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- Chapple, Christopher R, et al.
(author)
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Multicriteria Decision Analysis Applied to the Clinical Use of Pharmacotherapy for Overactive Bladder Symptom Complex
- 2020
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In: European urology focus. - : Elsevier BV. - 2405-4569. ; 6:3, s. 522-530
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Journal article (peer-reviewed)abstract
- The nonspecific storage symptom complex overactive bladder (OAB) is an important clinical condition in functional urology. Until recently, pharmacological therapy comprised antimuscarinic drugs, but more recently beta 3 agonists have added to the available agents. Traditional reporting of efficacy and safety of these agents relies upon regulatory placebo-controlled studies. There remains no head-to-head comparison of existing agents in the contemporary literature. Contemporary conclusions on comparative efficacy and safety drawn from the use of these agents are based on systematic reviews of the literature and associated meta-analyses.In this study, we used the analytical model of multicriteria decision analysis (MCDA) to compare contemporary pharmacotherapy for OAB.Efficacy and safety data from published, randomised, placebo-controlled trials of antimuscarinic antagonists, the beta 3 agonist, and the combination of an antimuscarinic and beta 3 agonist were used to populate the MCDA model.Experts assessed weights of the relative importance of favourable and unfavourable effects, which provided a common measure of benefits and safety that were combined in the MCDA model to give an overall ranking of the OAB drugs.When benefits are judged as more important than safety, fesoterodine 4 or 8mg used in a flexible dosing pattern provides the most favourable therapeutic option, over a wide sensitivity analysis relating to benefits and harms.In our analysis using an MCDA model, in both the flexible dosing pattern of fesoterodine and the solifenacin combination with mirabegron, the benefit-safety balance is better in terms of benefits and/or safety than any of the other available OAB drugs. Caution in interpretation of the data has to be expressed as the fesoterodine data are based on a flexible dosing regimen, which adds an additional dimension of personalising therapy.Overactive bladder (OAB) is a common condition with a significant impact on the quality of life. Possible symptoms include the following: (1) urgency-a compelling desire to urinate, which is difficult to defer; (2) urgency urinary incontinence-urgency leading to incontinence episodes; (3) frequency-increased frequency of wanting to pass urine; and (4) nocturia-increase in instances of getting up at night to urinate. To date, the mainstay of therapy for OAB has been antimuscarinic drugs and, more recently, the beta 3 agonist mirabegron. Ten international experts in urology, obstetrics, gynaecology, healthy ageing, and data analysis compared the benefit-risk balance of 14 OAB drugs licensed in Europe. The experts considered the importance of a favourable effect on the above four symptoms and also potential for side effects, but only three of these side effects, constipation, dry mouth, and dizziness, showed clinically relevant differences among the six drugs they considered. The observations recorded here suggest interesting differences between drugs across a wide range of possible trade-offs between benefit and safety. The different recruitment criteria used for each study may influence the results seen, so they need to be treated with caution. Comparison of flexibly dosed fesoterodine studies with fixed-dose fesoterodine studies introduces an additional potential bias; definitive conclusions can be drawn only if enough comparable placebo-controlled flexible dosing studies with other drugs were available.
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| 3. |
- Schmidt, Marcus, et al.
(author)
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A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors
- 2012
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 18:9, s. 2695-2703
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Journal article (peer-reviewed)abstract
- PURPOSE:Although the central role of the immune system for tumor prognosis is generally accepted a single robust marker is not yet available.EXPERIMENTAL DESIGN:Based on ROC (receiver operating characteristic) analyses robust markers were identified from a 60 gene B-cell derived metagene and analyzed in gene expression profiles of 1810 breast cancer, 1056 non-small cell lung cancer, 513 colorectal and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin embedded tissue of 330 breast cancer patients. The cell types were identified using immunohistochemical co-staining and confocal fluorescence microscopy.RESULTS:We identified immunoglobulin kappa C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis free survival across different molecular subtypes in node-negative breast cancer (n=965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n=845) [P less than 0.001]. In addition, IGKC gene expression was prognostic in non-small cell lung cancer and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin embedded tissues of 330 breast cancer patients. Tumor infiltrating plasma cells were identified as the source of IGKC expressionCONCLUSION:Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anti-cancer therapy. It could be validated in several independent cohorts and performed similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining.
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