MIR21 drives resistance to Heat Shock Protein 90 inhibition in cholangiocarcinoma

Cholangiocarcinomas (CCA) are resistant to chemotherapy, so new therapeutic agents are needed. We performed a screen to identify small molecule compounds that are active against CCAs. Levels of microRNA 21 (MIR21 or miRNA21) are increased in CCAs. We investigated whether miRNA21 mediates resistance of CCA cells and organoids to HSP90 inhibitors

Predictive value of early magnetic resonance imaging measures is differentially affected by the dose of interferon beta-1a given subcutaneously three times a week: an exploratory analysis of the PRISMS study

Background: On-treatment magnetic resonance imaging lesions may predict long-term clinical outcomes in patients receiving interferon β-1a. This study aimed to assess the effect of active T2 and T1 gadolinium-enhancing (Gd+) lesions on relapses and 3-month confirmed Expanded Disability Status Scale (EDSS) progression in the PRISMS clinical trial. Methods: Exploratory analyses assessed whether active T2 and T1 Gd + lesions at Month 6, or active T2 lesions at Month 12, predicted clinical outcomes over 4 years in PRISMS. Results: Mean active T2 lesion number at Month 6 was significantly lower with interferon beta-1a given subcutaneously (IFN β-1a SC) 44 μg and 22 μg 3×/week (tiw) than with placebo (p < 0.0001). The presence of ≥4 versus 0 active T2 lesions predicted disability progression at Years 3–4 in the IFN β-1a SC 22 μg group only (p < 0.05), whereas the presence of ≥2 versus 0–1 active T2 lesions predicted disability progression in the placebo/delayed treatment (DTx) (Years 2–4; p < 0.05) and IFN β-1a SC 22 μg groups (Years 3–4; p < 0.05). Greater active T2 lesion number at 6 months predicted relapses in the placebo/DTx group only (≥4 vs. 0, Years 1–4; ≥2 vs. 0–1, Years 2–4; p < 0.05), and the presence of T1 Gd + lesions at 6 months predicted disability progression in the IFN β-1a SC 44 μg group only (Year 1; p < 0.05). The presence of ≥2 versus 0–1 active T2 lesions at 12 months predicted disability progression over 3 and 4 years in the IFN β-1a SC 44 μg group. Conclusion: Active T2 lesions at 6 months predicted clinical outcomes in patients receiving placebo or IFN β-1a SC 22 μg, but not in those receiving IFN β-1a SC 44 μg. Active T2 lesions at 12 months may predict outcomes in those receiving IFN β-1a SC 44 μg and are possibly more suggestive of poor response to therapy than T2 results at 6 months.Other UBCNon UBCReviewedFacult

Effect of interferon beta-1a subcutaneously three times weekly on clinical and radiological measures and no evidence of disease activity status in patients with relapsing–remitting multiple sclerosis at year 1

Background: In the PRISMS study, interferon beta-1a subcutaneously (IFN β-1a SC) reduced clinical and radiological disease burden at 2 years in patients with relapsing–remitting multiple sclerosis. The study aimed to characterize efficacy of IFN β-1a SC 44 μg and 22 μg three times weekly (tiw) at Year 1. Methods: Exploratory endpoints included annualized relapse rate (ARR), 3-month confirmed disability progression (1-point Expanded Disability Status Scale increase if baseline was < 6.0 [0.5-point if baseline was ≥6.0]), active T2 lesions, and no evidence of disease activity (NEDA; defined as no relapses [subanalyzed by relapse severity], 3-month confirmed progression, or active T2 lesions). Effect of IFN β-1a SC in prespecified patient subgroups was also assessed. Results: Patients were randomized to IFN β-1a 22 μg (n = 189), 44 μg (n = 184), or placebo (n = 187). At 1 year, IFN β-1a SC tiw reduced ARR (p < 0.001), risk of disability progression (p ≤ 0.029), and mean number of active T2 lesions per patients per scan (p < 0.001) versus placebo. Clinical and radiological benefits were seen as early as Month 2 and 3. Outcomes in subgroups were consistent with those in the overall population. More patients treated with IFN β-1a SC tiw achieved NEDA status, versus placebo, regardless of relapse severity (p ≤ 0.006). Conclusion: Clinical, radiological, and NEDA outcomes at Year 1 were consistent with Year 2 results. Treatment efficacy was consistent in pre-specified patient subgroups.Other UBCNon UBCReviewedFacult

Teriflunomide vs injectable disease modifying therapies for relapsing forms of MS

Multiple sclerosis (MS) is a chronic, immune-mediated, inflammatory disease affecting the white and gray matter of the central nervous system. Several disease modifying therapies (DMTs) have been shown to significantly reduce relapse rates, slow disability worsening, and modify the overall disease course of MS. Decision-making when initiating a DMT should be shared between the patient and physician. Important factors such as prognostic indicators, safety, patient preferences, adherence, and convenience should also be considered. Treatment guidelines recommend switching a DMT when a patient experiences breakthrough disease activity, but also for patients who experience adverse events. Compared with injectable therapies, oral DMTs are often associated with increased treatment adherence and patient satisfaction, due to a less burdensome route of administration and greater tolerability. This review will summarize the available scientific evidence for injectable DMTs and the oral DMT teriflunomide, including considerations for both treatment-naïve patients initiating a DMT and patients switching from an injectable DMT

Additional file 2: of Predictive value of early magnetic resonance imaging measures is differentially affected by the dose of interferon beta-1a given subcutaneously three times a week: an exploratory analysis of the PRISMS study

Figure S2. Proportion with EDSS progression at each year in the placebo/delayed treatment and IFN β-1a 44 μg SC tiw groups by ≥4 versus 0 active T2 lesions at 6 months. (PDF 189 kb

Phase IV study of retention on fingolimod versus injectable multiple sclerosis therapies: a randomized clinical trial.

Objective:In relapsing-remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon β-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFERMS, a randomized, parallel-group, active-controlled, open-label, 48-week study. Methods:Patients were included if they had RRMS, were aged 18-65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function. Results:Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4-57.8%; p &lt; 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment. Conclusions:In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes

Teriflunomide vs injectable disease modifying therapies for relapsing forms of MS

Multiple sclerosis (MS) is a chronic, immune-mediated, inflammatory disease affecting the white and gray matter of the central nervous system. Several disease modifying therapies (DMTs) have been shown to significantly reduce relapse rates, slow disability worsening, and modify the overall disease course of MS. Decision-making when initiating a DMT should be shared between the patient and physician. Important factors such as prognostic indicators, safety, patient preferences, adherence, and convenience should also be considered. Treatment guidelines recommend switching a DMT when a patient experiences breakthrough disease activity, but also for patients who experience adverse events. Compared with injectable therapies, oral DMTs are often associated with increased treatment adherence and patient satisfaction, due to a less burdensome route of administration and greater tolerability. This review will summarize the available scientific evidence for injectable DMTs and the oral DMT teriflunomide, including considerations for both treatment-naïve patients initiating a DMT and patients switching from an injectable DMT.publishedVersio

Phase IV study of retention on fingolimod injectable multiple sclerosis therapies: a randomized clinical trial

Objective: In relapsing–remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon β-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFER MS , a randomized, parallel-group, active-controlled, open-label, 48-week study. Methods: Patients were included if they had RRMS, were aged 18–65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function. Results: Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4–57.8%; p < 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment. Conclusions: In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes

Additional file 1: of Predictive value of early magnetic resonance imaging measures is differentially affected by the dose of interferon beta-1a given subcutaneously three times a week: an exploratory analysis of the PRISMS study

Figure S1. Proportion with EDSS progression at each year by ≥2 versus 0–1 active T2 lesions at 6 months. (a) Placebo/delayed treatment group; (b) IFN β-1a 22 μg SC tiw group; (c) IFN β-1a 44 μg SC tiw group. (PDF 258 kb

Additional file 3: of Predictive value of early magnetic resonance imaging measures is differentially affected by the dose of interferon beta-1a given subcutaneously three times a week: an exploratory analysis of the PRISMS study

Table S1. (a) Performance of T2 lesions on predicting EDSS progression at Year 2 and Year 4. (b) Performance of T2 lesions on predicting relapse at Year 2 and Year 4. (DOCX 15 kb