Pub Date : 2020-01-02DOI: 10.1080/21678421.2019.1675709
T. Vlaar, A. Elbaz, F. Moisan
Abstract Objective: Previous studies, mostly from the United States, showed an increased risk of motor neuron disease (MND) in military personnel. We compared MND incidence rates in French military personnel to that in the general population. Methods: Among persons covered between 2010 and 2016 by the Caisse Nationale Militaire de Sécurité Sociale (CNMSS, military personnel) and the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés (CNAMTS, general population) aged ≥50 years, we identified incident MND cases and estimated populations at risk using national health insurance databases. We estimated relative risks (RRs) and 95% confidence intervals (CIs) separately for men and women using age-adjusted Poisson regression. Analyses were also stratified by 10-year age groups. We used the E-value approach and probabilistic bias analysis to assess robustness of the results regarding unmeasured confounding by smoking. Results: On average, 25 cases/year were newly diagnosed with MND among military personnel aged ≥50 years. The incidence rate was higher for male military personnel compared to the general population (RR = 1.16; 95% CI = 1.05–1.29) but was similar for women (RR = 1.02; 95% CI = 0.79–1.31). Although there were no significant interactions with age and sex, the association was mainly explained by men aged 70–79 years. The prevalence of ever-smoking should be at least 1.1-fold higher in male CNMSS compared to male CNAMTS members to make the association in male military personnel not significant. Conclusion: MND incidence was 16% higher in French male military personnel, in agreement with studies from other countries. Smoking may contribute to this finding. Further studies are needed to identify exposures that drive this association.
{"title":"Is the incidence of motor neuron disease higher in French military personnel?","authors":"T. Vlaar, A. Elbaz, F. Moisan","doi":"10.1080/21678421.2019.1675709","DOIUrl":"https://doi.org/10.1080/21678421.2019.1675709","url":null,"abstract":"Abstract Objective: Previous studies, mostly from the United States, showed an increased risk of motor neuron disease (MND) in military personnel. We compared MND incidence rates in French military personnel to that in the general population. Methods: Among persons covered between 2010 and 2016 by the Caisse Nationale Militaire de Sécurité Sociale (CNMSS, military personnel) and the Caisse Nationale d’Assurance Maladie des Travailleurs Salariés (CNAMTS, general population) aged ≥50 years, we identified incident MND cases and estimated populations at risk using national health insurance databases. We estimated relative risks (RRs) and 95% confidence intervals (CIs) separately for men and women using age-adjusted Poisson regression. Analyses were also stratified by 10-year age groups. We used the E-value approach and probabilistic bias analysis to assess robustness of the results regarding unmeasured confounding by smoking. Results: On average, 25 cases/year were newly diagnosed with MND among military personnel aged ≥50 years. The incidence rate was higher for male military personnel compared to the general population (RR = 1.16; 95% CI = 1.05–1.29) but was similar for women (RR = 1.02; 95% CI = 0.79–1.31). Although there were no significant interactions with age and sex, the association was mainly explained by men aged 70–79 years. The prevalence of ever-smoking should be at least 1.1-fold higher in male CNMSS compared to male CNAMTS members to make the association in male military personnel not significant. Conclusion: MND incidence was 16% higher in French male military personnel, in agreement with studies from other countries. Smoking may contribute to this finding. Further studies are needed to identify exposures that drive this association.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"107 - 115"},"PeriodicalIF":2.8,"publicationDate":"2020-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1675709","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44556353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-02DOI: 10.1080/21678421.2019.1675282
ALSUntangled reviews alternative and off-label therapies (AOTs) for people with ALS (PALS). Here we provide our opinion on RCH4, for which we have had more than 1700 requests (1). We were first asked to review this product 3 years ago by the family member of a person with ALS. Since then, in spite of our best efforts, we have not been able to obtain much useful disclosable information on RCH4. We define “useful” as information that helps us describe exactly what a product is and helps us complete our Table of Evidence (2). “Disclosable” means information that is in the public domain or that we have been given permission to discuss in a public forum. Since it does not appear to us that any new useful disclosable information is forthcoming, we elected to move forward with the information we have. This is the first and only ALSUntangled review on RCH4. A previous unfavorable review of this product by a person with ALS on their blog (3) has been inaccurately attributed to ALSUntangled (4,5). While this person has done valuable work with our team before, he has clearly stated that his RCH4 review is separate from any work he has done with us and was not formulated using ALSUntangled standard operating procedures (SOPs) which includes review by our international team of clinicians and scientists.
{"title":"ALSUntangled 51: RCH4","authors":"","doi":"10.1080/21678421.2019.1675282","DOIUrl":"https://doi.org/10.1080/21678421.2019.1675282","url":null,"abstract":"ALSUntangled reviews alternative and off-label therapies (AOTs) for people with ALS (PALS). Here we provide our opinion on RCH4, for which we have had more than 1700 requests (1). We were first asked to review this product 3 years ago by the family member of a person with ALS. Since then, in spite of our best efforts, we have not been able to obtain much useful disclosable information on RCH4. We define “useful” as information that helps us describe exactly what a product is and helps us complete our Table of Evidence (2). “Disclosable” means information that is in the public domain or that we have been given permission to discuss in a public forum. Since it does not appear to us that any new useful disclosable information is forthcoming, we elected to move forward with the information we have. This is the first and only ALSUntangled review on RCH4. A previous unfavorable review of this product by a person with ALS on their blog (3) has been inaccurately attributed to ALSUntangled (4,5). While this person has done valuable work with our team before, he has clearly stated that his RCH4 review is separate from any work he has done with us and was not formulated using ALSUntangled standard operating procedures (SOPs) which includes review by our international team of clinicians and scientists.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"150 - 153"},"PeriodicalIF":2.8,"publicationDate":"2020-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1675282","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42427900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-02DOI: 10.1080/21678421.2019.1663872
Lu Chen, Lu Tang, D. Fan
Abstract Objectives: To analyze the clinical features of flail arm syndrome (FAS) in a large Chinese clinic-based cohort, and to discuss whether it is proper to use a course of 12 months from symptoms onset as the criterion for FAS. Methods: This cohort study included patients with FAS or upper-limb-onset amyotrophic lateral sclerosis (UL-ALS) who visited Peking University Third Hospital between 2003 and 2013. Patients with FAS were diagnosed according to Wijesekera’s definition, and patients fulfilling all the diagnostic criteria of FAS except that the course of disease was less than 12 months were defined as “FAS-type ALS”. Group differences were analyzed using parametric and nonparametric tests as appropriate. Survival was analyzed using the Kaplan–Meier method and a Cox regression model. Results: One thousand nine hundred and thirty-five patients with ALS were recruited in the database, including 131 patients with FAS or FAS-type ALS and 767 with UL-ALS. The prognosis of FAS was significantly better than that of UL-ALS (p = 0.024) and FAS-type ALS (p < 0.0005), and the survival of patients with FAS-type ALS was worse than that of UL-ALS (p = 0.002). The difference in survival between those with proximal FAS (pFAS) and distal FAS (dFAS) (p = 0.188) was not significant. Conclusion: Since the prognosis of FAS-type ALS was significantly worse than that of FAS, our data suggest that a FAS subphenotype can be established after 12 months from first symptoms. It is important to note that FAS-type ALS phenotype may carry a worse prognosis than that of patients with UL-ALS.
{"title":"Twelve-month duration as an appropriate criterion for flail arm syndrome","authors":"Lu Chen, Lu Tang, D. Fan","doi":"10.1080/21678421.2019.1663872","DOIUrl":"https://doi.org/10.1080/21678421.2019.1663872","url":null,"abstract":"Abstract Objectives: To analyze the clinical features of flail arm syndrome (FAS) in a large Chinese clinic-based cohort, and to discuss whether it is proper to use a course of 12 months from symptoms onset as the criterion for FAS. Methods: This cohort study included patients with FAS or upper-limb-onset amyotrophic lateral sclerosis (UL-ALS) who visited Peking University Third Hospital between 2003 and 2013. Patients with FAS were diagnosed according to Wijesekera’s definition, and patients fulfilling all the diagnostic criteria of FAS except that the course of disease was less than 12 months were defined as “FAS-type ALS”. Group differences were analyzed using parametric and nonparametric tests as appropriate. Survival was analyzed using the Kaplan–Meier method and a Cox regression model. Results: One thousand nine hundred and thirty-five patients with ALS were recruited in the database, including 131 patients with FAS or FAS-type ALS and 767 with UL-ALS. The prognosis of FAS was significantly better than that of UL-ALS (p = 0.024) and FAS-type ALS (p < 0.0005), and the survival of patients with FAS-type ALS was worse than that of UL-ALS (p = 0.002). The difference in survival between those with proximal FAS (pFAS) and distal FAS (dFAS) (p = 0.188) was not significant. Conclusion: Since the prognosis of FAS-type ALS was significantly worse than that of FAS, our data suggest that a FAS subphenotype can be established after 12 months from first symptoms. It is important to note that FAS-type ALS phenotype may carry a worse prognosis than that of patients with UL-ALS.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"29 6","pages":"29 - 33"},"PeriodicalIF":2.8,"publicationDate":"2020-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1663872","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41295381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-02DOI: 10.1080/21678421.2019.1672750
Suma Babu, E. Macklin, K. Jackson, Elizabeth Simpson, K. Mahoney, Hong Yu, Jason Walker, Z. Simmons, W. David, P. Barkhaus, L. Simionescu, M. Dimachkie, A. Pestronk, J. Salameh, M. Weiss, B. Brooks, D. Schoenfeld, J. Shefner, Swati Aggarwal, M. Cudkowicz, N. Atassi
Abstract Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.
{"title":"Selection design phase II trial of high dosages of tamoxifen and creatine in amyotrophic lateral sclerosis","authors":"Suma Babu, E. Macklin, K. Jackson, Elizabeth Simpson, K. Mahoney, Hong Yu, Jason Walker, Z. Simmons, W. David, P. Barkhaus, L. Simionescu, M. Dimachkie, A. Pestronk, J. Salameh, M. Weiss, B. Brooks, D. Schoenfeld, J. Shefner, Swati Aggarwal, M. Cudkowicz, N. Atassi","doi":"10.1080/21678421.2019.1672750","DOIUrl":"https://doi.org/10.1080/21678421.2019.1672750","url":null,"abstract":"Abstract Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial versus placebo. This strategy can find an effective treatment faster than traditional strategy of conducting larger trials against placebo. Methods: Sixty amyotrophic lateral sclerosis (ALS) participants were randomized 1:1:1 to creatine 30 g/day (CRE), tamoxifen 40 mg/day (T40), or tamoxifen 80 mg/day (T80), with matching placebo. The primary outcome was 38-week change in ALS Functional Rating Scale-Revised (ALSFRS-R), analyzed in a repeated-measures ANOVA. Secondary outcomes included slow vital capacity (SVC), quantitative muscle strength, early drug discontinuation (EDD), adverse events (AEs), and survival. Results: CRE participants experienced higher rates of drug-related AEs (82% vs. 43% T40, 47% T80) and EDD (50% vs. 24% T40, 29% T80). T80 participants experienced slower adjusted mean decline in ALSFRS-R in points/month (–0.80 vs. –0.84 T40, –0.85 CRE) and quantitative muscle strength but not in SVC and higher rates of mortality. Conclusion: Efficacy of T80 ranked numerically superior to CRE and T40 with respect to ALSFRS-R decline. Following the selection paradigm, T80 would be chosen to test against placebo. The approach was not designed to distinguish among treatments that are nearly equally effective or ineffective. If treatments are equivalent, then under the paradigm, it does not matter which treatment is selected. Newer approaches for increasing trial efficiency, including an adaptive platform trial design, may mitigate limitations of the selection design.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"15 - 23"},"PeriodicalIF":2.8,"publicationDate":"2020-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1672750","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47101623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-02DOI: 10.1080/21678421.2019.1655060
Nimish J. Thakore, B. Lapin, E. Pioro
Abstract Objectives: To estimate the effect of riluzole on the stage-specific risk of progression of ALS. Methods: Patients from the PRO-ACT dataset were staged employing two methods (King's and FT9). Hazard ratios associated with riluzole treatment were estimated for forward transition between stages, using unadjusted and adjusted Markov multistate models. Results: Of 1903 patients, 1587 had received riluzole. Riluzole-treated patients survived non-significantly longer than those who did not (median 22.9 months vs. 18.3 months from time of initial observation, log rank p = 0.16). After adjusting for age and ALSFRS-R slope at first visit, riluzole significantly reduced risk of the following transitions: (1) King's stages: 1->2 (hazard ratio (HR) = 0.81), and 2->3 (HR = 0.82), 4->death (HR = 0.57), and (2) FT9 stages: 1->2 (HR = 0.84), 3->4 (HR = 0.71), and 4->death (HR = 0.67). In contrast, the beneficial effect of riluzole in bulbar-onset patients was in early rather than late King’s stages. Conclusions: This examination of cohorts closely followed in clinical trials finds a beneficial effect of riluzole that is predominantly but not exclusively in later stages of ALS. This analytic framework has utility to discern stage-specific treatment effects, and for refined health economic analyses.
{"title":"Stage-specific riluzole effect in amyotrophic lateral sclerosis: a retrospective study","authors":"Nimish J. Thakore, B. Lapin, E. Pioro","doi":"10.1080/21678421.2019.1655060","DOIUrl":"https://doi.org/10.1080/21678421.2019.1655060","url":null,"abstract":"Abstract Objectives: To estimate the effect of riluzole on the stage-specific risk of progression of ALS. Methods: Patients from the PRO-ACT dataset were staged employing two methods (King's and FT9). Hazard ratios associated with riluzole treatment were estimated for forward transition between stages, using unadjusted and adjusted Markov multistate models. Results: Of 1903 patients, 1587 had received riluzole. Riluzole-treated patients survived non-significantly longer than those who did not (median 22.9 months vs. 18.3 months from time of initial observation, log rank p = 0.16). After adjusting for age and ALSFRS-R slope at first visit, riluzole significantly reduced risk of the following transitions: (1) King's stages: 1->2 (hazard ratio (HR) = 0.81), and 2->3 (HR = 0.82), 4->death (HR = 0.57), and (2) FT9 stages: 1->2 (HR = 0.84), 3->4 (HR = 0.71), and 4->death (HR = 0.67). In contrast, the beneficial effect of riluzole in bulbar-onset patients was in early rather than late King’s stages. Conclusions: This examination of cohorts closely followed in clinical trials finds a beneficial effect of riluzole that is predominantly but not exclusively in later stages of ALS. This analytic framework has utility to discern stage-specific treatment effects, and for refined health economic analyses.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"140 - 143"},"PeriodicalIF":2.8,"publicationDate":"2020-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1655060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46602615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-02DOI: 10.1080/21678421.2019.1681455
R. V. van Eijk, A. Genge
The randomized, placebo-controlled trial (RCT) has long been recognized as the gold standard for assessing therapeutic benefit. The randomization ensures that both the observed and unobserved prognostic variables are balanced across treatment arms. Many regulatory agencies require, therefore, RCTs to obtain an unbiased estimate of a drug’s risk–benefit ratio. The conduct of a RCT demands, however, a considerable amount of resources and time. The median costs of phase II and III clinical trials are $8.6 million and $21.4 million, respectively (1); costs that are likely to further increase in the near future (2). These excessive expenditures are especially problematic for rare diseases such as amyotrophic lateral sclerosis (ALS), where funding, awareness and resources could be limited. Therefore, there is a need to improve the efficiency of clinical trial design while maintaining scientific rigor. In this issue of the Journal, Babu et al. (3) deviate from the classical two-armed RCT by applying a ranking and selection paradigm in order to determine which of three treatment strategies (i.e., creatine, tamoxifen 40mg or tamoxifen 80mg) is the most promising for a future pivotal trial. Notwithstanding the recent advancements in preclinical and early clinical models, phase II clinical trials are often the first opportunity for investigators to obtain a hint of therapeutic benefit. Improving the phase II selection process of promising ALS drugs is, therefore, essential, especially when one considers the expanding pipeline of ALS compounds (4). The selection paradigm as proposed by Babu et al. may give preliminary insights in the efficacy and safety of new drugs. As patients can only be allocated to active arms, enrollment rates could be positively affected. The lack of a concurrent placebo arm is, however, also its major drawback. This diminishes the interpretation of the safety data and may provide insufficient insight in the therapeutic benefit. In the end, this could lead to the erroneous selection of a treatment. Further refinement of the proposed methodology may help to ameliorate these limitations. In the last decades, there has been a steady increase in the use of innovative or adaptive design elements in RCTs (5), deviating from the fixed sample size, fixed eligibility criteria and fixed allocation ratios as seen in classical trial design. Adaptive designs use the accruing information during a RCT to make interim decisions regarding, for example, the continuation of subgroups, the re-estimation of sample sizes or to stop a trial early. These design adaptation may help to improve the efficiency of clinical trials when there is sufficient evidence for either superiority or futility. Especially the futility adaptations could prove value for ALS clinical trials (6). The probability that a compound will successfully pass the different phases of drug development, including regulatory approval, is less than 10% for rare diseases (7). In case of ALS, th
{"title":"The rise of innovative clinical trial designs: what’s in it for amyotrophic lateral sclerosis?","authors":"R. V. van Eijk, A. Genge","doi":"10.1080/21678421.2019.1681455","DOIUrl":"https://doi.org/10.1080/21678421.2019.1681455","url":null,"abstract":"The randomized, placebo-controlled trial (RCT) has long been recognized as the gold standard for assessing therapeutic benefit. The randomization ensures that both the observed and unobserved prognostic variables are balanced across treatment arms. Many regulatory agencies require, therefore, RCTs to obtain an unbiased estimate of a drug’s risk–benefit ratio. The conduct of a RCT demands, however, a considerable amount of resources and time. The median costs of phase II and III clinical trials are $8.6 million and $21.4 million, respectively (1); costs that are likely to further increase in the near future (2). These excessive expenditures are especially problematic for rare diseases such as amyotrophic lateral sclerosis (ALS), where funding, awareness and resources could be limited. Therefore, there is a need to improve the efficiency of clinical trial design while maintaining scientific rigor. In this issue of the Journal, Babu et al. (3) deviate from the classical two-armed RCT by applying a ranking and selection paradigm in order to determine which of three treatment strategies (i.e., creatine, tamoxifen 40mg or tamoxifen 80mg) is the most promising for a future pivotal trial. Notwithstanding the recent advancements in preclinical and early clinical models, phase II clinical trials are often the first opportunity for investigators to obtain a hint of therapeutic benefit. Improving the phase II selection process of promising ALS drugs is, therefore, essential, especially when one considers the expanding pipeline of ALS compounds (4). The selection paradigm as proposed by Babu et al. may give preliminary insights in the efficacy and safety of new drugs. As patients can only be allocated to active arms, enrollment rates could be positively affected. The lack of a concurrent placebo arm is, however, also its major drawback. This diminishes the interpretation of the safety data and may provide insufficient insight in the therapeutic benefit. In the end, this could lead to the erroneous selection of a treatment. Further refinement of the proposed methodology may help to ameliorate these limitations. In the last decades, there has been a steady increase in the use of innovative or adaptive design elements in RCTs (5), deviating from the fixed sample size, fixed eligibility criteria and fixed allocation ratios as seen in classical trial design. Adaptive designs use the accruing information during a RCT to make interim decisions regarding, for example, the continuation of subgroups, the re-estimation of sample sizes or to stop a trial early. These design adaptation may help to improve the efficiency of clinical trials when there is sufficient evidence for either superiority or futility. Especially the futility adaptations could prove value for ALS clinical trials (6). The probability that a compound will successfully pass the different phases of drug development, including regulatory approval, is less than 10% for rare diseases (7). In case of ALS, th","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"3 - 4"},"PeriodicalIF":2.8,"publicationDate":"2020-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1681455","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42705198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-02DOI: 10.1080/21678421.2019.1663214
Maria Khoueiry, Elia G. Malek, J. Salameh
Abstract Sandhoff disease is an under-recognized disease that may present as a lower motor neuron disorder in adulthood. We report the case of siblings presenting in their late 40s with a motor neuron disease phenotype and were misdiagnosed as amyotrophic lateral sclerosis and later found to have Sandhoff disease. Sandhoff disease should be considered in patients presenting with a slowly progressive predominately lower motor neuron disorder. A simple low-cost blood test can confirm the diagnosis.
{"title":"Adult onset Sandhoff disease: a rare mimicker of amyotrophic lateral sclerosis","authors":"Maria Khoueiry, Elia G. Malek, J. Salameh","doi":"10.1080/21678421.2019.1663214","DOIUrl":"https://doi.org/10.1080/21678421.2019.1663214","url":null,"abstract":"Abstract Sandhoff disease is an under-recognized disease that may present as a lower motor neuron disorder in adulthood. We report the case of siblings presenting in their late 40s with a motor neuron disease phenotype and were misdiagnosed as amyotrophic lateral sclerosis and later found to have Sandhoff disease. Sandhoff disease should be considered in patients presenting with a slowly progressive predominately lower motor neuron disorder. A simple low-cost blood test can confirm the diagnosis.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"144 - 146"},"PeriodicalIF":2.8,"publicationDate":"2020-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1663214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46541488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-02DOI: 10.1080/21678421.2019.1666875
Nathalie Braun, E. Macklin, E. Sinani, A. Sherman, Markus Weber
Abstract Over the past two decades, the El Escorial criteria (EEC) have been used as eligibility criteria in major randomized controlled trials. One of the goals of the revised EEC was to allow earlier diagnosis and, thus earlier trial inclusion by introducing a new category, namely “clinically probable laboratory supported” ALS. This category allowed EMG findings to be taken into account assuming that EMG is more sensitive than the clinical examination in detecting lower motor neuron signs. Recently, Edaravone has been licensed in several countries for the treatment of ALS based on a randomized controlled trial in a selected group of ALS patients excluding the EEC category “clinically probable laboratory supported”. The major reason was that in a post hoc analysis of the first Edaravone trial this group comprised many slow progressors. As it is unclear whether this bias towardslow progressors was a study-specific problem or related to the category itself, we performed an analysis in the PRO-ACT dataset. In the PRO-ACT dataset, progression in ALS patients included at baseline into the “clinically probable laboratory supported” category was significantly slower (–0.53 in ALSFRS/month) compared to the other EEC categories (–0.68 in ALSFRS/month; p < 0.001) and exhibited a significantly longer diagnostic delay (13.5 months vs. 11.7 months, p < 0.001). This suggests that the bias toward slow progressors in the “clinically probable laboratory supported” category is an inherent problem of the category and thus does not fulfill the previous goal of earlier diagnosis, raising several questions concerning the application of this category.
{"title":"The revised El Escorial criteria “clinically probable laboratory supported ALS”—once a promising now a superfluous category?","authors":"Nathalie Braun, E. Macklin, E. Sinani, A. Sherman, Markus Weber","doi":"10.1080/21678421.2019.1666875","DOIUrl":"https://doi.org/10.1080/21678421.2019.1666875","url":null,"abstract":"Abstract Over the past two decades, the El Escorial criteria (EEC) have been used as eligibility criteria in major randomized controlled trials. One of the goals of the revised EEC was to allow earlier diagnosis and, thus earlier trial inclusion by introducing a new category, namely “clinically probable laboratory supported” ALS. This category allowed EMG findings to be taken into account assuming that EMG is more sensitive than the clinical examination in detecting lower motor neuron signs. Recently, Edaravone has been licensed in several countries for the treatment of ALS based on a randomized controlled trial in a selected group of ALS patients excluding the EEC category “clinically probable laboratory supported”. The major reason was that in a post hoc analysis of the first Edaravone trial this group comprised many slow progressors. As it is unclear whether this bias towardslow progressors was a study-specific problem or related to the category itself, we performed an analysis in the PRO-ACT dataset. In the PRO-ACT dataset, progression in ALS patients included at baseline into the “clinically probable laboratory supported” category was significantly slower (–0.53 in ALSFRS/month) compared to the other EEC categories (–0.68 in ALSFRS/month; p < 0.001) and exhibited a significantly longer diagnostic delay (13.5 months vs. 11.7 months, p < 0.001). This suggests that the bias toward slow progressors in the “clinically probable laboratory supported” category is an inherent problem of the category and thus does not fulfill the previous goal of earlier diagnosis, raising several questions concerning the application of this category.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"24 - 28"},"PeriodicalIF":2.8,"publicationDate":"2020-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1666875","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45305999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-02DOI: 10.1080/21678421.2019.1672749
A. Arosio, R. Cristofani, O. Pansarasa, V. Crippa, C. Riva, R. Sirtori, V. Menendez, N. Riva, F. Gerardi, C. Lunetta, Cristina Cereda, A. Poletti, C. Ferrarese, L. Tremolizzo, G. Sala
Abstract Aim: The demonstration that chaperone-mediated autophagy (CMA) contributes to the degradation of TDP-43, the main constituent of cytoplasmic inclusions typically found in motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS), has pointed out a possible involvement of CMA in aggregate formation. To explore this possibility, in this study, we verified the presence of a possible systemic CMA alteration in sALS patients and its effect on TDP-43 expression. Materials and methods: Gene and protein expression of the cytosolic chaperone HSC70 and the lysosome receptor LAMP2A, the two pivotal mediators of CMA, was assessed in peripheral blood mononuclear cells (PBMCs) derived from 30 sALS patients and 30 healthy controls. The expression of TDP-43 and co-chaperones BAG1 and BAG3 was also analyzed. Results: We found reduced HSC70 expression in patient cells, with no change in LAMP2A, and increased insoluble TDP-43 protein levels, with an aberrant intracellular localization. We also observed an unbalanced expression of co-chaperones BAG1 and BAG3. HSC70 down-regulation was confirmed in immortalized lymphoblastoid cell lines derived from sporadic and TARDBP mutant ALS patients. Lastly, we demonstrated that HSC70 silencing directly increases TDP-43 protein levels in human neuroblastoma cells. Discussion: Our results do not support the existence of a systemic CMA alteration in sALS patients but indicate a direct involvement of HSC70 alterations in ALS pathogenesis.
{"title":"HSC70 expression is reduced in lymphomonocytes of sporadic ALS patients and contributes to TDP-43 accumulation","authors":"A. Arosio, R. Cristofani, O. Pansarasa, V. Crippa, C. Riva, R. Sirtori, V. Menendez, N. Riva, F. Gerardi, C. Lunetta, Cristina Cereda, A. Poletti, C. Ferrarese, L. Tremolizzo, G. Sala","doi":"10.1080/21678421.2019.1672749","DOIUrl":"https://doi.org/10.1080/21678421.2019.1672749","url":null,"abstract":"Abstract Aim: The demonstration that chaperone-mediated autophagy (CMA) contributes to the degradation of TDP-43, the main constituent of cytoplasmic inclusions typically found in motor neurons of patients with sporadic amyotrophic lateral sclerosis (sALS), has pointed out a possible involvement of CMA in aggregate formation. To explore this possibility, in this study, we verified the presence of a possible systemic CMA alteration in sALS patients and its effect on TDP-43 expression. Materials and methods: Gene and protein expression of the cytosolic chaperone HSC70 and the lysosome receptor LAMP2A, the two pivotal mediators of CMA, was assessed in peripheral blood mononuclear cells (PBMCs) derived from 30 sALS patients and 30 healthy controls. The expression of TDP-43 and co-chaperones BAG1 and BAG3 was also analyzed. Results: We found reduced HSC70 expression in patient cells, with no change in LAMP2A, and increased insoluble TDP-43 protein levels, with an aberrant intracellular localization. We also observed an unbalanced expression of co-chaperones BAG1 and BAG3. HSC70 down-regulation was confirmed in immortalized lymphoblastoid cell lines derived from sporadic and TARDBP mutant ALS patients. Lastly, we demonstrated that HSC70 silencing directly increases TDP-43 protein levels in human neuroblastoma cells. Discussion: Our results do not support the existence of a systemic CMA alteration in sALS patients but indicate a direct involvement of HSC70 alterations in ALS pathogenesis.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"51 - 62"},"PeriodicalIF":2.8,"publicationDate":"2020-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1672749","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44721731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2019-11-29DOI: 10.1080/21678421.2019.1697029
Glutathione is a naturally occurring antioxidant which helps cells eliminate damaging free radicals (2). It is part of the “glutathione system” which includes chemicals that help synthesize glutathione as well as chemicals that use glutathione to fight oxidative stress (3). Glutathione exists in different forms including the active (reduced) form referred to as GSH, and the spent (oxidized) form referred to as glutathione disulfide (GSSG); GSH protects cells while rising GSSG indicates worsening oxidative stress (2). GSH itself is available as an oral, intranasal, inhaled or injectable supplement. These formulations are advertised on websites as a treatment for ALS (4,5). Some cysteine-containing supplements such as Immunocal and N-acetylcysteine (NAC) are used to increase intracellular GSH (3,6,7) and so their potential role in treating ALS will also be reviewed here.
{"title":"ALSUntangled No. 52: Glutathione","authors":"","doi":"10.1080/21678421.2019.1697029","DOIUrl":"https://doi.org/10.1080/21678421.2019.1697029","url":null,"abstract":"Glutathione is a naturally occurring antioxidant which helps cells eliminate damaging free radicals (2). It is part of the “glutathione system” which includes chemicals that help synthesize glutathione as well as chemicals that use glutathione to fight oxidative stress (3). Glutathione exists in different forms including the active (reduced) form referred to as GSH, and the spent (oxidized) form referred to as glutathione disulfide (GSSG); GSH protects cells while rising GSSG indicates worsening oxidative stress (2). GSH itself is available as an oral, intranasal, inhaled or injectable supplement. These formulations are advertised on websites as a treatment for ALS (4,5). Some cysteine-containing supplements such as Immunocal and N-acetylcysteine (NAC) are used to increase intracellular GSH (3,6,7) and so their potential role in treating ALS will also be reviewed here.","PeriodicalId":7740,"journal":{"name":"Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration","volume":"21 1","pages":"154 - 157"},"PeriodicalIF":2.8,"publicationDate":"2019-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/21678421.2019.1697029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46714038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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