Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing, autoimmune, inflammatory disorder that typically affects the optic nerves and spinal cord. At least two thirds of cases are associated ...with aquaporin-4 antibodies (AQP4-IgG) and complement-mediated damage to the central nervous system. In a previous small, open-label study involving patients with AQP4-IgG-positive disease, eculizumab, a terminal complement inhibitor, was shown to reduce the frequency of relapse.
In this randomized, double-blind, time-to-event trial, 143 adults were randomly assigned in a 2:1 ratio to receive either intravenous eculizumab (at a dose of 900 mg weekly for the first four doses starting on day 1, followed by 1200 mg every 2 weeks starting at week 4) or matched placebo. The continued use of stable-dose immunosuppressive therapy was permitted. The primary end point was the first adjudicated relapse. Secondary outcomes included the adjudicated annualized relapse rate, quality-of-life measures, and the score on the Expanded Disability Status Scale (EDSS), which ranges from 0 (no disability) to 10 (death).
The trial was stopped after 23 of the 24 prespecified adjudicated relapses, given the uncertainty in estimating when the final event would occur. The mean (±SD) annualized relapse rate in the 24 months before enrollment was 1.99±0.94; 76% of the patients continued to receive their previous immunosuppressive therapy during the trial. Adjudicated relapses occurred in 3 of 96 patients (3%) in the eculizumab group and 20 of 47 (43%) in the placebo group (hazard ratio, 0.06; 95% confidence interval CI, 0.02 to 0.20; P<0.001). The adjudicated annualized relapse rate was 0.02 in the eculizumab group and 0.35 in the placebo group (rate ratio, 0.04; 95% CI, 0.01 to 0.15; P<0.001). The mean change in the EDSS score was -0.18 in the eculizumab group and 0.12 in the placebo group (least-squares mean difference, -0.29; 95% CI, -0.59 to 0.01). Upper respiratory tract infections and headaches were more common in the eculizumab group. There was one death from pulmonary empyema in the eculizumab group.
Among patients with AQP4-IgG-positive NMOSD, those who received eculizumab had a significantly lower risk of relapse than those who received placebo. There was no significant between-group difference in measures of disability progression. (Funded by Alexion Pharmaceuticals; PREVENT ClinicalTrials.gov number, NCT01892345; EudraCT number, 2013-001150-10.).
To evaluate whether the overcorrected medial proximal tibial angle (MPTA) affects the clinical outcomes after open-wedge high tibial osteotomy (OWHTO) and to assess the correlation between knee joint ...line obliquity (KJLO) changes and the compensatory changes in the hip and ankle joints.
Consecutive patients who underwent OWHTO from July 2006 to August 2015 were included. Exclusion criteria were bilateral OWHTO and follow-up of <2 years. The patients were retrospectively divided into 2 groups according to postoperative MPTA; a normal group (MPTA <95°) and an overcorrected MPTA group (MPTA ≥95°). The groups were compared with respect to the clinical and radiologic outcomes after OWHTO. Clinical parameters, including Japanese Orthopedic Association (JOA) score, Oxford Knee Score (OKS), and Knee Injury and Osteoarthritis Outcome Score (KOOS), were evaluated. Radiologic outcomes, including the hip-knee-ankle angle (HKA), joint line convergence angle (JLCA), MPTA, KJLO, ankle joint line obliquity (AJLO), and hip abduction angle (HAA), were evaluated preoperatively and at the final follow-up.
Ninety-four patients (normal group; n = 52, overcorrected group; n = 42) were included in this study. After OWTHO, the mean increases in HKA and MPTA were 11.0° ± 3.2° and 10.4° ± 2.7°, respectively, whereas the change in KJLO was only 3.7° ± 2.9°. The mean AJLO (4.3 ± 3.9 to −1.3 ± 3.3, P < .001) and HAA (3.7 ± 2.5 to −1.1 ± 2.3, P < .001) significantly decreased after OWHTO. The mean postoperative MPTA in the overcorrected group was 96.9° ± 1.5°, whereas the mean postoperative KJLO was only 3.1° ± 2.0°. No significant differences were noted in all clinical scores between the groups at the final follow-up.
A certain degree of overcorrected MPTA (≥95°) did not affect the clinical outcomes after OWHTO because of compensatory changes in the hip and ankle joints.
Level Ⅲ, retrospective comparative study.
Our previous phase 2, open-label study of 11 infants and young children with life-threatening perinatal or infantile hypophosphatasia showed 1 year safety and efficacy of asfotase alfa, an enzyme ...replacement therapy. We aimed to report the long-term outcomes over approximately 7 years of treatment.
We did a prespecified, end of study, 7 year follow-up of our single-arm, open-label, phase 2 trial in which children aged 3 years or younger with life-threatening perinatal or infantile hypophosphatasia were recruited from ten hospitals (six in the USA, two in the UK, one in Canada, and one in the United Arab Emirates). Patients received asfotase alfa (1 mg/kg three times per week subcutaneously, adjusted to 3 mg/kg three times per week if required) for up to 7 years (primary treatment period plus extension phase) or until the product became commercially available; dosage adjustments were made at each visit according to changes in the patient's weight. The primary objectives of this extension study were to assess the long-term tolerability of asfotase alfa, defined as the number of patients with one or more treatment-emergent adverse events, and skeletal manifestations associated with hypophosphatasia, evaluated using the Radiographic Global Impression of Change (RGI-C) scale (-3 indicating severe worsening, and +3 complete or near-complete healing). Respiratory support, growth, and cognitive and motor functions were also evaluated. All efficacy and safety analyses were done in all patients who received any asfotase alfa (full-analysis population). This study and extension phase are registered with ClinicalTrials.gov, number NCT01205152, and EudraCT, number 2009-009369-32.
11 participants were recruited between Oct 6, 2008, and Dec 4, 2009. Ten patients completed a 6 month treatment period and entered the extension phase; nine received asfotase alfa for at least 6 years and completed the study, with four being treated for more than 7 years. Skeletal healing was sustained over 7 years of treatment; all evaluable patients had RGI-C scores of at least +2 at year 6 (n=9; median score +2·0 range 2·0-3·0) and year 7 (n=7; median score +2·3 2·0-3·0). No patient who completed the study required respiratory support after year 4. Weight Z scores improved to within normal range from year 3 to study end; length or height Z scores improved but remained below normal. Age-equivalent scores on gross motor, fine motor, and cognitive subscales of the Bayley Scales of Infant and Toddler Development also improved. All 11 patients had at least one treatment-emergent adverse event. The most common adverse events were pyrexia (eight 73% of 11 patients), upper respiratory tract infection (eight 73%), craniosynostosis (seven 64%), and pneumonia (seven 64%). Serious adverse events related to asfotase alfa occurred in three (27%) patients (severe chronic hepatitis; moderate immediate post-injection reaction; and severe craniosynostosis with severe conductive deafness).
Patients with perinatal or infantile hypophosphatasia treated with asfotase alfa for up to 7 years showed early, sustained improvements in skeletal mineralisation. Respiratory function, growth, and cognitive and motor function also improved, and asfotase alfa was generally well tolerated.
Alexion Pharmaceuticals, Inc.
Purpose
Residual feeling of leg length discrepancy (LLD) is a common cause of patient dissatisfaction following total hip arthroplasty (THA). The purpose of this study is to propose a method for ...determining an optimal leg length correction goal in THA.
Methods
We conducted a retrospective study of 132 patients to examine the radiographic LLD (R-LLD), perceived LLD (P-LLD), and whether or not the patient has an uncomfortable feeling about the leg length after THA.
Results
The residual discomfort rate in all patients was 9.1% (12/132 patients), and ten of these 12 patients felt uncomfortable due to a longer leg length. When R-LLD was within 7 mm, the rate was 6.8% (8/118 patients), which is nearly equal to the rate of 7.8% (5/64 patients) in cases in which R-LLD was within 2 mm. On the other hand, when R-LLD was 8 mm or more, the rate was 57.1% (4/7 patients).
Conclusions
The results of our study show that 7 mm may be a reasonable threshold for reducing the residual discomfort. However, even with little or no R-LLD, some patients will continue to experience discomfort. We think that this is because of pre-operative differences between R-LLD and P-LLD in such cases. If the patient has a pelvic declination on the affected hip side and a lumbar scoliosis angle that is convex toward the affected hip side before surgery, the ideal length may be a little shorter than the radiographic isometry, since such patients are likely to feel a longer leg length than that shown radiographically.
To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia.
Medical records from ...academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age <6 months were eligible: vitamin B6–dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator–free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life.
Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P < .05) with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean SD: 18.1 15.4 U/L) was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator–free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years.
Patients with perinatal or infantile hypophosphatasia and vitamin B6–dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life.
ClinicalTrials.gov: NCT01419028.
Purpose
The study aimed to evaluate the optimal timing for plate removal after open-wedge high tibial osteotomy (OWHTO) without loss of correction and to investigate risk factors for loss of ...correction after plate removal. The study presents the hypothesis that plate removal without loss of correction was possible when gap filling reached zone 2 (25–50%) on anteroposterior radiographs.
Methods
Ninety-one patients (101 knees) who underwent OWHTO using the TomoFix
®
plate were enrolled. Plate removal was performed at an average 16.4 ± 5.4 months after OWHTO. Clinical evaluation included plate-related symptoms, the Japanese Orthopedic Association Knee Score (JOA score), and Oxford Knee Score (OKS). Radiological outcomes, including the hip–knee–ankle angle (HKA), weight-bearing line ratio (WBLR), medial proximal tibial angle (MPTA), and posterior tibial slope (PTS), were evaluated preoperatively, at plate removal and at 1 year after plate removal. Computed tomography (CT) was performed at plate removal to evaluate the flange bone union, progression rates of gap filling, and posterior cortex bone union. In addition, the risk factors for loss of correction after plate removal were evaluated.
Results
At plate removal, 63 (62.4%) knees had plate-related symptoms (mild, 56 knees; moderate, 7 knees; severe, 0). After plate removal, the JOA score did not change, whereas OKS further improved; six knees developed loss of correction. On CT evaluation at plate removal, the flange bone union was achieved in all cases; the progression rates of gap filling and posterior cortex bone union were 47.0% ± 16.6% and 62.8% ± 16.5%, respectively. A posterior cortex union rate of < 43.3% was the only predictor for loss of correction after plate removal (odds ratio: 1.38,
P
< 0.01).
Conclusions
Plate removal without loss of correction after OWHTO was possible when bone union of the posterior cortex reached the center of the osteotomy gap even in incompletely filled gaps.
Level of evidence
Therapeutic case series, Level IV.
Abstract
Context
Long-term data on enzyme replacement treatment of hypophosphatasia (HPP) are limited.
Objective
To evaluate efficacy and safety of asfotase alfa in patients aged ≤5 years with HPP ...followed for up to 6 years.
Design
Phase 2 open-label study (July 2010 to September 2016).
Setting
Twenty-two sites; 12 countries.
Participants
Sixty-nine patients median (range) age: 16.0 (0.02 to 72) months with severe HPP and sign/symptom onset before age 6 months.
Intervention
Asfotase alfa 2 mg/kg three times/week or 1 mg/kg six times/week subcutaneously.
Main Outcome Measures
Primary efficacy measure: Radiographic Global Impression of Change (RGI-C) score −3 (severe worsening) to +3 (complete/near-complete healing). Additional outcome measures: respiratory status, growth, and safety. Post hoc analysis: characteristics of radiographic responders vs nonresponders at Year 1 (RGI-C: ≥+2 vs <+2).
Results
During median (minimum, maximum) 2.3 (0.02, 5.8) years of treatment, RGI-C scores improved significantly at Month 6 +2.0 (−1.7, +3.0), Year 1 +2.0 (−2.3, +3.0), and Last Assessment +2.3 (−2.7, +3.0); P < 0.0001 all. Of 24 patients requiring respiratory support at Baseline, 11 (46%) no longer needed support. Height/weight z scores generally increased. Nine patients died (13%). All patients experienced at least one adverse event; pyrexia was most common. Compared with responders n = 50 (72%), nonresponders n = 19 (28%) had more severe disease at Baseline and a higher rate of neutralizing antibodies (NAbs) at Last Assessment.
Conclusions
Most infants/young children given asfotase alfa showed early radiographic and clinical improvement sustained up to 6 years; radiographic nonresponders had more severe disease and more frequent NAbs at Last Assessment.
Most infants and young children with hypophosphatasia, treated with asfotase alfa, showed improved skeletal manifestations, respiratory function, and growth within 1 year, maintained up to 6 years.
Nano-fibrillated bacterial cellulose (NFBC) is a safe, biocompatible material that can be prepared by culturing a cellulose-producing bacterium in a culture supplemented with carboxymethylcellulose ...(CMC) or hydroxypropylcellulose (HPC). CM-NFBC and HP-NFBC, prepared using CMC or HPC, show hydrophilicity and amphiphilicity, respectively, and thus they could be useful carriers for hydrophobic anticancer agents such as paclitaxel (PTX). In the present study, we prepared novel PTX formulations for intraperitoneal administration by associating PTX with either CM-NFBC or HP-NFBC and studied their therapeutic efficacy on peritoneally disseminated gastric cancer in a xenograft nude mouse model. Freeze-dried PTX formulations (PTX/CM-NFBC and PTX/HP-NFBC) were quickly reconstituted with saline without any foaming, compared to nanoparticle albumin-bound PTX (nab-PTX, Abraxane®). Both PTX/NFBC formulations extended the mean survival times in our xenograft murine models compared with either free PTX or nab-PTX. The PTX/NFBC formulations reduced systemic side effects of free PTX relating to weight loss. In our disseminated gastric peritoneal cancer model, the PTX/NFBC formulation increased the therapeutic index for PTX by increasing the therapeutic efficacy and decreasing toxicity. NFBCs should receive consideration as improved carriers for the clinical delivery of hydrophobic anticancer drugs such as PTX in malignancies in the abdominal cavity with peritoneal metastasis and dissemination.
Display omitted
•Paclitaxel (PTX) formulation with nanofibrillated bacterial cellulose (NFBC) was made.•Intraperitoneal PTX/NFBC produced higher therapeutic effects than other formulations.•Intraperitoneal PTX/NFBC alleviated the severe systemic side effects caused by Taxol®.
Open wedge high tibial osteotomy (OWHTO) brings new complications such as screw breakages with or without correction loss and time-dependent increased posterior tibial slopes (PTS) due to the opening ...gap. For preventive purposes, we changed our OWHTO procedure from anteromedial plating without filling the gap (non-grafted group, n = 40, 2009–2012) to medial plating with bone-substitute insertion (grafted group, n = 45, 2012–2015). The objectives of this study were to evaluate the complication patterns and the effects of the modifications.
Patients undergoing OWHTO with TomoFix plates were included in this retrospective study. Demographics, clinical outcomes (flexion range and Japanese Orthopaedic Association score) and radiological outcomes (femorotibial angle) were assessed in both groups pre-operatively and 2-years postoperatively. The plate installation angle PIA and screw insertion depth SID were measured on computed tomographic slices at 6 months. PIA/SID was defined as the angle between the tibial anteroposterior axis and plate–width axis/the distance between the proximal screw tip and the proximal tibiofibular joint. The non-grafted group was further divided into complication and non-complication subgroups. Screw breakages were assessed during plate removal (1.5–2.5 years postoperatively).
There were no differences in baseline characteristics or radiological/clinical outcomes between the non-grafted and grafted groups. There were 0 and 11 complications in the grafted and non-grafted groups, respectively. Complications included 7 screw breakages, 4 correction losses, and 5 time-dependent increased PTS with some overlaps. PIA and SID were significantly lower (p < 0.001) and higher (p < 0.001), respectively, in the grafted group and significantly lower (p = 0.018) and higher (p = 0.040), respectively, in the non-complication subgroup within the non-grafted group. The cutoff value of PIA for complications was calculated at 48.0°.
Medial plating OWHTO (PIA<48°) using bone-substitute with deeper screw insertion reinforces the opening gap for better angular stability compared with anteromedial plating without bone-substitute.
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