier examination. Clinical signs of pyoderma were scored at each examination (11 parameters scored 0–3). No other systemic antibacterial or anti‐inflammatory treatments nor topical antibacterial or anti‐inflammatory treatments were permitted during both phases. The two groups were compared using Fischer's exact test for sex and clinical signs, and the Wilcoxon Rank‐Sum test for age, weight, number of relapses before inclusion, and duration of treatment in phase 1. The number of dogs remaining free of relapse, i.e. free of any pyoderma lesion, was compared between the two groups using a survival analysis with the Log‐Rank Test. The average time before relapse was compared between the two groups using the Wilcoxon Rank‐Sum test. In phase 1, one case was lost to follow‐up; two cases were excluded due to treatment failure and an additional two cases because of resistance in vitro to cephalexin. Various species of staphylococci sensitive to cephalexin were isolated in the 23 remaining dogs. In phase 2, 13 dogs received placebo and 10 received cephalexin. The two groups were not statistically different according to clinical signs (six cases of folliculitis in each group, three and five cases of furunculosis, one and two cases of cellulitis in Groups 1 and 2, respectively), sex, age, weight, number of previous relapses, and duration of treatment in phase 1. There was a significant difference between the two groups in the number of dogs that did not relapse. Two dogs in Group 1 did not relapse. Further, the rate of relapse over time was more rapid in the dogs receiving placebo. The average time until relapse in Groups 1 (6.6 months) compared to Group 2 (2.5 months) was significantly different. Resistance to cephalexin did not increase during the study. We conclude that cephalexin weekend therapy can be beneficial in dogs with idiopathic recurrent pyoderma. Funding: Virbac SA.

Evidence of Wallerian degeneration in normal appearing white matter in the early stages of relapsing-remitting multiple sclerosis: a HMRS study.

Wallerian degeneration in normal appearing white matter in early relapsing-remitting multiple sclerosis (RRMS), and its correlation with the number of relapses and disease duration. Background Recent pathological studies have demonstrated Wallerian degeneration in normal appearing white matter (NAWM) in multiple sclerosis (MS), in established RRMS, and in chronic MS. However, the presence of Wallerian degeneration early in the disease and its correlation with relapse and with disease duration has not been studied. We performed proton magnetic resonance spectroscopic imaging in 21 MS patients, and 4 healthy controls, age and gender matched, aged under 45 years, with a maximum of 4 years since first bout, and an EDSS score of less than 3.0. N-acetyl-aspartate (NAA) (an index of axonal integrity) was measured in the NAWM from the pons and the cerebellar peduncles. We observed that the NAA levels were abnormally low in the NAWM in the early RRMS patients (p = 0.04, Student's t-test). The decrease in the NAA concentration correlated with disease duration in the two areas studied (p = 0.03 for pons and p = 0.04 for cerebellar peduncle); and with the number of previous relapses (Pearson's correlation = -0.582, p < 0.002). Wallerian degeneration measured by the NAA concentration at pons and cerebellar peduncles is present early in the disease and correlates with the number of relapses and disease duration.

Lower levels of N-acetylaspartate in multiple sclerosis patients with the apolipoprotein E epsilon4 allele.

In multiple sclerosis (MS), the epsilon4 allele of apolipoprotein E (APOE epsilon4) has been associated with more rapid clinical worsening and more severe tissue damage on magnetic resonance imaging. To use proton magnetic resonance spectroscopy ((1)H-MRS) to further explore the biochemical changes in the brains of patients with MS associated with APOE epsilon4. A 2-year clinical and (1)H-MRS follow-up cohort study. The MS outpatient clinic, Department of Neurology, and Magnetic Resonance Center of Karl-Franzens University. We performed (1)H-MRS of the central portion of both hemispheres and APOE genotyping in 72 patients (52 women and 20 men; mean +/- SD age, 34.8 +/- 8.8 years) with clinically definite relapsing-remitting MS. Repeated studies were performed in 44 patients after a mean +/- SD interval of 34 +/- 9 months. Levels of N-acetylaspartate as measured by (1)H-MRS. Patients with MS and an epsilon4 allele (n = 19) had a significantly lower mean +/- SD N-acetylaspartate-creatine ratio than those without an epsilon4 allele (n = 53) (1.73 +/- 0.26 vs 1.89 +/- 0.24; P =.04) despite the absence of significant differences in age at onset, disease duration, Expanded Disability Status Scale score, and number of previous relapses between subgroups. During follow-up, the drop in the N-acetylaspartate-creatine ratio of epsilon4 carriers was also significantly larger (-0.31 vs -0.10; P =.01). This was paralleled by a higher number of relapses (mean +/- SD, 4.1 +/- 2.7 vs 1.7 +/- 1.6; P =.02) and a faster although nonsignificant progression of disability (mean +/- SD (Delta)Expanded Disability Status Scale score, 0.9 +/- 1.8 vs 0.3 +/- 1.1; P =.19). The APOE epsilon4 allele has a negative effect on the course of MS, and increasing axonal damage may be an important mechanism.

Dysregulation of the hypothalamo-pituitary-adrenal axis is related to the clinical course of MS.

To investigate whether dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis is related to clinical characteristics in MS. The authors performed the combined dexamethasone-corticotropin-releasing hormone test (Dex-CRH test) in 60 MS patients and 29 healthy control subjects. In addition, the short adrenocorticotropic hormone (ACTH) test was performed in 39 consecutive patients. All patients had active disease and none were treated with glucocorticoids, immunosuppressants, or immunomodulators. The patients had an exaggerated rise in plasma cortisol concentrations in the Dex-CRH test (p < 0.05), indicating hyperactivity of the HPA system. The degree of hyperactivity was moderate in relapsing-remitting MS patients (n = 38; area under the time-course curve for cortisol [AUC-Cort] 226.2+/-38.9 arbitrary units [AU], mean +/- SEM), intermediate in secondary progressive MS patients (n = 16; AUC-Cort, 286.8+/-60.2 AU), and marked in primary progressive MS patients (n = 6; AUC-Cort, 670.6+/-148.6 AU). Differences were significant between the three patient groups (p < 0.005), and between control subjects (n = 29; AUC-Cort, 150.8+/-34.1 AU) and each patient group. Indicators of HPA axis activation correlated with neurologic disability (Kurtzke's Expanded Disability Status Scale), but not with the duration of the disease, number of previous relapses, previous corticosteroid treatments, or depressed mood (Hamilton Depression Scale). The ACTH test was normal in 31 of the 33 patients studied. HPA axis hyperactivity in MS is related to the clinical type of disease, with a suggestion of increasing HPA axis dysregulation with disease progression.