Spotlight on MuSK Positive Myasthenia Gravis: Clinical Characteristics, Treatment and Outcomes

Background: To investigate the clinical characteristics, treatment and outcomes of myasthenia gravis with antibodies to the muscle-specific tyrosine kinase (MuSK-MG).Methods: We retrospectively reviewed 21 patients with confirmed MuSK-MG between January 2012 to January 2020 in our center. Detailed clinical data and long-term follow up information were summarized.Results: Females (17/21, 81%) predominated in MuSK-MG and the mean age of onset in this group was 51.86±16.16 years. MuSK-MG patients was divided into three subgroups according to the symptom of muscle weakness at onset: ocular myasthenia gravis (OMG, 47.6%), bulbar myasthenia gravis (BMG, 42.9%), and generalized myasthenia gravis (GMG, 9.5%). The mean progression time from symptoms onset to other muscle groups involvement in OMG patients was 4.38±2.54 months. Pyridostigmine bromide was adopted in 81.0% patients and 90.5% patients received corticosteroids. Compared to the usage in hospital, the median daily dose of corticosteroids decreased significantly at the last follow-up. 85.7% patients received a long-term follow-up with an average time of 1202.17 ± 976.73 days. At the end of the follow-up period: 4.8% patient received complete stable remission, 42.9% patients were in minimal manifestations, 19.0% had improved, 4.8% experienced an unchanged condition and 9.5% patients died.Conclusion: Female patients were more prevalent in this study and MuSK-MG patients had a rapid progress to a generalized state. Although about 50% MuSK-MG patients can achieve a favorable outcome with conventional immunosuppressants, complete stable remission is rare and about 15% respond poorly, more effective medications should be explored in these patients.

Casein Glycomacropeptide: An Alternative Protein Substitute in Tyrosinemia Type I

Tyrosinemia type I (HTI) is treated with nitisinone, a tyrosine (Tyr) and phenylalanine (Phe)-restricted diet, and supplemented with a Tyr/Phe-free protein substitute (PS). Casein glycomacropeptide (CGMP), a bioactive peptide, is an alternative protein source to traditional amino acids (L-AA). CGMP contains residual Tyr and Phe and requires supplementation with tryptophan, histidine, methionine, leucine, cysteine and arginine. Aims: a 2-part study assessed: (1) the tolerance and acceptability of a low Tyr/Phe CGMP-based PS over 28 days, and (2) its long-term impact on metabolic control and growth over 12 months. Methods: 11 children with HTI were recruited and given a low Tyr/Phe CGMP to supply all or part of their PS intake. At enrolment, weeks 1 and 4, caregivers completed a questionnaire on gastrointestinal symptoms, acceptability and ease of PS use. In study part 1, blood Tyr and Phe were assessed weekly; in part 2, weekly to fortnightly. In parts 1 and 2, weight and height were assessed at the study start and end. Results: Nine of eleven children (82%), median age 15 years (range 8.6–17.7), took low Tyr/Phe CGMP PS over 28 days; it was continued for 12 months in n = 5 children. It was well accepted by 67% (n = 6/9), tolerated by 100% (n = 9/9) and improved gastrointestinal symptoms in 2 children. The median daily dose of protein equivalent from protein substitute was 60 g/day (range 45–60 g) with a median of 20 g/day (range 15 to 30 g) from natural protein. In part 2 (n = 5), a trend for improved blood Tyr was observed: 12 months pre-study, median Tyr was 490 μmol/L (range 200–600) and Phe 50 μmol/L (range 30–100); in the 12 months taking low Tyr/Phe CGMP PS, median Tyr was 430 μmol/L (range 270–940) and Phe 40 μmol/L (range 20–70). Normal height, weight and BMI z scores were maintained over 12 months. Conclusions: In HTI children, CGMP was well tolerated, with no deterioration in metabolic control or growth when studied over 12 months. The efficacy of CGMP in HTI needs further investigation to evaluate the longer-term impact on blood Phe concentrations and its potential influence on gut microflora

A 10 Year Retrospective Observational Study on The Utility and Prescription Standards of Dexamethasone in Pediatric Neuro-oncosurgery in a Tertiary Care Centre.

Object: This study aimed to retrospectively assess dexamethasone utility in pediatric CNS tumor patients over a 10-year period, to better understand dosing variability, and highlight optimal practice. Methods: All pediatric CNS tumor cases managed operatively for a ten year period at a single center were reviewed. Information was gathered on demographics, dexamethasone doses, course durations, weaning regimes, PPI co-prescription, adverse events, and route of administration. Comparison within these groups was analyzed through use of statistical testing. Results: 127 patients received 193 dexamethasone courses. Median age was 7 years, with a median weight of 27.9kg. Most common tumor type was astrocytoma (24.8%). Median daily dose was 8mg, with twice daily dosing most common. Median course duration was 8 days,. Median weaning duration was 11.5 days. Daily dose was not correlated with patient weight and the median daily dose per kg was 0.2319mg/kg. Dexamethasone dose per kg was significantly inversely correlated with age. 44.9% of patients received intravenous dexamethasone only. 32.7% received oral dexamethasone only. 22.4% received multiple different routes of administration throughout their course. Intravenous dexamethasone was more commonly used in young age groups. Incidence of adverse effects was 14.5% with Cushing’s syndrome most common. Dexamethasone dose per kg was not significantly different between patients with and without adverse effects; however, average dexamethasone course duration was significantly different between these groups. No relationship was noted between adverse effects incidence and administration route. 64.2% of patients received concurrent PPI with 35.8% receiving no PPI. Conclusions: Large variation was seen in practice, with prescriptions appearing based on clinician preference and symptom severity rather than patient age or weight. Dexamethasone administration route interestingly showed no relationship with incidence of adverse effects. Future guidelines should consider lower dose regimens with less frequent dosing as these may benefit quality of life.

#28: Serum Posaconazole Concentrations Among Children, Adolescents, and Young Adults Receiving Delayed-Release Tablet And Intravenous Posaconazole

Background Posaconazole is a broad-spectrum antifungal used for prophylaxis and treatment of invasive fungal infections. There are limited data on the optimal dosing, safety, and effectiveness of the delayed-released tablets (DRT) and intravenous (IV) formulations in immunocompromised pediatric and adolescent patients. Methods A retrospective chart review was performed to study all immunocompromised patients who received DRT or IV formulations of posaconazole at our institution from January 1, 2014, to July 31, 2019, and had at least one plasma trough concentration. Plasma concentrations ≥0.7 µg /mL were considered therapeutic for prophylaxis, and ≥1.0 µg/mL for treatment. We describe our experience including dosing, plasma trough concentrations, safety, and tolerability. Results We identified 54 patients (28 males/26 females) who received DRT or IV formulations of posaconazole. The median age was 14 years (range 2–21 years). Thirty-one (57%) patients received posaconazole for treatment and 23 (43%) for prophylaxis. The most common underlying condition was hematological malignancies (66%) and 19 patients (35%) had received an allogeneic HSCT and were receiving immunosuppressive therapy. Overall, 36 (67%) patients achieved targeted initial plasma trough concentrations (median 1.3 µg/mL, IQR 0.758–1.760 µg/mL) (Figure). The median daily dose among patients <13 years of age who achieved the targeted initial plasma trough concentrations was 7.3 mg/kg/day (IQR 6.8–11.0) for the DRT formulation and 9.8 mg/kg/day (IQR 7.4–11.7) for the IV formulation. The median daily dose among patients ≥ 13 years of age who achieved the targeted initial plasma trough concentrations was 4.9 mg/kg/day (IQR 4.1–6.5) for the DRT formulation and 5.6 mg/kg/day (IQR 3.9–5.8) for the IV formulation. Concomitant use of H2-receptor blockers (H2RA) and/or proton pump inhibitors (PPI) medications were not associated with failure to achieve target trough levels (P = 0.96). Thirty-six patients (67%) developed transaminitis, mostly grade 1. Conclusions Our results show that DRT and IV formulations are safe and effective in immunocompromised children, adolescents, and young adults. Higher dosing per body weight of DRT and IV posaconazole may be required in patients <13 years of age compared with patients 13 years of age and older to achieve therapeutic plasma concentrations. It appears that neither a PPI nor an H2RA has an effect on the plasma exposure of the DRT.

Use of Lisdexamfetamine or Amphetamine? Interpretation of Chiral Amphetamine Analyses

Amphetamine is frequently detected in forensic toxicological cases. Differentiating between the two isomers of amphetamine (d-amphetamine and l-amphetamine) and determining their relative proportion are fundamental to correctly interpret the results of toxicological analyses. The aim of this study was to examine the profile of amphetamine as well as storage stability of the isomers in authentic samples from patients chronically treated with lisdexamfetamine (LDX), the most prescribed medical amphetamine product in Sweden. Blood and urine samples were collected from 18 patients. The samples were analyzed with an achiral (racemate) method for quantification of amphetamine and with a chiral method to determine the proportion of each isomer of amphetamine. The median daily dose of LDX was 40 mg (range, 20–70 mg). The median amphetamine concentration was 0.06 µg/g (range, 0.02–0.15 µg/g) in blood and 6 µg/mL (range, 1–22 µg/mL) in urine. Only d-amphetamine was found in the blood and urine samples from the included patients. Furthermore, no formation of l-amphetamine occurred during the storage for 3 months at 4°C, 9 months at −20°C and three freeze–thaw cycles. The results from this study may be helpful in the interpretation of whether the source of identified amphetamine in biological samples is from LDX drug intake or not.

Clinical Experience with High-Dose Polymyxin B against Carbapenem-Resistant Gram-Negative Bacterial Infections—A Cohort Study

Population pharmacokinetic studies have suggested that high polymyxin B (PMB) doses (≥30,000 IU/kg/day) can improve bacterial kill in carbapenem-resistant Gram-negative bacteria (CR-GNB). We aim to describe the efficacy and nephrotoxicity of patients with CR-GNB infections prescribed high-dose PMB. A single-centre cohort study was conducted from 2013 to 2016 on septic patients with CR-GNB infection and prescribed high-dose PMB (~30,000 IU/kg/day) for ≥72 h. Study outcomes included 30-day mortality and acute kidney injury (AKI) development. Factors associated with AKI were identified using multivariable regression. Forty-three patients with 58 CR-GNB received high-dose PMB; 57/58 (98.3%) CR-GNB were susceptible to PMB. The median daily dose and duration of high-dose PMB were 32,051 IU/kg/day (IQR, 29,340–34,884 IU/kg/day) and 14 days (IQR, 7–28 days), respectively. Thirty-day mortality was observed in 7 (16.3%) patients. AKI was observed in 25 (58.1%) patients with a median onset of 8 days (IQR, 6–13 days). Higher daily PMB dose (aOR,1.01; 95% CI, 1.00–1.02) and higher number of concurrent nephrotoxins (aOR, 2.14; 95% CI; 1.03–4.45) were independently associated with AKI. We observed that a sizable proportion developed AKI in CR-GNB patients described high-dose PMB; hence, the potential benefits must be weighed against increased AKI risk. Concurrent nephrotoxins should be avoided to reduce nephrotoxicity.

Interim analysis for post-marketing surveillance of dabrafenib and trametinib combination therapy in Japanese patients with unresectable and metastatic melanoma with BRAF V600 mutation

Purpose To investigate the safety and efficacy of dabrafenib and trametinib combination therapy for BRAF V600 mutation-positive unresectable and metastatic melanoma in over 100 Japanese patients of a real-world clinical setting. Patients The surveillance period of interim post-marketing surveillance (PMS) analysis was from June 2016 to November 2018, and 112 patients with unresectable and metastatic BRAF V600 melanoma who received dabrafenib and trametinib were enrolled. Results The safety analysis set included 112 patients whom almost all patients had stage IV disease (n = 97, 86.61%) with an Eastern Cooperative Oncology Group performance status 0 or 1 (n = 102, 91.07%), and mean (standard deviation) lactate dehydrogenase level was 354.3 (456.4) U/L (n = 105) at baseline. Median daily dose of dabrafenib was 300.0 mg/day (118–300), and median daily dose of trametinib was 2.00 mg/day (1.0–4.0). Adverse drug reactions (ADRs) were reported in 84 patients (75%), and common ADRs (incidence ≥ 5%) were pyrexia (n = 49, 43.75%), hepatic function abnormal (n = 11, 9.82%), rash and blood creatine phosphokinase increased (n = 9 each, 8.04%), and erythema nodosum (n = 6, 5.36%). Majority of ADRs reported in this study were consistent with that reported in previous trials. In the efficacy analysis set of 110 patients, the objective response rate was 55.45% (95% confidence interval 45.67–64.93%), and median progression-free survival was 384.0 days (251.0 days-not reached). Conclusions No new safety or efficacy concerns were observed in this interim PMS analysis in Japanese patients with unresectable and metastatic melanoma with BRAF gene mutation who received dabrafenib and trametinib combination therapy.

Experience of protein C administration in children with acquired deficiency

Тhere is increasing experience of protein C concentrate administration in world practice, but despite that, information of this drug administration in patients with oncohematological diseases and primary immunodeficiency syndromes is lacking. Objective: to study the effectiveness of protein C concentrate administration in pediatric patients with acquired protein C deficiency during the treatment of oncological, hematological or immunological diseases. Medical charts of 12 patients who received inpatient treatment and protein C concentrate administration in the Dmitry Rogachev National Clinical Research Center from 01/01/2012–12/31/18 were analyzed. Depending on the presence or absence of thrombosis, the patients were divided into two groups. Single and daily doses, the number of injections per day, the duration of therapy and the percentage of activity of protein C activity were studied in both groups. Вoth groups included 6 patients, median of a single administrated dose of protein C was lower in the group of patients with thrombosis than in patients without them (20 and 71.4 IU/kg, p < 0.0001), while there were obtained no differences between treatment efficacy (p = 0.45). When comparing the administered dose of the drug in children with unresolved and resolved thrombosis, it was found that the median single dose in patients with ineffective treatment was lower than in those who had effective treatment (8.78 and 71.4 IU/kg, respectively, p < 0.0001); the median daily dose was also lower in the group with ineffective treatment (20 and 71.4 IU/kg, respectively, p < 0.005). Рrotein C administration in children with acquired deficiency for the purpose of antithrombotic prophylaxis can be potentially effective, especially in those patients who already have a thrombosis at the moment of administration. The effectiveness of such prophylaxis may depend on the dose of the injected concentrate. To determine the appropriate dose and mode of administration of the drug in children a prospective study is required. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology.

Efficacy and Safety of Sodium Zirconium Cyclosilicate for Treatment of Hyperkalemia: An 11-Month Open-Label Extension of HARMONIZE

Background: Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for treatment of hyperkalemia. An open-label extension (OLE) of the ­HARMONIZE study evaluated efficacy and safety of SZC for ≤11 months. Methods: Patients from HARMONIZE with point-of-care device i-STAT K+ 3.5–6.2 mmol/L received once-daily SZC 5–10 g for ≤337 days. End points included achievement of mean serum K+ ≤5.1 mmol/L (primary) or ≤5.5 mmol/L (secondary). Results: Of 123 patients who entered the extension (mean serum K+ 4.8 mmol/L), 79 (64.2%) completed the study. The median daily dose of SZC was 10 g (range 2.5–15 g). The primary end point was achieved by 88.3% of patients, and 100% achieved the secondary end point. SZC was well tolerated with no new safety concerns. Conclusion: In the HARMONIZE OLE, most patients maintained mean serum K+ within the normokalemic range for ≤11 months during ongoing SZC treatment.

Abstract 17231: Sodium Channel Blockers Shorten Prolonged QTC in Patients With Rett Syndrome

Introduction: Rett syndrome (RTT) is an X-linked disorder caused by mutations in the MECP2 gene resulting in various neurological, respiratory, and gastrointestinal symptoms. Up to 25% of deaths in RTT are sudden. Prolonged corrected QT (QTc) has also been reported and thought to be a cause of sudden death in RTT. Previous studies in mice with RTT showed that MECP2 mutations lead to persistent increased cardiac sodium current causing prolonged QTc and increasing risks of ventricular tachycardia. The aim of this study was to determine whether sodium channel blockers lidocaine (acutely) and mexiletine (chronically) shorten QTc in RTT patients. Hypothesis: Sodium channel blockers such as lidocaine (acutely) and mexiletine (chronically) significantly shorten QTc (≥ 30ms from baseline) in RTT patients with prolonged QTc. Methods: RTT patients with prolonged QTc were prospectively enrolled to receive a lidocaine attenuation test. The test consisted of a loading dose of 1 mg/kg intravenous lidocaine followed by a continuous infusion at 50 μg / (kg·min). Patients were deemed responders should their QTc shorten by 30 ms or more. These patients were then prescribed mexiletine for chronic therapy. Results: A total of 6 patients (all females) were given lidocaine and mexiletine. The median age of the cohort at the time of testing was 12 years (8-19 years), and the median QTc before therapy was 480.5 ms (476-506 ms). All 6 patients responded positively to lidocaine with median QTc shortening of 44.5 ms (33-54 ms, P = 0.018). The median daily dose of mexiletine was 8.75 mg/kg. The median duration of therapy was 5 months (4-12 months). Mexiletine shortened QTc by an average of 47 ms at latest follow-up ( P = 0.016). One patient developed whole-body tremors as a side effect of mexiletine, which was stopped. Conclusions: Sodium channel blockers that target late sodium channels were effective in shortening QTc thereby confirming the presence of late sodium current causing prolonged QTc in RTT. Therefore mexiletine could be used clinically in RTT patients with long QTc. Larger and longer studies are needed to confirm these drugs’ positive effects in shortening the QTc and reducing arrhythmic events in RTT patients.