Vigabatrin-Induced Peripheral Visual Field Defects in Patients With Refractory Partial Epilepsy

Purpose: Vigabatrin can cause retinopathy, resulting in bilateral visual field constriction. Previous analyses of results from a prospective, observational study assessing vigabatrin-induced visual field constriction (described below) employed a partially subjective interpretation of static perimetery. In an effort to affirm these previous findings through more objective, quantitative methodology, we now report data from a subset analysis of refractory partial epilepsy patients in the study who underwent Goldmann kinetic perimetry. Methods: Patients aged ≥8 years with refractory partial seizures were enrolled and grouped: those receiving vigabatrin for ≥6 months (Group I); those who had received vigabatrin for ≥6 months and then had discontinued for ≥6 months (Group II); and those naïve to vigabatrin (Group III). Patients underwent static or kinetic perimetry or both every 4–6 months for ≤3 years. For kinetic perimetry, the temporal and nasal visual fields were measured along the horizontal meridian with the largest (V4e, IV4e) and smallest (I2e, I1e) isopters, respectively. Results: Of 735 patients enrolled, 341 had Goldmann perimetry data. Of these, 258 received vigabatrin. Sixteen percent of vigabatrin-exposed patients had moderate visual field defects (30°–60° retained temporal vision), and 3% had severe defects (\u3c30° retained temporal vision). Visual function questionnaire results indicated a weak correlation between visual field constriction severity and visual symptoms. Conclusions: These results affirm both an analysis of the same study based primarily on static perimetry and findings from cross-sectional studies. The present analysis verifies that visual field constriction, when it occurs, is most often mild or moderate and is not associated with symptoms of abnormal visual function. The clinical decision to prescribe vigabatrin should be based on a benefit-risk analysis for each individual patient

Optimal testing of multiple hypotheses with common effect direction

We present a theoretical basis for testing related endpoints. Typically, it is known how to construct tests of the individual hypotheses, but not how to combine them into a multiple test procedure that controls the familywise error rate. Using the closure method, we emphasize the role of consonant procedures, from an interpretive as well as a theoretical viewpoint. Surprisingly, even if each intersection test has an optimality property, the overall procedure obtained by applying closure to these tests may be inadmissible. We introduce a new procedure, which is consonant and has a maximin property under the normal model. The results are then applied to PROactive, a clinical trial designed to investigate the effectiveness of a glucose-lowering drug on macrovascular outcomes among patients with type 2 diabete

Organ-specific inhibition of metastatic colon carcinoma by CXCR3 antagonism

Liver and lung metastases are the predominant cause of colorectal cancer (CRC)-related mortality. Recent research has indicated that CXCR3/chemokines interactions that orchestrate haematopoetic cell movement are implicated in the metastatic process of malignant tumours, including that of CRC cells to lymph nodes. To date, however, the contribution of CXCR3 to liver and lung metastasis in CRC has not been addressed. To determine whether CXCR3 receptors regulate malignancy-related properties of CRC cells, we have used CXCR3-expressing CRC cell lines of human (HT29 cells) and murine (C26 cells) origins that enable the development of liver and lung metastases when injected into immunodeficient and immunocompetent mice, respectively, and assessed the effect of CXCR3 blockade using AMG487, a small molecular weight antagonist. In vitro, activation of CXCR3 on human and mouse CRC cells by its cognate ligands induced migratory and growth responses, both activities being abrogated by AMG487. In vivo, systemic CXCR3 antagonism by preventive or curative treatments with AMG487 markedly inhibited the implantation and the growth of human and mouse CRC cells within lung without affecting that in the liver. In addition, we measured increased levels of CXCR3 and ligands expression within lung nodules compared with liver tumours. Altogether, our findings indicate that activation of CXCR3 receptors by its cognate ligands facilitates the implantation and the progression of CRC cells within lung tissues and that inhibition of this axis decreases pulmonary metastasis of CRC in two murine tumour models

Optimal testing of multiple hypotheses with common effect direction

We present a theoretical basis for testing related endpoints. Typically, it is known how to construct tests of the individual hypotheses, and the problem is how to combine them into a multiple test procedure that controls the familywise error rate. Using the closure method, we emphasize the role of consonant procedures, from an interpretive as well as a theoretical viewpoint. Suprisingly, even if each intersection test has an optimality property, the overall procedure obtained by applying closure to these tests may be inadmissible. We introduce a new procedure, which is consonant and has a maximin property under the normal model. The results are then applied to PROactive, a clinical trial designed to investigate the effectiveness of a glucose-lowering drug on macrovascular outcomes among patients with type 2 diabetes.Closure Method, Consonance, Familywise Error Rate, Multiple Endpoints, Multiple Testing, O’Brien’s method.