Publications by authors named "Thomas Prior"

105 Publications

High turnover of types III and VI collagen in progressive idiopathic pulmonary fibrosis.

Respirology 2021 Apr 9. Epub 2021 Apr 9.

Department of Respiratory Medicine, Herlev and Gentofte University Hospital, Copenhagen, Denmark.

Background And Objective: Prediction of idiopathic pulmonary fibrosis (IPF) progression is vital for the choice and timing of treatment and patient follow-up. This could potentially be achieved by prognostic blood biomarkers of extracellular matrix (ECM) remodelling.

Methods: Neoepitope biomarkers of types III and VI collagen turnover (C3M, C6M, PRO-C3 and PRO-C6) were measured in 185 patients with newly diagnosed IPF. Disease severity at baseline and progression over 6 months was assessed by lung function tests and 6-min walk tests. All-cause mortality was assessed over a 3-year follow-up period.

Results: High baseline levels of C3M, C6M, PRO-C3 and PRO-C6 were associated with more advanced disease at the time of diagnosis. Baseline levels of C6M and PRO-C3 were also associated with mortality over 3 years of follow-up (hazard ratio [HR]: 2.3, 95% CI: 1.3-3.9, p = 0.002 and HR: 1.8, 95% CI: 1.1-3.0, p = 0.03). Patients with several increased biomarkers at baseline, representing a high ECM remodelling phenotype, had more advanced disease at baseline, higher risk of progression or death at 6 months (OR: 1.4, 95% CI: 1.1-1.8, p = 0.002) and higher mortality over 3 years of follow-up (HR: 2.4, 95% CI: 1.3-4.5, p = 0.007).

Conclusion: Blood biomarkers of types III and VI collagen turnover, assessed at the time of diagnosis, are associated with several indices of disease severity, short-term progression and long-term mortality. These biomarkers can help to identify patients with a high ECM remodelling phenotype at high risk of disease progression and death.
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http://dx.doi.org/10.1111/resp.14056DOI Listing
April 2021

Midostaurin reduces relapse in FLT3-mutant acute myeloid leukemia: the Alliance CALGB 10603/RATIFY trial.

Leukemia 2021 Mar 2. Epub 2021 Mar 2.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

The prospective randomized, placebo-controlled CALGB 10603/RATIFY trial (Alliance) demonstrated a statistically significant overall survival benefit from the addition of midostaurin to standard frontline chemotherapy in a genotypically-defined subgroup of 717 patients with FLT3-mutant acute myeloid leukemia (AML). The risk of death was reduced by 22% on the midostaurin-containing arm. In this post hoc analysis, we analyzed the cumulative incidence of relapse (CIR) on this study and also evaluated the impact of 12 4-week cycles of maintenance therapy. CIR analyses treated relapses and AML deaths as events, deaths from other causes as competing risks, and survivors in remission were censored. CIR was improved on the midostaurin arm (HR = 0.71 (95% CI, 0.54-0.93); p = 0.01), both overall and within European LeukemiaNet 2017 risk classification subsets when post-transplant events were considered in the analysis as events. However, when transplantation was considered as a competing risk, there was overall no significant difference between the risks of relapse on the two randomized arms. Patients still in remission after consolidation with high-dose cytarabine entered the maintenance phase, continuing with either midostaurin or placebo. Analyses were inconclusive in quantifying the impact of the maintenance phase on the overall outcome. In summary, midostaurin reduces the CIR.
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http://dx.doi.org/10.1038/s41375-021-01179-4DOI Listing
March 2021

Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance.

Appl Clin Genet 2021 25;14:11-25. Epub 2021 Jan 25.

Pathology, University Hospitals Center for Human Genetics, Cleveland, OH, USA.

Spinal muscular atrophy (SMA) is a heritable neuromuscular disorder that causes degeneration of the alpha motor neurons from anterior horn cells in the spinal cord, which causes severe progressive hypotonia and muscular weakness. With a carrier frequency of 1 in 40-50 and an estimated incidence of 1 in 10,000 live births, SMA is the second most common autosomal recessive disorder. Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene on 5q13 but keep the modifying gene. The most common mutation causing SMA is a homozygous deletion of the exon 7, which can be readily detected and used as a sensitive diagnostic test. Because produces a reduced number of full-length transcripts, the number of copies can modify the clinical phenotype and as such, becomes an essential predictive factor. Population-based SMA carrier screening identifies carrier couples that may pass on this genetic disorder to their offspring and allows the carriers to make informed reproductive choices or prepare for immediate treatment for an affected child. Three treatments have recently been approved by the Food and Drug Administration (FDA). Nusinersen increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the transcript. Onasemnogene abeparvovec is a gene therapy that utilizes an adeno-associated virus serotype 9 vector to increase low functional SMN protein levels. Risdiplam is a small molecule that alters splicing in order to increase functional SMN protein. Newborn screening for SMA has been shown to be successful in allowing infants to be treated before the loss of motor neurons and has resulted in improved clinical outcomes. Several of the recommendations and guidelines in the review are based on studies performed in the United States.
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http://dx.doi.org/10.2147/TACG.S239603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846873PMC
January 2021

Fatigue in idiopathic pulmonary fibrosis measured by the Fatigue Assessment Scale during antifibrotic treatment.

Eur Clin Respir J 2020 Nov 30;8(1):1853658. Epub 2020 Nov 30.

Center for Rare Lung Disease, Department of Respiratory Medicine and Allergy, Aarhus University Hospital, Aarhus, Denmark.

: Fatigue is a common complaint in patients with idiopathic pulmonary fibrosis (IPF) and has been reported in a considerable percentage of patients. Fatigue is also a registered side effect of pirfenidone, one of two approved antifibrotic drugs. The Fatigue Assessment Scale (FAS) was developed for assessment of fatigue in sarcoidosis and validated in patients with sarcoidosis. FAS has been used in a few IPF studies but has not been validated. : To study the change in FAS after initiation of pirfenidone or nintedanib in the treatment of patients with IPF during a six-month period. : Between April 2017 and January 2018, all incident patients with IPF starting antifibrotic treatment were invited to complete FAS before, four weeks, three, and six months after initiation of antifibrotic treatment. Baseline characteristics including lung function were registered. : Fifty-two patients were included, mean FVC% 84.8, mean DLCO% 51.4. Nintedanib was started in 25 patients; 27 patients started pirfenidone. Sixty-four percent of patients had a FAS score >22 indicating substantial fatigue at baseline. There was no statistically significant difference in FAS score for patients treated with nintedanib or pirfenidone at any time point. FAS score increased statistically significantly during the six-month follow-up. This change was driven by patients without substantial fatigue at baseline with an increase in FAS score of 8.4 points; patients with substantial fatigue at baseline experienced no statistically significant change. : A majority of patients with IPF suffered from substantial fatigue at the time of diagnosis. Fatigue progressed over time and increasing fatigue was associated with younger age, nintedanib treatment and low degree of fatigue at baseline. There was no significant difference in FAS score between the two antifibrotic treatments at any time point, even though fatigue is not a registered side effect in nintedanib.
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http://dx.doi.org/10.1080/20018525.2020.1853658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717873PMC
November 2020

Characterization of Reference Materials for Spinal Muscular Atrophy Genetic Testing: A Genetic Testing Reference Materials Coordination Program Collaborative Project.

J Mol Diagn 2021 01 14;23(1):103-110. Epub 2020 Nov 14.

Informatics and Data Science Branch, Division of Laboratory Systems, CDC, Atlanta, Georgia. Electronic address:

Spinal muscular atrophy (SMA) is an autosomal recessive disorder predominately caused by bi-allelic loss of the SMN1 gene. Increased copies of SMN2, a low functioning nearly identical paralog, are associated with a less severe phenotype. SMA was recently recommended for inclusion in newborn screening. Clinical laboratories must accurately measure SMN1 and SMN2 copy number to identify SMA patients and carriers, and to identify individuals likely to benefit from therapeutic interventions. Having publicly available and appropriately characterized reference materials with various combinations of SMN1 and SMN2 copy number variants is critical to assure accurate SMA clinical testing. To address this need, the CDC-based Genetic Testing Reference Materials Coordination Program, in collaboration with members of the genetic testing community and the Coriell Institute for Medical Research, has characterized 15 SMA reference materials derived from publicly available cell lines. DNA samples were distributed to four volunteer testing laboratories for genotyping using three different methods. The characterized samples had zero to four copies of SMN1 and zero to five copies SMN2. The samples also contained clinically important allele combinations (eg, zero copies SMN1, three copies SMN2), and several had markers indicative of an SMA carrier. These and other reference materials characterized by the Genetic Testing Reference Materials Coordination Program are available from the Coriell Institute and are proposed to support the quality of clinical laboratory testing.
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http://dx.doi.org/10.1016/j.jmoldx.2020.10.011DOI Listing
January 2021

Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial.

Blood Adv 2020 10;4(19):4945-4954

Department of Biomedicine and Prevention, University Tor Vergata, Rome, Italy.

The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.
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http://dx.doi.org/10.1182/bloodadvances.2020002904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556122PMC
October 2020

Attitude and Barriers in Palliative Care and Advance Care Planning in Nonmalignant Chronic Lung Disease: Results From a Danish National Survey.

J Palliat Care 2020 Oct 23;35(4):232-235. Epub 2020 Jun 23.

Center for Rare Lung Disease, Department of Respiratory Diseases and Allergy, 11297Aarhus University Hospital, Aarhus, Denmark.

Introduction: Patients with chronic obstructive pulmonary disease and interstitial lung disease have a significant burden of symptoms. Many are not offered palliative care (PC). Our aim was to investigate the attitudes to and barriers for PC among physicians.

Method: A web-based survey was conducted among members of the Danish Respiratory Society. The questionnaire included contextual (gender, age, clinical experience, type of center, patient caseload) and outcome questions (knowledge and use of statements for PC and advance care planning [ACP], practice of communication about end-of-life decisions, practice for referral to PC, barriers regarding structural surroundings, clinical skills, and organization).

Results: One hundred fifty-six (45%) physicians responded. Median age was 40 - 49 years and 55% were female. Fifty-two percent were specialists; 71% worked at a university hospital. The majority of physicians (60%) reported barriers for discussions about PC and ACP; 63% reported lack of time, 52% lack of multidisciplinary staff settings, 63% reported the unpredictability of the prognosis, and 20% insufficient awareness of patient's culture, religion, or spirituality. Fewer specialists than nonspecialists reported barriers toward ACP. The majority had knowledge of guidelines in PC and ACP, but only a minority used these in daily clinical practice.

Conclusion: The attitude toward PC and ACP conversations was positive and implementation was regarded as important, but only a minority performed these conversations in practice. Main barriers were lack of time and staff. Palliative care guidelines were known but only scarcely used. Structural changes at the organizational level to improve access to palliation for patients with nonmalignant chronic lung diseases are needed.
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http://dx.doi.org/10.1177/0825859720936012DOI Listing
October 2020

Group sequential monitoring based on the maximum of weighted log-rank statistics with the Fleming-Harrington class of weights in oncology clinical trials.

Authors:
Thomas J Prior

Stat Methods Med Res 2020 Dec 10;29(12):3525-3532. Epub 2020 Jun 10.

Department of Statistical Modeling & Methodology, Janssen Research & Development, LLC, Spring House, PA, USA.

Clinical trials in oncology often involve the statistical analysis of time-to-event data such as progression-free survival or overall survival to determine the benefit of a treatment or therapy. The log-rank test is commonly used to compare time-to-event data from two groups. The log-rank test is especially powerful when the two groups have proportional hazards. However, survival curves encountered in oncology studies that differ from one another do not always differ by having proportional hazards; in such instances, the log-rank test loses power, and the survival curves are said to have "non-proportional hazards". This non-proportional hazards situation occurs for immunotherapies in oncology; immunotherapies often have a delayed treatment effect when compared to chemotherapy or radiation therapy. To correctly identify and deliver efficacious treatments to patients, it is important in oncology studies to have available a statistical test that can detect the difference in survival curves even in a non-proportional hazards situation such as one caused by delayed treatment effect. An attempt to address this need was the "max-combo" test, which was originally described only for a single analysis timepoint; this article generalizes that test to preserve type I error when there are one or more interim analyses, enabling efficacious treatments to be identified and made available to patients more rapidly.
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http://dx.doi.org/10.1177/0962280220931560DOI Listing
December 2020

Responsiveness and minimal clinically important difference of SGRQ-I and K-BILD in idiopathic pulmonary fibrosis.

Respir Res 2020 Apr 21;21(1):91. Epub 2020 Apr 21.

Center for Rare Lung Diseases, Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200, Aarhus N, Denmark.

Background: Idiopathic pulmonary fibrosis (IPF) specific version of St. George's Respiratory Questionnaire (SGRQ-I) and King's Brief Interstitial Lung Disease questionnaire (K-BILD) are validated health-related quality of life (HRQL) instruments, but no or limited data exist on their responsiveness and minimal clinically important difference (MCID). The objectives of this study were to assess responsiveness of SGRQ-I and K-BILD and determine MCID separately for deterioration and improvement in a large, prospective cohort of patients with IPF in a real-world setting.

Methods: Consecutive patients with IPF were recruited. SGRQ-I, K-BILD, SGRQ, Shortness of Breath Questionnaire, pulmonary function tests and 6-min walk test measurements were obtained at baseline and at six and 12 months; at six and 12 months, patients also completed Global Rating of Change Scales. Responsiveness was assessed using correlation coefficients and linear regression. Cox regression was used for mortality analyses. MCID was estimated using receiver operating characteristic curves with separate analyses for improvement and deterioration.

Results: A total of 150 IPF patients were included and 124 completed the 12-month follow-up. Based on all HRQL anchors and most physiological anchors, responsiveness analyses supported the evidence pointing towards SGRQ-I and K-BILD as responsive instruments. Multivariate analyses showed an association between SGRQ-I and mortality (HR: 1.18, 95% CI: 1.02 to 1.36, p = 0.03) and a trend was found for K-BILD (HR: 0.82, 95% CI: 0.64 to 1.05, p = 0.12). MCID was estimated for all domains of SGRQ-I and K-BILD. MCID for improvement differed from deterioration for both SGRQ-I Total (3.9 and 4.9) and K-BILD Total (4.7 and 2.7).

Conclusions: SGRQ-I and K-BILD were responsive to change concerning both HRQL and most physiological anchors. MCID was determined separately for improvement and deterioration, resulting in different estimates; especially a smaller estimate for deterioration compared to improvement in K-BILD.

Trial Registration: Clinicaltrials.gov, no. NCT02818712. Registered 30 June 2016.
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http://dx.doi.org/10.1186/s12931-020-01359-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175493PMC
April 2020

Cytogenetic and molecular diagnostic testing associated with prenatal and postnatal birth defects.

Birth Defects Res 2020 03;112(4):293-306

Center for Human Genetics, University Hospitals Cleveland Medical Center, Cleveland, Ohio.

Genetic testing is beneficial for patients and providers when in search of answers to medical problems related to the prenatal or early postnatal period. It can help to identify the cause or confirm a diagnosis associated with developmental delay, intellectual disability, dysmorphic features, heart defects, multiple malformations, short stature, stillbirth, neonatal death, or fertility problems. Genetic testing can be used to rule out single-gene or chromosome abnormalities. Different diagnostic cytogenetic and molecular genetic techniques are applied in clinical genetics laboratories, from conventional ones to the state of the art chromosomal microarrays and next-generation sequencing. Each of the genetic techniques or methods has its strengths and limitations, however different methods complement each-other in trying to identify the genetic variation(s) responsible for a medical condition, especially the ones related to birth defects.
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http://dx.doi.org/10.1002/bdr2.1648DOI Listing
March 2020

A case report of genetic prion disease with two different PRNP variants.

Mol Genet Genomic Med 2020 03 17;8(3):e1134. Epub 2020 Jan 17.

National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.

Background: Prion diseases are a group of lethal neurodegenerative conditions that occur when the normal, cellular form of the prion protein (PrP ) is converted into an abnormal, scrapie, form of the protein (PrP ). Disease may be caused by genetic, infectious, or sporadic etiologies. The genetic form of prion disease comprises~10%-15% of all cases. Prion disease is typically inherited in an autosomal dominant manner. The low incidence of disease makes it highly unlikely that a patient would have two different pathogenic variants. However, we recently identified a case in which the patient did have two pathogenic PRNP variants and presented with an atypical phenotype.

Methods: The patient was evaluated at the Washington Hospital Healthcare System in Fremont, CA. The clinical information for this case report was obtained retrospectively. Variants in the PRNP were identified by polymerase chain reaction (PCR) amplification of exon two of the gene followed by bi-directional sequence analysis. To determine the phase of the identified variants, a restriction enzyme digestion was utilized, followed by sequence analysis of the products. Cerebral spinal fluid (CSF) was analyzed for surrogate markers of prion disease, 14-3-3 and Tau proteins. CSF real-time quaking-induced conversion (RT-QuIC) assays were also performed.

Results: The patient was a compound heterozygote for the well-characterized c.628G>A (p.Val210Ile) variant and the rare octapeptide deletion of two repeats [c.202_249del48 (p.P68_Q83del)]. Clinically, the patient presented with an early onset demyelinating peripheral neuropathy, followed by later onset cognitive symptoms.

Conclusion: This presentation is reminiscent of prion protein knockout mice whose predominate symptom, due to complete loss of PrP, was late-onset peripheral neuropathy. To our knowledge this is the first case reported of a patient with prion disease who had two different pathogenic variants in PRNP.
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http://dx.doi.org/10.1002/mgg3.1134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057106PMC
March 2020

Validation of the King's Brief Interstitial Lung Disease questionnaire in Idiopathic Pulmonary Fibrosis.

BMC Pulm Med 2019 Dec 19;19(1):255. Epub 2019 Dec 19.

Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.

Background: Health-related quality of life (HRQL) is impaired in patients with idiopathic pulmonary fibrosis (IPF). The King's Brief Interstitial Lung Disease questionnaire (K-BILD) is a validated measure of HRQL, but no previous studies have focused on the validity of K-BILD in IPF. Moreover, the relationship between K-BILD and dyspnoea or the 6-min walk test (6MWT) has not been assessed. The aim of this study was to validate K-BILD in the largest cohort of patients with IPF to date and assess how K-BILD correlates to dyspnoea and 6MWT.

Methods: Firstly, K-BILD was translated into Danish using validated translation procedures. Consecutive patients with IPF were recruited. At baseline, patients completed K-BILD, the IPF-specific version of St. Georges Respiratory Questionnaire, University of California, San Diego Shortness of Breath Questionnaire (SOBQ) Short Form-36, and pulmonary function tests and 6MWT were performed. After 14 days, K-BILD and Global Rating of Change Scales were completed. Internal consistency, concurrent validity, test-retest reliability and known groups validity were assessed. Analyses were also performed in subgroups of patients with different time since diagnosis.

Results: At baseline, 150 patients with IPF completed the questionnaires, and 139 patients completed the questionnaires after 14 days. K-BILD had a high internal consistency (Cronbach's α = 0.92). The concurrent validity was strong compared to SOBQ (r = - 0.66) and moderate compared to 6MWT (r = 0.43). Intraclass correlation coefficients (ICC = 0.91) and a Bland Altman plot demonstrated a good reliability. K-BILD was also able to discriminate between patients with different stages of disease (p < 0.002, Δscore > 7.4) and most results were comparable in patients with different time since diagnosis.

Conclusion: K-BILD is a valid and reliable instrument in patients with IPF and in patients with different time since diagnosis. To a major extent, K-BILD scores reflected the impact of dyspnoea on HRQL and the impact of physical functional capacity measured by the 6MWT to a moderate degree. Compared to PFTs alone, K-BILD provides additional information on the burden of living with IPF, and importantly, K-BILD is simple to implement in both research and clinical contexts.

Trial Registration: Clinicaltrials.org (NCT02818712) on 30 June 2016.
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http://dx.doi.org/10.1186/s12890-019-1018-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924069PMC
December 2019

Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.

Blood 2020 01;135(5):371-380

The Ohio State University Comprehensive Cancer Center, Columbus, OH.

Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.
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http://dx.doi.org/10.1182/blood.2019002697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993016PMC
January 2020

Interstitial Lung Disease in Rheumatoid Arthritis Remains a Challenge for Clinicians.

J Clin Med 2019 Nov 21;8(12). Epub 2019 Nov 21.

.Regional Hospital, Falkevej 1-3, 8600 Silkeborg, Denmark.

Interstitial lung disease (ILD) is a serious complication of rheumatoid arthritis (RA) contributing to significantly increased morbidity and mortality. Other respiratory complications, such as chronic obstructive pulmonary disease and bronchiectasis, are frequent in RA. Infections and drug toxicity are important differential diagnoses and should be considered in the diagnostic work-up of patients with RA presenting with respiratory symptoms. This review provides an overview of the epidemiology and pathogenesis of RA-ILD, the radiological and histopathological characteristics of the disease as well as the current and future treatment options. Currently, there is no available evidence-based therapy for RA-ILD, and immunosuppressants are the mainstay of therapy. Ongoing studies are exploring the role of antifibrotic therapy in patients with progressive fibrotic ILD, which may lead to a new treatment approach for subgroups of patients with RA-ILD.
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http://dx.doi.org/10.3390/jcm8122038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947091PMC
November 2019

Outcome measures in a cohort of ambulatory adults with spinal muscular atrophy.

Muscle Nerve 2020 02 11;61(2):187-191. Epub 2019 Dec 11.

Department of Neurology, Division of Neuromuscular Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio.

Introduction: With the advent of disease-altering therapies for spinal muscular atrophy (SMA), there is a requirement to better characterize outcome measures, particularly in milder forms of disease.

Methods: Maximal voluntary isometric contraction testing and 6-minute walk test (6MWT) performed in ambulatory SMA adults as part of the SMA-VALIANT trial were analyzed. Test-retest reliability and correlation with other candidate biomarkers and outcomes were investigated.

Results: Maximal voluntary isometric contraction testing and 6MWT showed good test-retest reliability (intraclass correlation coefficient = 0.98 and 0.85, respectively). Maximal voluntary isometric contraction testing and 6MWT demonstrated very strong correlation (r = 0.83, P <. 0001), and each correlated with the SMA Functional Rating Scale (r = 0.7, P < .0001 and r = 0.65, P = .0001, respectively), lean muscle mass (r = 0.68, P < .0001 and r = 0.56, P = .001, respectively), and ulnar compound muscle action potential (r = 0.57, P = .0008 and r = 0.47, P = .008, respectively).

Discussion: Maximal voluntary isometric contraction testing and 6MWT are suitable outcomes for use in ambulatory adults with SMA. Maximal voluntary isometric contraction testing may be preferable because of superior test-retest reliability and closer associations with other outcomes and biomarkers of neuromuscular function.
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http://dx.doi.org/10.1002/mus.26756DOI Listing
February 2020

Age-dependent SMN expression in disease-relevant tissue and implications for SMA treatment.

J Clin Invest 2019 11;129(11):4817-4831

Department of Neuroscience and.

BACKGROUNDSpinal muscular atrophy (SMA) is caused by deficient expression of survival motor neuron (SMN) protein. New SMN-enhancing therapeutics are associated with variable clinical benefits. Limited knowledge of baseline and drug-induced SMN levels in disease-relevant tissues hinders efforts to optimize these treatments.METHODSSMN mRNA and protein levels were quantified in human tissues isolated during expedited autopsies.RESULTSSMN protein expression varied broadly among prenatal control spinal cord samples, but was restricted at relatively low levels in controls and SMA patients after 3 months of life. A 2.3-fold perinatal decrease in median SMN protein levels was not paralleled by comparable changes in SMN mRNA. In tissues isolated from nusinersen-treated SMA patients, antisense oligonucleotide (ASO) concentration and full-length (exon 7 including) SMN2 (SMN2-FL) mRNA level increases were highest in lumbar and thoracic spinal cord. An increased number of cells showed SMN immunolabeling in spinal cord of treated patients, but was not associated with an increase in whole-tissue SMN protein levels.CONCLUSIONSA normally occurring perinatal decrease in whole-tissue SMN protein levels supports efforts to initiate SMN-inducing therapies as soon after birth as possible. Limited ASO distribution to rostral spinal and brain regions in some patients likely limits clinical response of motor units in these regions for those patients. These results have important implications for optimizing treatment of SMA patients and warrant further investigations to enhance bioavailability of intrathecally administered ASOs.FUNDINGSMA Foundation, SMART, NIH (R01-NS096770, R01-NS062869), Ionis Pharmaceuticals, and PTC Therapeutics. Biogen provided support for absolute real-time RT-PCR.
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http://dx.doi.org/10.1172/JCI124120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819103PMC
November 2019

Validation of the IPF-specific version of St. George's Respiratory Questionnaire.

Respir Res 2019 Aug 28;20(1):199. Epub 2019 Aug 28.

Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark.

Background: Patients with idiopathic pulmonary fibrosis (IPF) have impaired health-related quality of life (HRQL). To measure HRQL, an IPF-specific version of the St. George's Respiratory Questionnaire (SGRQ-I) was developed, but not sufficiently validated. This study aimed to assess the validity (i.a. known-groups validity and concurrent validity) and test-retest reliability of SGRQ-I in IPF patients with different disease durations.

Methods: Patients with IPF were consecutively recruited and completed SGRQ, SGRQ-I, King's Brief Interstitial Lung Disease questionnaire (K-BILD), University of California, San Diego Shortness of Breath Questionnaire (SOBQ) and Short Form-36 (SF-36) along with pulmonary function tests and a 6-min walk test (6MWT) at baseline. After two weeks, SGRQ-I and Global Rating of Change Scales (GRCS) were completed.

Results: At baseline and after two weeks, 150 and 134 patients completed the questionnaires, respectively. The internal consistency of SGRQ-I was high (Cronbach's α = 0.92). Good concurrent validity was demonstrated by high intraclass correlation coefficients (ICC = 0.97), Bland-Altman plots and moderate to strong correlations to K-BILD, SOBQ and SF-36 (r = - 0.46 to 0.80). High ICC (0.92) and a Bland-Altman plot indicated good test-retest reliability. SGRQ-I was good at discriminating between patients with different stages of disease (Δscore > 18.1, effect sizes > 0.10). Validity was similar across groups of different disease duration.

Conclusions: SGRQ-I proved to be valid at distinguishing between different disease severities, valid compared to other HRQL instruments, applicable across different disease durations and reliable upon repetition. SGRQ-I is a valid option for measuring HRQL in patients with IPF.

Trial Registration: The study was registered at clinicaltrials.org ( NCT02818712 ) on 15 June 2016.
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http://dx.doi.org/10.1186/s12931-019-1169-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714302PMC
August 2019

Long-term non-invasive ventilation for stable chronic hypercapnic COPD.

Eur Clin Respir J 2019 23;6(1):1644893. Epub 2019 Jul 23.

Lillebaelt Hospital, University Hospital of Southern Denmark, Odense, Denmark.

: Long-term non-invasive ventilation (LTNIV) for the stable hypercapnic chronic obstructive pulmonary disease (COPD)-patients have been a subject of much debate in the last two decades. The aim of this study was to compile the current knowledge on LTNIV in order to evaluate the effects on mortality and hypercapnia. : Literature search in Pubmed, Ovid, and Embase for RCTs in Humans from January 2000 through January 2019 in written English. : Six studies with a total of 861 patients were included. LTNIV in stable hypercapnic COPD patients significantly reduced PaCO but only one study found significant reduction in mortality. : Our meta-analyses demonstrate that LTNIV significantly reduced PaCO in stable patients with chronic hypercapnic respiratory failure compared to standard care alone, and subgroup analyses on studies with a predefined plan for ventilation, showed a considerable trend towards significant reduction in mortality. The take home messages on LTNIV in stable hypercapnic COPD are: It is essential that the patients have stable chronic hypercapnia.The degree of stability can best be assessed after a minimum of 2 weeks following an acute hypercapnic respiratory failure (AHRF).It is important to ventilate the patient with the goal to reduce PaCO by at least 20% or below 6.5 kPa.
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http://dx.doi.org/10.1080/20018525.2019.1644893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691917PMC
July 2019

Impact of Age and Motor Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving Single-Dose Gene Replacement Therapy.

Pediatr Neurol 2019 09 13;98:39-45. Epub 2019 May 13.

Center for Gene Therapy at the Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, Ohio State University, Columbus, Ohio; Department of Neurology, Ohio State University, Columbus, Ohio.

Background: This study characterizes motor function responses after early dosing of AVXS-101 (onasemnogene abeparvovec) in gene replacement therapy in infants with severe spinal muscular atrophy type 1 (SMA1).

Methods: This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study (NCT02122952). Infants were grouped according to age at dosing and baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores <20 (n = 3), (2) late dosing, dosed at age three months or greater (n = 6), and (3) early dosing/high motor, dosed age less than three months with scores ≥20 (n = 3).

Results: Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months).

Conclusions: The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.05.005DOI Listing
September 2019

Risk factors for diagnostic delay in idiopathic pulmonary fibrosis.

Respir Res 2019 May 24;20(1):103. Epub 2019 May 24.

Department of Respiratory Medicine, Herlev and Gentofte Hospital, Kildegårdsvej 28, 2900, Hellerup, Denmark.

Background: Surveys and retrospective studies of patients with idiopathic pulmonary fibrosis (IPF) have shown a significant diagnostic delay. However, the causes and risk factors for this delay are not known.

Methods: Dates at six time points before the IPF diagnosis (onset of symptoms, first contact to a general practitioner, first hospital contact, referral to an interstitial lung disease (ILD) centre, first visit at an ILD centre, and final diagnosis) were recorded in a multicentre cohort of 204 incident IPF patients. Based on these dates, the delay was divided into specific patient-related and healthcare-related delays. Demographic and clinical data were used to determine risk factors for a prolonged delay, using multivariate negative binomial regression analysis.

Results: The median diagnostic delay was 2.1 years (IQR: 0.9-5.0), mainly attributable to the patients, general practitioners and community hospitals. Male sex was a risk factor for patient delay (IRR: 3.84, 95% CI: 1.17-11.36, p = 0.006) and old age was a risk factor for healthcare delay (IRR: 1.03, 95% CI: 1.01-1.06, p = 0.004). The total delay was prolonged in previous users of inhalation therapy (IRR: 1.99, 95% CI: 1.40-2.88, p <  0.0001) but not in patients with airway obstruction. Misdiagnosis of respiratory symptoms was reported by 41% of all patients.

Conclusion: Despite increased awareness of IPF, the diagnostic delay is still 2.1 years. Male sex, older age and treatment attempts for alternative diagnoses are risk factors for a delayed diagnosis of IPF. Efforts to reduce the diagnostic delay should focus on these risk factors.

Trial Registration: This study was registered at http://clinicaltrials.gov (NCT02772549) on May 10, 2016.
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http://dx.doi.org/10.1186/s12931-019-1076-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534848PMC
May 2019

The impact of cross-border IVF on maternal and neonatal outcomes in multiple pregnancies: Experience from a UK fetal medicine service.

Eur J Obstet Gynecol Reprod Biol 2019 Jul 2;238:63-67. Epub 2019 May 2.

Centre for Fetal Care, Queen Charlotte's & Chelsea Hospital, Imperial College Healthcare NHS trust, London, United Kingdom; Imperial College London, United Kingdom. Electronic address:

Objectives: To determine whether women seeking NHS care for IVF multiple pregnancies were more likely to have sought IVF treatment overseas and whether this was associated with different maternal and neonatal outcomes.

Study Design: A single large tertiary centre, for perinatal care in northwest London. Sixty-five women were referred to our fetal medicine centre, between 2012-2016, with IVF conceived multiple pregnancies.

Inclusion Criteria: In Vitro fertilisation and conception of twins/ triplets/quadruplets.

Exclusion Criteria: Intra-uterine insemination, ovulation induction, Clomid-conception and singleton pregnancies. The primary outcome measure was the Country where IVF treatment was performed. The secondary outcomes measures included the specifics of IVF treatment (e.g. number of embryos transferred), subsequent pregnancy outcomes (e.g. live-births and prematurity) and neonatal outcomes (e.g. length and cost of care).

Results And Conclusion: Thirty-eight women had IVF overseas; they were older and had more pre-existing medical conditions. Eleven pregnancies used donor embryos, of which ten were from overseas treatment. 75% of women treated overseas conceived a triplet or higher order pregnancy compared to fewer than 10% of women who conceived in the UK. Almost half of all women treated overseas had more than two embryos transferred. Overseas IVF pregnancies had poorer obstetric and neonatal outcomes: 24% of live born babies died in the neonatal period compared to 0% in the UK group. The average neonatal costs per baby born from overseas IVF were £20, 600: two-and-a-half times higher than for those whose mothers conceived in the UK. Higher order multiple pregnancies are greatly over-represented by those undergoing IVF in overseas clinics. These are associated with poorer obstetric and neonatal outcomes. Perhaps paradoxically, improving NHS provision of fertility services might improve outcomes for the mother and babies while reducing the long-term burden to both fertility patients and the NHS.
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http://dx.doi.org/10.1016/j.ejogrb.2019.04.030DOI Listing
July 2019

Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype.

Hum Genet 2019 Mar 20;138(3):241-256. Epub 2019 Feb 20.

Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH, USA.

Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by loss or mutation of the survival motor neuron 1 (SMN1) gene and retention of SMN2. We performed targeted capture and sequencing of the SMN2, CFTR, and PLS3 genes in 217 SMA patients. We identified a 6.3 kilobase deletion that occurred in both SMN1 and SMN2 (SMN1/2) and removed exons 7 and 8. The deletion junction was flanked by a 21 bp repeat that occurred 15 times in the SMN1/2 gene. We screened for its presence in 466 individuals with the known SMN1 and SMN2 copy numbers. In individuals with 1 SMN1 and 0 SMN2 copies, the deletion occurred in 63% of cases. We modeled the deletion junction frequency and determined that the deletion occurred in both SMN1 and SMN2. We have identified the first deletion junction where the deletion removes exons 7 and 8 of SMN1/2. As it occurred in SMN1, it is a pathogenic mutation. We called variants in the PLS3 and SMN2 genes, and tested for association with mild or severe exception patients. The variants A-44G, A-549G, and C-1897T in intron 6 of SMN2 were significantly associated with mild exception patients, but no PLS3 variants correlated with severity. The variants occurred in 14 out of 58 of our mild exception patients, indicating that mild exception patients with an intact SMN2 gene and without modifying variants occur. This sample set can be used in the association analysis of candidate genes outside of SMN2 that modify the SMA phenotype.
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http://dx.doi.org/10.1007/s00439-019-01983-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503527PMC
March 2019

Fetal abdominal cysts: antenatal course and postnatal outcomes.

J Perinat Med 2019 May;47(4):418-421

Centre for Fetal Care, Queen Charlotte's and Chelsea Hospital, Imperial College Healthcare NHS Trust, London, UK.

Background There is little information on which to base the prognostic counselling as to whether an antenatally diagnosed fetal abdominal cyst will grow or shrink, or need surgery. This study aims to provide contemporary data on prenatally diagnosed fetal abdominal cysts in relation to their course and postnatal outcomes. Methods Fetal abdominal cysts diagnosed over 11 years in a single centre were identified. The gestational age at diagnosis and cyst characteristics at each examination were recorded (size, location, echogenity, septation and vascularity) and follow-up data from postnatal visits were collected. Results Eighty abdominal cysts were identified antenatally at 28+4 weeks (range 11+0-38+3). Most (87%) were isolated and the majority were pelvic (52%), simple (87.5%) and avascular (100%). Antenatally, 29% resolved spontaneously; 29% reduced in size; 9% were stable and 33% increased in size. Forty-one percent of cysts under 20 mm diameter increased in size, while only 20% of cysts with a diameter of over 40 mm increased in size. The majority of cysts were ovarian in origin (n=45, 56%), followed by intestinal (n=15, 18%), choledochal (n=3, 4%), liver (n=2, 3%) and renal/adrenal origins (n=2, 3%), respectively. In 16% (n=13), the antenatal diagnosis was not obvious. Seventy-five percent of the cysts that persisted postnatally required surgical intervention. Conclusion Most antenatally diagnosed fetal abdominal cysts were ovarian in origin. Though most disappeared antenatally, nearly three quarters required surgical intervention when present after birth. Cysts of intestinal origin are more difficult to diagnose antenatally and often require surgery.
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http://dx.doi.org/10.1515/jpm-2018-0311DOI Listing
May 2019

Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening.

J Neuromuscul Dis 2018 ;5(2):145-158

Cure SMA, Elk Grove Village, IL, USA.

Background: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity.

Objective: To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number.

Methods: A working group comprised of 15 SMA experts participated in a modified Delphi process, moderated by a neutral third-party expert, to develop treatment guidelines.

Results: The overarching recommendation is that all infants with two or three copies of SMN2 should receive immediate treatment (n = 13). For those infants in which immediate treatment is not recommended, guidelines were developed that outline the timing and appropriate screens and tests to be used to determine the timing of treatment initiation.

Conclusions: The identification SMA affected infants via newborn screening presents an unprecedented opportunity for achievement of maximal therapeutic benefit through the administration of treatment pre-symptomatically. The recommendations provided here are intended to help formulate treatment guidelines for infants who test positive during the newborn screening process.
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http://dx.doi.org/10.3233/JND-180304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004919PMC
November 2018

Natural history of infantile-onset spinal muscular atrophy.

Ann Neurol 2017 Dec 8;82(6):883-891. Epub 2017 Dec 8.

Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH.

Objective: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.

Methods: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed.

Results: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17).

Interpretation: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891.
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http://dx.doi.org/10.1002/ana.25101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5776712PMC
December 2017

[Idiopathic pulmonary fibrosis is an overlooked disease].

Ugeskr Laeger 2017 Nov;179(23)

Idiopathic pulmonary fibrosis is a chronic, progressive and fatal disease which primarily occurs in male patients over 60 years with a smoking history. Cryobiopsy is a new promising method for obtaining lung tissue for histologic analysis with fewer complications than surgical lung biopsy. Cryobiopsy allows more patients to be diagnosed. Antifibrotic treatment has shown to decrease progression and prolong survival time in both early and later stages of the disease. Early diagnosis and treatment are therefore of great importance to prevent disease progression and reduce mortality.
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November 2017

Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy.

N Engl J Med 2017 11;377(18):1713-1722

From the Center for Gene Therapy at the Research Institute at Nationwide Children's Hospital (J.R.M., S.A.-Z., L.R.R.-K., L.L., L.A., K.B., K.C., S.L., C.M., K.M., B.K.K.) and the Departments of Pediatrics (J.R.M., S.A.-Z., R.S., L.L., L.A., K.B., K.C., J.T.K., B.K.K.), Neurology (J.R.M., W.D.A., L.R.R.-K., A.H.M.B., B.K.K.), Pathology (T.W.P.), and Molecular and Cellular Biochemistry (A.H.M.B.), Ohio State University - both in Columbus; and AveXis, Bannockburn, IL (S.N., J.L., D.M.S., C.W., J.A.C., M.D.H., A.K., S.C., L.B., K.D.F., B.K.K.).

Background: Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease.

Methods: Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×10 vg per kilogram of body weight), and 12 received a high dose (2.0×10 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts).

Results: As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone.

Conclusions: In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).
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http://dx.doi.org/10.1056/NEJMoa1706198DOI Listing
November 2017

Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I.

Muscle Nerve 2018 02 18;57(2):193-199. Epub 2017 Sep 18.

Department of Neurology, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Simches 5-240, Boston, Massachusetts, 02114, USA.

Introduction: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA).

Methods: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude.

Results: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts.

Discussion: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.
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http://dx.doi.org/10.1002/mus.25776DOI Listing
February 2018