Outcomes in a Modern Cohort of Treated Patients with Multiple Sclerosis from Diagnosis Up to 15 Years.

BACKGROUND: Before disease-modifying therapies (DMTs) were available, the natural history of multiple sclerosis (MS) regarding attainment of accepted disability milestones was reported with fairly wide variance comparing outcomes across studies. The influence of DMTs on these outcomes is unknown. This study aimed to calculate attainment of disability milestones during the first 15 years after onset of DMT-treated relapsing forms of MS (RMS). METHODS: As a retrospective study, all available disability data (collected routinely) on all newly diagnosed patients with RMS seen and initially diagnosed in a single clinic between 1989 and 2006 were reviewed. Times from first symptoms and diagnosis until first treatment with DMTs were also reviewed. Time-to-event statistics were applied using disability milestones. RESULTS: Mean follow-up of 184 adult patients from symptom onset was 13.7 years. Of patients followed up for 15 years after onset, 16 of 86 (19%) reached an Expanded Disability Status Scale (EDSS) score of 6.0. Estimated median time to reach an EDSS score of 3.0 was 10.7 years and to reach an EDSS score of 4.0 was 18.1 years. CONCLUSIONS: There were striking differences between the present results and older data sets and similar results to the few available modern data sets. This analysis of a modern treated RMS cohort provides outcomes data that may be compared favorably with the natural history of RMS.

Multiple sclerosis relapses contribute to long-term disability.

BACKGROUND: Treatments affect both relapse-related disability and short-term disability change, but measurements of their impact on long-term outcomes remain a challenge. OBJECTIVE: To ascertain the contribution of relapse-associated disability to overall disability in relapse-onset multiple sclerosis (RMS) using long-term data collected in our clinic. MATERIALS AND METHODS: Retrospective study of a cohort of newly diagnosed patients with RMS, (n = 176) was undertaken, measuring all confirmed changes in disability up to 15 years after onset. Worsening was assessed yearly and in 5-year epochs and was attributed to either relapse (RW) or slow progression (PW). RESULTS: At data lock, 139/176 (81%) of patients were still actively followed, with Expanded Disability Status Scale (EDSS) available for 10 years post-onset in 145/176 (82%) patients and 15 years post-onset EDSS in 83 patients (mean follow-up entire group 12.7 years post-onset). RW accounted for a large amount of worsening seen in the first 15 years of RMS. RW was less frequent over time, but accounted for most EDSS changes in the first decade of MS (167/267, 63% of EDSS changes), and remained important even in years 11-15 (17/50, 34% of EDSS changes). Median change in disability due to RW vs PW was similar over the entire 15 years. CONCLUSIONS: Worsening of treated MS was associated with relapses in many RMS patients throughout the first 15 years after onset, suggesting an opportunity for long-term benefit through relapse reduction.

Akt and autophagy cooperate to promote survival of drug-resistant glioma.

Although the phosphatidylinositol 3-kinase to Akt to mammalian target of rapamycin (PI3K-Akt-mTOR) pathway promotes survival signaling, inhibitors of PI3K and mTOR induce minimal cell death in PTEN (phosphatase and tensin homolog deleted from chromosome 10) mutant glioma. Here, we show that the dual PI3K-mTOR inhibitor PI-103 induces autophagy in a form of glioma that is resistant to therapy. Inhibitors of autophagosome maturation cooperated with PI-103 to induce apoptosis through the mitochondrial pathway, indicating that the cellular self-digestion process of autophagy acted as a survival signal in this setting. Not all inhibitors of mTOR synergized with inhibitors of autophagy. Rapamycin delivered alone induced autophagy, yet cells survived inhibition of autophagosome maturation because of rapamycin-mediated activation of Akt. In contrast, adenosine 5'-triphosphate-competitive inhibitors of mTOR stimulated autophagy more potently than did rapamycin, with inhibition of mTOR complexes 1 and 2 contributing independently to induction of autophagy. We show that combined inhibition of PI3K and mTOR, which activates autophagy without activating Akt, cooperated with inhibition of autophagy to cause glioma cells to undergo apoptosis. Moreover, the PI3K-mTOR inhibitor NVP-BEZ235, which is in clinical use, synergized with the lysosomotropic inhibitor of autophagy, chloroquine, another agent in clinical use, to induce apoptosis in glioma xenografts in vivo, providing a therapeutic approach potentially translatable to humans.