Conversion from valproic acid onto topiramate in adolescents and adults with epilepsy.

OBJECTIVE: To explore efficacy and tolerability outcomes of topiramate (TPM) in patients with epilepsy transitioning from valproic acid (VPA) because of insufficient efficacy and/or tolerability onto TPM. METHODS: Multicenter, open label, single arm, non-interventional study examining patients (> or =12 years) with epilepsy, transitioning onto TPM from baseline mono-or combination therapy with VPA. TPM was added onto the existing antiepileptic drug (AED) treatment and started at a dose of 25 mg once daily. The dose was titrated up with 25 mg/day increments, once every 1-2 weeks, until a final dose between 50-200 mg/day was reached. Based on clinical judgment, the treating physician decided whether or not and when the existing AED treatment especially with VPA could be withdrawn. Documented were type and frequency of seizures, TPM dose, quality of life (QOLIE-10 questionnaire), subjective perception of improvement, and adverse events (AE). RESULTS: One hundred and forty-seven patients (59% women, mean age 41 years) switched from baseline VPA treatment onto TPM because of insufficient efficacy (61%) and/or poor tolerability (81%). Average duration of follow-up was 20.3 weeks with an overall discontinuation rate of 16.3% of patients, mainly because of AE (in 8.2% of 147 patients). At study endpoint, the intended shift to TPM monotherapy was achieved in 70% of patients at a median dose of 150 mg/day. A seizure reduction of > or =50% was achieved in 75% of patients in the last scheduled period (week 8-20), and 51% of patients entering that period remained seizure-free. Quality of life improved significantly as compared with baseline for all domains of QOLIE-10 (P < 0.001). Most frequent AEs were weight decrease (4.8%), paraesthesia and fatigue (4.1% each), speech disorder and headaches (2.7% each). CONCLUSIONS: In patients with epilepsy not satisfactorily treated with VPA, conversion to TPM was associated with improved seizure control as well as improvement in several aspects of quality of life.

Conversion from carbamazepine or oxcarbazepine to topiramate in adolescents and adults with epilepsy.

OBJECTIVE: To explore effectiveness, tolerability and changes in quality of life in patients with epilepsy converting to topiramate (TPM) from carbamazepine (CBZ) or oxcarbazepine (OXC) due to insufficient effectiveness and/or tolerability. METHODS: A multicenter, open-label, non-interventional trial was used to examine patients (> or = 12 years) with epilepsy, changing to TPM monotherapy from baseline mono- or combination therapy with CBZ or OXC. TPM was added to the existing antiepileptic drug (AED) treatment and started at a dose of 25 mg once daily. The dose was titrated up with 25 mg/day increments, once every 1-2 weeks, until a final dose between 50 and 200 mg/day was reached. On the basis of clinical judgment, the treating physician decided whether or not the existing AED treatment with CBZ or OXC could then be withdrawn. Type and number of seizures, preferred TPM dose, quality of life (QOLIE-10 questionnaire), subjective perception of improvement and adverse events (AE) were documented. RESULTS: 140 patients (53.5% women, mean age 47 years) decided to switch to TPM due to insufficient effectiveness (75% of patients) and/or poor tolerability (80%) of the CBZ/OXC treatment. Average duration of follow-up was 24 weeks with an overall discontinuation rate of 19.3%, mainly due to AEs (12.1%). At study endpoint, the intended shift to TPM monotherapy was achieved in 73% of patients at a median TPM dose of 100 mg/day. A seizure reduction of > or = 50% was achieved in 91% of patients in the last scheduled period (weeks 12-26); 62% of patients entering that period remained seizure free. Quality of life at endpoint improved significantly when compared with baseline for all domains of QOLIE-10 (P < 0.001). Most frequent AEs (reported by > or = 5% of patients) were paresthesia (9.3%), weight loss (7.9%), convulsions (5.7%) and memory disorders (5.0%). CONCLUSION: In patients with epilepsy, previously not satisfactorily treated with CBZ or OXC, conversion to TPM may result in an improvement in seizure control as well as in quality of life.

Microsatellite instability did not predict individual survival of unselected patients with colorectal cancer.

INTRODUCTION: High microsatellite instability (MSI-H) occurs in about 15% of colorectal cancers (CRC) and clinical as well as pathological features differ from tumours exhibiting low microsatellite instability (MSI-L) or microsatellite stability (MSS). Conflicting data exists about the relevance of MSI in predicting the prognosis and benefit of 5-fluorouracil (5-FU) based chemotherapy in patients with CRC. We investigated the usefulness of MSI as a predictor of distinct clinical attributes influencing recurrence rate and disease-free survival (DFS) subject to the use of adjuvant or palliative chemotherapy with 5-FU in stage II- stage IV CRC. METHODS: We collected data and tumours of 416 consecutive stage I to IV CRC patients from 2000 to 2002, and followed them for a median time of 33 months. Microsatellite loci recommended by the National Cancer Institute were analysed. Cox proportional hazard modelling was used to compare clinical data and survival as well as associations for MSI and 5-FU treatment status of patients with MSI-H, MSI-L or MSS CRC. RESULTS: We identified 52 MSI-H (13%), 21 MSI-L (5%) and 343 MSS (82%) tumours. CRC with MSI-H tended to have a decreased likelihood of metastasising to regional lymph nodes (p=0.055), whilst age of diagnosis and tumour location did not differ. In an analysis that did not take into account the use of chemotherapy, univariate and multivariate analyses failed to show a difference between MSI-H and MSS groups with respect to disease-free and overall survival. Furthermore, survival under application of 5-FU did not correlate with MSI status. CONCLUSION: No clear influence of MSI status on overall survival and response to 5-FU chemotherapy was found.

[Adjuvant and palliative chemotherapy of colorectal cancer in Germany outside controlled trials]. / Adjuvante und palliative Chemotherapie des kolorektalen Karzinoms in Deutschland ausserhalb kontrollierter Studien.

BACKGROUND AND OBJECTIVE: Colorectal cancer is the second most common malignant tumour in Germany with an unfavorable prognosis especially in a locally advanced or metastasizing stage. Although adjuvant and palliative chemotherapy significantly improve 5-year survival, consensus recommendations have in the past been inadequately transformed into clinical practice. It was the aim of this study to analyse the implementation of existing guidelines in a cohort from a defined area of Germany. PATIENTS AND METHODS: In a multicentre study done between January 2000 and January 2002, tumour stage, primary care, adjuvant or palliative chemotherapy and follow-up of 444 patients (216 males, 228 females) with newly diagnosed colorectal cancer were recorded. RESULTS: 301 patients had colonic and 143 patients rectal cancer. The median age at diagnosis was 65 11.3 years. 36 of 96 (38%) patients with stage II colon cancer and 66 of 87 (76%) with stage III disease received adjuvant chemotherapy. 8 of 51 (16%) patients with rectal cancer stage II and 22 of 38 (58%) patients with stage III underwent adjuvant radio- and chemotherapy. The 68 of 84 (81%) patients with stage IV CRC who received palliative chemotherapy were given almost exclusively 5-FU monotherapy. Initial or sequential combination chemotherapy with oxaliplatin or irinotecan were performed in only 24 of 84 (29%) patients. CONCLUSIONS: Stage III colon cancer was predominantly treated according to the existing standard guidelines. In contrast combined radio- and chemotherapy for rectal cancer stage II and III was only performed in one third of the patients, another third receiving neither adjuvant radiation nor chemotherapy. Initial combined or sequential combined chemotherapy for metastasizing colorectal cancer was rarely performed.

Creatine has no beneficial effect on skeletal muscle energy metabolism in patients with single mitochondrial DNA deletions: a placebo-controlled, double-blind 31P-MRS crossover study.

The purpose of our randomized, double-blind, placebo-controlled crossover study in 15 patients with chronic progressive external ophthalmoplegia (CPEO) or Kearns-Sayre syndrome (KSS) because of single large-scale mitochondrial (mt) DNA deletions was to determine whether oral creatine (Cr) monohydrate can improve skeletal muscle energy metabolism in vivo. Each treatment phase with Cr in a dosage of 150 mg/kg body weight/day or placebo lasted 6 weeks. The effect of Cr was estimated by phosphorus-31 magnetic resonance spectroscopy ((31)P-MRS), clinical and laboratory tests. (31)P-MRS analysis prior to treatment showed clear evidence of severe mitochondrial dysfunction. However, there were no relevant changes in (31)P-MRS parameters under Cr. In particular, phosphocreatine (PCr)/ATP at rest did not increase, and there was no facilitation of post-exercise PCr recovery. Clinical scores and laboratory tests did not alter significantly under Cr, which was tolerated without major side-effects in all patients. Cr supplementation did not improve skeletal muscle oxidative phosphorylation in our series of patients. However, one explanation for our negative findings may be the short study duration or the limited number of patients included.

Asymptomatic atopy is associated with increased indoleamine 2,3-dioxygenase activity and interleukin-10 production during seasonal allergen exposure.

BACKGROUND: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan (TRP)-catabolizing enzyme with regulatory effects on T cells. T cell inhibition is achieved through both TRP depletion and TRP metabolite accumulation in specific local tissue microenvironments. The expression of IDO activity by different types of antigen-presenting cells (APCs) has been shown to play a role in many instances of immunoregulation and tolerance induction. Induction of IDO after the engagement of the high-affinity receptor for IgE, FcepsilonRI, on atopic monocytes has been suggested to regulate T cell responses in atopic disorders. Interleukin-10 (IL-10), a cytokine known for its down-regulatory functions in the immune system, has recently been associated with the stable expression of IDO in mature tolerogenic dendritic cells. OBJECTIVE: This study was devised to understand the role of systemic IDO and IL-10 in the prevention of clinical apparent allergy. METHODS: The concentration of TRP and the break-down product kynurenine were measured by high-performance liquid chromatography in- and off-season in sera from patients with seasonal allergic rhinitis (n=12) and from clinically asymptomatic atopic patients sensitized to specific aeroallergens (n=12). Non-atopic (NA) individuals (n=12) served as control. The concentration of plasma IL-10 was determined in parallel from these donors by ELISA in- and off-season. RESULTS: In clinically unresponsive but aeroallergen-sensitized atopic individuals significantly higher systemic activity of IDO and increased plasma IL-10 levels were found during allergen exposure but not off-season compared to symptomatic atopic individuals with allergic rhinitis and NA individuals. CONCLUSION: Enhanced systemic IDO activity as well as increased systemic levels of IL-10 may contribute to the containment of allergic T cell responses and could be involved in the maintenance of a state of clinical unresponsiveness.

Linkage analysis of asthma and atopy including models with genomic imprinting.

Asthma and atopy are two closely related, common complex traits in which a number of genetic and environmental factors are suspected to play a role. We have performed parametric and nonparametric multi-marker linkage analysis for the Busselton data set, which is part of problem 1 of Genetic Analysis Workshop 12. In particular, we have focused on the dichotomous trait atopy, as well as on dichotomized versions of the quantitative traits RASTI and loge slope. The lod score analysis with adequate modeling of a parent-of-origin effect, by use of the program GENEHUNTER-IMPRINTING, was a special interest. The most prominent findings are a multipoint mod score of 3.12 at D13S153 for RASTI, and a multipoint mod score of 4.32 at the same locus for atopy, both with four-penetrance imprinting models that point to a gene subject to maternal imprinting. In addition, there are marked differences between imprinting and non-imprinting mod scores. These results corroborate earlier findings of linkage between atopy and D13S153, but add the aspect of paternal gene expression. Furthermore, suggestive evidence for linkage to atopy is found near D6S291, D7S530, and D14S74. The best-fitting models for chromosome 6 and 14 may suggest that genomic imprinting takes plae at these two loci as well.