A multivariate analysis of prognostic factors for melanoma patients with lesions greater than or equal to 3.65 mm in thickness. The importance of revealing alternative Cox models.

Fourteen prognostic factors were examined in 79 patients with clinical Stage I melanoma greater than or equal to 3.65 mm in thickness. All nine patients with melanoma of the hands or feet died of melanoma. A Cox proportional hazards (multivariate) analysis of the remaining 70 patients showed that a combination of the following four variables best predicted bony or visceral metastases: 1) a nearly absent or minimal lymphocyte response at the base of the tumor, 2) histologic type other than superficial spreading melanoma, 3) location on the trunk, and 4) positive nodes or no initial node dissection. Ulceration and/or ulceration width were not useful in predicting outcome either singly or in combination with other variables. Patients with negative lymph nodes and primary tumors of the trunk, hands, and feet did not do better than patients with positive nodes at those sites. Conversely, non of 16 patients with negative lymph nodes and extremity melanomas (excluding the hands and feet) or head and neck melanomas developed visceral or bony metastases (i.e., five-year disease-free survival rate 100%).     

Selegiline orally disintegrating tablets for the treatment of Parkinson's disease

Selegiline orally disintegrating tablet is a potent, selective and irreversible inhibitor of monoamine oxidase type B. It is delivered in an innovative formulation that largely bypasses the gut and first-pass hepatic metabolism by allowing transbuccal absorption. Selegiline orally disintegrating tablet dissolves in the mouth within seconds and is rapidly absorbed directly into the systemic circulation, increasing parent drug bioavailability and lowering plasma metabolites compared with conventional oral formulations. Adding selegiline orally disintegrating tablet to levodopa in patients experiencing 'wearing-off' episodes significantly decreases off time and increases dyskinesia-free 'on' time. Adding selegiline orally disintegrating tablet to levodopa also significantly improves Unified Parkinson's Disease Rating Scale motor scores and patients' and physicians' ratings of disease severity. Selegiline orally disintegrating tablet has been demonstrated to be safe and well tolerated in placebo-controlled clinical trials.     

RPE cells resist bystander killing by CTLs, but are highly susceptible to antigen-dependent CTL killing

PURPOSE: Retinal pigmented epithelial (RPE) cells maintain the blood-retinal barrier, sustain retinal photoreceptor cell health and function, and may play a role in ocular immune privilege. If RPE immunomodulatory activities were antigen specific, their expression would require antigen presentation. In a study of antigen processing and major histocompatibility complex (MHC) class I-restricted presentation by RPE cells, the cells' sensitivity to the activity of cytotoxic T lymphocytes (CTLs) was determined. METHODS: RPE was cultured, with and without proinflammatory cytokines and antigen, followed by the addition of beta-galactosidase (beta-gal)-specific CTLs. Cytotoxic activity was measured by the CTL-dependent activation of caspase-3 in the RPE. Sensitivity to the CTLs was used to evaluate the activity of pathways of antigen processing and presentation using an antigen (beta-gal) that was either applied to or expressed in RPE. RESULTS: RPE cells were sensitive targets for activated CTL-mediated killing in vitro only if prepulsed with cognate peptide, or if beta-gal-expressing RPE was pretreated to induce upregulation of immunoproteasome. Activated CTLs induced apoptosis in RPE within 3 hours of coculture with antigen-positive RPE monolayers. Application of CTLs in a resting state to antigen-positive RPE led to their activation in the absence of exogenous antigen-presenting cells (APCs). This antigen-dependent activation and killing required 24 hours of co-incubation of RPE with resting CD8 T cells specific for beta-gal. Although RPE cells are highly phagocytic, functional evidence for processing that allowed phagocytosed antigens to load into class I MHC was not detected. RPE was minimally sensitive to bystander killing by activated CTLs. CONCLUSIONS: Although there are many reports of T-cell inhibition by RPE, we found that CTLs efficiently killed RPE cells by induction of apoptosis in an antigen-dependent manner. The survival of RPE in the face of extensive CTL destruction of adjacent photoreceptor cells in vivo appears to be based on their insensitivity to injury via bystander mechanisms.