Severe relapse in a multiple sclerosis patient associated with ipilimumab treatment of melanoma Dear EditorWe are writing about a case of relapse in a patient with previously stable relapsing-remitting multiple sclerosis (RRMS) after treatment with ipilimumab (BristolMyers Squibb Co., New York, NY) for metastatic melanoma. Ipilimumab is a humanized monoclonal antibody for treatment of malignant melanoma. The mechanism of action involves blocking CTLA-4, a cell surface molecule on T cells that downregulates T cell activation by binding CD80 and CD86. Ipilimumab enhances the anti-tumoral response while increasing the likelihood of autoimmunity. 1 Adverse effects include colitis and dermatitis and there are recent reports of neurological complications, but none affecting MS. [2][3][4]

Telomere attrition ultimately leads to the activation of protective cellular responses, such as apoptosis or senescence. Impairment of such mechanisms can allow continued proliferation despite the presence of dysfunctional telomeres. Under such conditions, high levels of genome instability are often engendered. Data from both mouse and human model systems indicate that a period of genome instability might facilitate tumorigenesis. Here, we use a liposarcoma model system to assay telomere maintenance mechanism (TMM)-specific genetic alterations. A multiassay approach was used to assess the TMMs active in tumors. Genomic DNA from these samples was then analyzed by high-resolution DNA mapping array to identify genetic alterations. Our data reveal a higher level of genome instability in alternative lengthening of telomere (ALT)-positive tumors compared with telomerase-positive tumors, whereas tumors lacking both mechanisms have relatively low levels of genome instability. The bulk of the genetic changes are amplifications, regardless of the mode of telomere maintenance used. We also identified genetic changes specific to the ALT mechanism (e.g., deletion of chromosome 1q32.2-q44) as well as changes that are underrepresented among ALT-positive tumors, such as amplification of chromosome 12q14.3-q21.2. Taken together, these studies provide insight into the molecular pathways involved in the regulation of ALT and reveal several loci that might be exploited either as prognostic markers or targets of chemotherapeutic intervention. [Cancer Res 2007;67(19):9221-8]

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The degree to which relapses with incomplete recovery (RW) contribute to the overall picture of worsening disability in relapse-onset multiple sclerosis (RMS) remains unclear. 1,2 Clarification of this issue may determine the extent to which elimination of relapses through immunotherapy can result in long-term benefits. Incomplete recovery from relapses implies a contribution of these circumscribed events to the irreversible process of tissue destruction. 3,4 Better understanding of the impact of relapses vs slow progression may also help us understand the complex relationship between inflammation vs degeneration, which evolves over a lifetime of RMS. Some epidemiologists opine that the majority of disability accumulated in MS over time results from a more or less degenerative process involving slow progression, whereas relapses contribute little to the long-term picture. 5 This view is challenged in more recent studies. 6,7 We sought to calculate the frequency of RW in the first 15 years of longitudinally followed RMS patients, using a clinical definition of incomplete recovery from relapse, and to compare the frequency of year-to-year slow progressive worsening (PW). Furthermore, we 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. K E Y W O R D S expanded disability status scale, MS, progression, relapse | 337 SCOTT eT al.

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