Predicting the On-Study Relapse Rate for Multiple Sclerosis Patients in Clinical Trials

Background: The annual relapse rate has been commonly used as a primary efficacy endpoint in phase III multiple sclerosis (MS) clinical trials. The aim of this study was to determine the relative contribution of different possible prognostic factors available at baseline to the on-study relapse rate in MS. Methods: A total of 821 patients from the placebo arms of the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database were available for this analysis. The univariate relationships between on-study relapse rate and the baseline demographic, clinical, and MRI-based predictors were assessed. The multiple relationships were then examined using a Poisson regression model. Two predictor subsets were selected. Subset 1 included age at disease onset, disease duration, gender, Expanded Disability Status Scale (EDSS) at baseline, number of relapses in the last 24 months prior to baseline, and the disease course (RR and SP). Subset 2 consisted of Subset 1 plus gadolinium enhancement status in MRI. The number of patients for developing the models with no missing values was 727 for Subset 1 and 306 for Subset 2. Results:The univariate relationships show that the on-study relapse rate was higher for younger and for female patients, for RR patients than for SP patients, and for patients with positive enhancement status at entry (Wilcoxon test, p<0.05). A higher on-study relapse rate was associated with a shorter disease duration, lower entry EDSS, more pre-study relapses and more enhancing lesions in T1 at entry. The fitted Poisson model shows that disease duration (estimate=-0.02) and previous relapse number (estimate=0.59 for 1, 0.91 for 2 and 1.45 for 3 or more relapses vs 0 relapse) remain. We were able to confirm these findings in a second, independent dataset. Conclusions: The relapse number prior to entry into clinical trials together with disease duration are the best predictors for the on-study relapse rate. Disease course and gadolinium enhancement status, given the other covariates, have no significant influence on the on-study relapse rate

Interferon beta in multiple sclerosis: experience in a British specialist multiple sclerosis centre

Background: The efficacy of interferon beta (IFN beta) is well established in relapsing-remitting multiple sclerosis (MS). However, the use of this drug in clinical practice is complex, especially because it is only partially effective, its long term efficacy and side effects are unknown, its efficacy may be abrogated by the development of neutralising antibodies, compliance is variable, and its cost effectiveness is controversial. Objectives and Methods: Analysis of a prospectively followed up series of 101 MS patients treated with IFN beta was undertaken to: (1) monitor the outcome of IFN beta treatment in clinical practice; (2) compare the immunogenicity of the three commercial IFN beta preparations available; (3) assess the proportion of patients fulfilling the current guidelines of the Association of British Neurologists for stopping IFN beta therapy. Results: During a median treatment period of 26 months (range 2–85), the relapse rate decreased by 41%. Although the reduction in the relapse rate was similar for all three commercial products, none of the Avonex treated patients were relapse free, compared with 19% of the Betaferon treated and 27% of the Rebif treated patients (p=0.02). Neutralising antibodies were not detected in Avonex treated patients (0 of 18), compared with 12 of 32 (38%) Betaferon treated and 10 of 23 (44%) Rebif treated patients (p=0.02). Forty of 101 (40%) patients satisfied the current (2001) Association of British Neurologists criteria for stopping IFN beta treatment at some stage during their treatment. Conclusion: IFN beta is effective in reducing the relapse rate in patients with relapsing-remitting MS in routine clinical practice. However, after a median treatment duration of 26 months, 40% of initially relapsing-remitting MS patients seem to have ongoing disease activity, presenting as disabling relapses or insidious progression

Studies of FLT3 mutations in paired presentation and relapse samples from patients with acute myeloid leukemia: implications for the role of FLT3 mutations in leukemogenesis, minimal residual disease detection, and possible therapy with FLT3 inhibitors

FLT3 mutations, either internal tandem duplications (ITDs) or aspartate residue 835 (D835) point mutations, are present in approximately one third of patients with acute myeloid leukemia (AML) and have been associated with an increased relapse rate. We have studied FLT3 mutations in paired presentation and relapse samples to ascertain the biology of these mutations and to evaluate whether they can be used as markers of minimal residual disease. At diagnosis, 24 patients were wild-type FLT3, and 4 acquired a FLT3 mutation at relapse (2 D835+, 2 ITD+), with a further patient acquiring an ITD at second relapse. Of 20 patients positive at diagnosis (18 ITD+, 2 D835+), 5 who were all originally ITD+ had no detectable mutation at relapse, as determined by a sensitive radioactive polymerase chain reaction. One of these patients had acquired an N-Ras mutation not detectable at presentation. Furthermore, another patient had a completely different ITD at relapse, which could not be detected in the presentation sample. These results indicate that FLT3 mutations are secondary events in leukemogenesis, are unstable, and thus should be used cautiously for the detection of minimal residual disease

Inter and intra-hemispheric structural imaging markers predict depression relapse after electroconvulsive therapy: a multisite study.

Relapse of depression following treatment is high. Biomarkers predictive of an individual's relapse risk could provide earlier opportunities for prevention. Since electroconvulsive therapy (ECT) elicits robust and rapidly acting antidepressant effects, but has a &gt;50% relapse rate, ECT presents a valuable model for determining predictors of relapse-risk. Although previous studies have associated ECT-induced changes in brain morphometry with clinical response, longer-term outcomes have not been addressed. Using structural imaging data from 42 ECT-responsive patients obtained prior to and directly following an ECT treatment index series at two independent sites (UCLA: n = 17, age = 45.41±12.34 years; UNM: n = 25; age = 65.00±8.44), here we test relapse prediction within 6-months post-ECT. Random forests were used to predict subsequent relapse using singular and ratios of intra and inter-hemispheric structural imaging measures and clinical variables from pre-, post-, and pre-to-post ECT. Relapse risk was determined as a function of feature variation. Relapse was well-predicted both within site and when cohorts were pooled where top-performing models yielded balanced accuracies of 71-78%. Top predictors included cingulate isthmus asymmetry, pallidal asymmetry, the ratio of the paracentral to precentral cortical thickness and the ratio of lateral occipital to pericalcarine cortical thickness. Pooling cohorts and predicting relapse from post-treatment measures provided the best classification performances. However, classifiers trained on each age-disparate cohort were less informative for prediction in the held-out cohort. Post-treatment structural neuroimaging measures and the ratios of connected regions commonly implicated in depression pathophysiology are informative of relapse risk. Structural imaging measures may have utility for devising more personalized preventative medicine approaches

Evaluation of A Post-Treatment Follow-Up Program in Patients with Oral Squamous Cell Carcinoma

Objectives The duration and the frequency of follow-up after treatment of oral squamous cell carcinoma are not standardized in the current literature. The purpose of this study was to evaluate our local standard post-treatment and follow-up protocol. Materials and methods Overall, 228 patients treated curatively from 01/2006 to 07/2013 were reviewed. To evaluate the follow-up program, data on the secondary event were used. To determine risk groups, all patients with tumor recurrence were specifically analyzed. Relapse-free rate were estimated by the Kaplan-Meier product limit method. The chi-square test was used to identify independent risk factors for tumor relapse. Results In total, 29.8 % patients had a secondary event. The majority of the relapse cases (88.2 %) were detected within 2 years postoperatively, 61.8 % of them within the first year. Most events were local recurrences (34.7 %). UICC-stage IV was significantly associated with tumor recurrence (p = 0.001). Gender (p = 0.188), age (p = 0.195), localization (p = 0.739), T-stage (p = 0.35), N-stage (p = 0.55), histologic grade (p = 0.162), and tobacco and alcohol use (p = 0.248) were not significantly associated with tumor recurrence. Patients with positive neck nodes relapsed earlier (p = 0.011). The majority of relapses (86.3 %) were found in asymptomatic patients at routine follow-up. Conclusions The results of this study suggest an intensified follow-up within the first 2 years after surgery. Clinical relevance Given the higher relapse rate of patients exhibiting an UICC-stage IV and/or positive neck nodes, it seems to be from special interest to perform in this group a risk-adapted follow-up with monthly examinations also in the second year

RESULTS OF CHEMOTHERAPY BY UKCCSG PROTOCOL IN CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA : CLINICAL CHARACTERISTICS AND OUTCOME

Objectives: Acute lymphoblastic leukemia (ALL) represents a clonal expansion and arrest of normal lymphoid hematopoiesis. ALL remains the most common malignancy in children. The survival rate of the patients is significantly increased since the 1960s. This study was undertaken to evaluate the 5- year overall survival (OS) rates of patients with ALL in a single center in IRAN. Methodology: A total of 292 children with ALL up to 19 years old who had been treated by UKCCSG protocol at the Oncology Department in Shafa Hospital from March 1997 to October 2007 were evaluated for their age, gender, as well as FAB types, presenting features, outcomes of therapy and relapse. Results: The mean age of the patients was 6.7 years (SD= 3.8, median 6 years). In this series, 184 patients (63.01%) were male. There was a complete remission induction rate of 84.9% during first induction course of therapy. Five-year overall survival was 61.9% and it was better (p=0.006) in standard risk group. Relapse rate after first remission was 23.9% and death due to relapse was more in high risk group, but it was not significant (p=0.053). There were 74(66.6%) of total deaths in induction period and 21(18.9%) after relapse. Overall infections (71.9%) were major cause of deaths in induction period. OS was better in boys, age group between (1-10 yo) and initial white blood cells count (10,000-50,000x103/mm3) but there were not significant (p=0.38, p=0.30, p=0.20, respectively). Conclusion: Five-year overall survival was 61.9% of the children with new ALL who were undergoing chemotherapy by UKCCSG protocol. High mortality rate in induction period was mainly due to infections which decreased five-year overall survival in this study

Absenteeism, Health Insurance, and Business Cycles

We use a dependent competing risks hazard rate model to investigate individual sickness absence behaviour in Norway, on the basis of register data covering more than 2 million absence spells. Our findings are: i) that business cycle improvements yield lower work-resumption rates for persons who are absent, and higher relapse rates for persons who have already resumed work; ii) that absence sometimes represents a health investment, in the sense that longer absence ‘now’ reduces the subsequent relapse propensity; and iii) that the work-resumption rate increases when sickness benefits are exhausted, but that work-resumptions at this point tend to be short-lived.Absenteeism; Dependent risks

Prognostic factors in seminomas with special respect to HCG: Results of a prospective multicenter study

Objective: In a prospective multicenter trial, it was our intention to elucidate clinical prognostic factors of seminomas with special reference to the importance of human chorionic gonadotropin (HCG) elevations in histologically pure seminomas. Methods: Together with 96 participating urological departments in Germany, Austria, and Switzerland, we recruited 803 seminoma patients between 1986 and 1991. Out of 726 evaluable cases, 378 had elevated, while 348 had normal HCG values in the cubital vein. Histology was reviewed by two reference pathologists. HCG levels were determined in local laboratories and in a study laboratory. Standard therapy was defined as radiotherapy in stages I (30 Gy) and IIA/B (36 Gy) to the paraaortal and the ispilateral (stage I) and bilateral (stage IIA/B) iliac lymph nodes; higher stages received polychemotherapy and surgery in case of residual tumor masses. Statistics included chi-square tests, linear Cox regression, and log-rank test. Results: The HCG elevation is associated with a larger tumor mass (primary tumor and/or metastases). HCG-positive and HCG-negative seminomas had no different prognostic outcome after standard therapy. The overall relapse rate of 6% and the survival rate of 98% after 36 months (median) indicate an excellent prognosis. The calculation of the relative risk of developing a relapse discovered only stage of the disease and elevation of the lactate dehydrogenase concentration and its prolonged marker decay as independent prognostic factors for seminomas. A more detailed analysis of the prognostic significance of the stage revealed that the high relapse rate in stage IIB seminomas after radiotherapy (24%) is responsible for this result. Conclusions: We conclude that HCG-positive seminomas do not represent a special entity. Provided standard therapy is applied, HCG has no influence on the prognosis. Patients with stage IIB disease should be treated with chemotherapy because of the demonstrated higher relapse rate outside the retroperitoneum. Copyright (C) 1999 S. Karger AG. Basel

Liver transplantation for alcoholic liver disease: a retrospective analysis of recidivism, survival and risk factors predisposing to alcohol relapse

Background and study aims : Alcoholic liver disease (ALD) is the second most common indication for liver transplantation. The aim of this study was to evaluate the alcohol relapse rate and long-term survival after liver transplantation for ALD and to identify risk factors predisposing to alcohol relapse. Patients and methods : Between 2000 and 2007, 108 patients transplanted for ALD in the Ghent University Hospital were included in this retrospective analysis. Relapse was defined as any drinking after transplantation, problem drinking as more than 2 units/day for women and 3 units/day for men. A wide range of variables was obtained from a questionnaire and medical records. Results : The mean follow-up was 55 months. Relapse was observed in 29%, 16% in problem drinking. The one-and five-year survival was 87% and 74% respectively. No significant difference in survival was found between non-relapsers, occasional drinkers and problem drinkers. The following risk factors were found to be significantly associated with relapse into problem drinking in an univariate analysis : a shorter pre-transplant abstinence period, the presence of a first degree relative with alcohol abuse and a higher number of prior attempts to quit. In multivariable analysis, the presence of a first degree relative with alcohol abuse was found associated with relapse into problem drinking. Conclusions : The presence of a first degree relative with alcohol abuse is a valuable pre-transplant variable evaluating an ALD patient's eligibility for liver transplantation. Other variables are also helpful to outline the broader context of the drinking behavior of the patient