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Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) are progressive neuromuscular disorders resulting from mutations in the dystrophin gene. BMD presents similarly to DMD, but generally has a milder clinical course. Clinical features include progressive weakness beginning in the proximal leg and pelvic musculature with eventual involvement of the upper limb, shoulder, and neck muscles. Muscular degeneration in these areas is often associated with orthopedic complications such as scoliosis requiring surgical intervention. The presence of dystrophin in cardiac, smooth, and skeletal muscle as well as in the brain produces complex multisystem involvement that increases the risk of morbidity and mortality during anesthetic care. Common perioperative concerns include the potential for difficult airway management, comorbid cardiac disease with alterations in conduction and contractility, reduced pulmonary capacity, rhabdomyolysis, and an increased sensitivity to various anesthetic agents. We present a 19-year-old male with BMD who required anesthetic care for posterior spinal fusion. Previous reports of anesthetic care for these patients are reviewed, the end-organ involvement discussed, and options for anesthetic care presented. [ABSTRACT FROM AUTHOR]

This study of vosaroxin evaluated dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), pharmacokinetics (PK), clinical activity and pharmacodynamics in relapsed/refractory leukemia. Dosing was weekly (days 1, 8 and 15) or twice weekly (days 1, 4, 8 and 11). Seventy-three treated patients had a median age of 65 years, 85% had acute myeloid leukemia and 78% had refractory disease. Weekly schedule: 42 patients received 18-90 mg/m(2); MTD was 72 mg/m(2). Twice-weekly schedule: 31 patients received 9-50 mg/m(2); MTD was 40 mg/m(2). DLT was stomatitis; primary non-hematologic toxicity was reversible gastrointestinal symptoms and febrile neutropenia. Thirty-day all-cause mortality was 11%. Five patients had complete or incomplete remissions; median duration was 3.1 months. A morphologic leukemia-free state (bone marrow blast reduction to <5%) occurred in 11 additional patients. Antileukemic activity was associated with total dose or weekly time above 1 μmol/l plasma vosaroxin concentration (P<0.05). Vosaroxin exposure was dose proportional over 9-90 mg/m(2). The average terminal half-life was ~25 h and clearance was non-renal. No induction or inhibition of vosaroxin metabolism was evident. Vosaroxin-induced DNA damage was detected as increased intracellular γH2AX. Vosaroxin had an acceptable safety profile, linear PK and encouraging clinical activity in relapsed/refractory leukemia. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy leads to progressive deterioration in skeletal and cardiac muscle function. Steroids prolong ambulation and improve respiratory muscle strength. The authors hypothesized that steroid treatment would stabilize cardiac muscle function. Echocardiograms performed from 1997 to 2004 for 111 subjects 21 years of age or younger with Duchenne muscular dystrophy were restrospectively reviewed. The medical record was reviewed for steroid treatment. Untreated and steroids-treated subjects did not differ in age, height, weight, body mass index, systolic and diastolic blood pressure, or left ventricular mass. The shortening fraction was lower in the untreated group. Of those treated, 29 received prednisone and 19 received deflazacort. There was no difference in the shortening fraction between the two treated subgroups. Treated subjects not receiving steroids still had a normal shortening fraction, which was no different from the shortening fraction of those still receiving treatment. As compared with the treated subjects, the untreated subjects 10 years of age or younger were 4.4 times more likely to have a shortening fraction less than< 28% ( p = 0.03), and the untreated subjects older than 10 years were 15.2 times more likely to have a shortening fraction less than< 28% ( p < 0.01). This retrospective study suggests that the progressive decline in cardiac function of patients with Duchenne muscular dystrophy can be altered by steroid treatment. The effect appears to be sustained beyond the duration of treatment and independent of steroid type. [ABSTRACT FROM AUTHOR]

A relationship was proved between constitutive activity of leukemic cell c-jun-N-terminal kinase (JNK) and treatment failure in AML. Specifically, early treatment failure was predicted by the presence of constitutive JNK activity. The mechanistic origins of this association was sought. A multidrug resistant leukemic cell line, HL-60/ADR, characterized by hyperexpression of c-jun and JNK activity, was transfected with a mutant c-jun vector, whose substrate N-terminal c-jun serines were mutated. Down-regulated expression occurred of c-jun/AP-1-dependent genes, catalase and glutathione-S-transferase (GST) π, which participate in cellular homeostasis to oxidative stress and xenobiotic exposure. MRP-efflux was abrogated in HL-60/ADR cells with dominant-negative c-jun, perhaps because MRP1 protein expression was also lost. Heightened sensitivity to dau-norubicin resulted in cells subjected to this change. Biochemical analysis in 67 primary adult AML samples established a statistical correlation between cellular expression of c-jun and JNK activity, JNK activity with hyperleukocytosis at presentation of disease, and with exuberant MRP efflux. These find-ings reflect the survival role for c-jun/AP-1 and its regulatory kinase previously demonstrated for yeast in homeostatic response to oxidative stress and in operation of ATP-binding cassette efflux pumps, and may support evolutionary conservation of such function. Thus, JNK and c-jun may be salient drug targets in multidrug resistant AML. [ABSTRACT FROM AUTHOR]

The treatment outcome for most adults with acute myeloid leukemia (AML) remains unacceptable. Additional agents or substitution of high-dose cytarabine for conventional-dose cytarabine during induction does not improve the remission rate or overall survival. There is substantial toxicity with high-dose cytarabine during induction. Thus, induction therapy for newly diagnosed patients with AML should consist of cytarabine (100 mg/m(2) as a continuous intravenous infusion over 24 hours for 7 days) and daunorubicin, idarubicin, or mitoxantrone. Meta-analysis demonstrates a modest benefit for idarubicin. Most patients who achieve a remission should receive further therapy with two to four cycles of high-dose cytarabine. Allogeneic stem cell transplant is reserved for patients with poor risk features. There is no role for autologous stem cell transplant in first remission outside a clinical trial. The majority of adults relapse. Salvage therapy usually consists of high-dose cytarabine. Allogeneic or autologous stem cell transplantation is preferred in second or subsequent remission. Uncommon diseases such as AML, for which the outcome remains poor, should be treated on clinical trials whenever possible. [ABSTRACT FROM AUTHOR]

In the use of autologous PBPC transplantation in patients with multiple myeloma, contamination of PBPC with myeloma cells is commonly observed. Enrichment for CD34+ cells has been employed as a method of reducing this contamination. In this study the reduction of myeloma cells in PBPC was accomplished by the positive selection of CD34+ cells using immunomagnetic bead separation (Isolex 300 system). PBPC were mobilized from 18 patients using cyclophosphamide (4.5 g/m2) and G-CSF (10 μg/kg/day). A median of two leukaphereses and one selection was performed per patient. The median number of mononuclear cells processed was 3.50 × 1010 with a recovery of 1.11 × 108 cells after selection. The median recovery of CD34+ cells was 48% (range 17–78) and purity was 90% (29–99). The median log depletion of CD19+ cells was 3.0. IgH rearrangement, assessed by PCR, was undetectable in 13 of 24 evaluable CD34+ enriched products. Patients received 200 mg/m2 of melphalan followed by the infusion of a median of 2.91 × 106/kg CD34+ cells (1.00–16.30). The median time to absolute neutrophil count >0.5 × 109/l was 11 days, and sustained platelet recovery of >20 × 109/l was 14 days. We conclude that immunomagnetic-based enrichment of CD34+ cells results in a marked reduction in myeloma cells without affecting engraftment kinetics. [ABSTRACT FROM AUTHOR]

Abstract Background Steroid use has prolonged ambulation in Duchenne muscular dystrophy (DMD) and combined with advances in respiratory care overall management has improved such that cardiac manifestations have become the major cause of death. Unfortunately, there is no consensus for DMD-associated cardiac disease management. Our purpose was to assess effects of steroid use alone or in combination with angiotensin converting enzyme inhibitors (ACEI) or angiotension receptor blocker (ARB) on cardiovascular magnetic resonance (CMR) derived circumferential strain (εcc). Methods We used CMR to assess effects of corticosteroids alone (Group A) or in combination with ACEI or ARB (Group B) on heart rate (HR), left ventricular ejection fraction (LVEF), mass (LVM), end diastolic volume (LVEDV) and circumferential strain (εcc) in a cohort of 171 DMD patients >5 years of age. Treatment decisions were made independently by physicians at both our institution and referral centers and not based on CMR results. Results Patients in Group A (114 studies) were younger than those in Group B (92 studies)(10 ± 2.4 vs. 12.4 ± 3.2 years, p < 0.0001), but HR, LVEF, LVEDV and LVM were not different. Although εcc magnitude was lower in Group B than Group A (-13.8 ± 1.9 vs. -12.8 ± 2.0, p = 0.0004), age correction using covariance analysis eliminated this effect. In a subset of patients who underwent serial CMR exams with an inter-study time of ~15 months, εcc worsened regardless of treatment group. Conclusions These results support the need for prospective clinical trials to identify more effective treatment regimens for DMD associated cardiac disease.

Muscular dystrophy (MD) patients can suffer from significant cardiac disease with resultant major morbidity and mortality. The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) sought to better characterize our previously described outcomes associated with VAD therapy across multiple centers. We examined outcomes of patients with MD and dilated cardiomyopathy implanted with a durable VAD at participating centers from 9/2012 to 1/2023. A total of 48 VADs were implanted in 33 patients across 15 sites. While four patients received a VAD from 2012 to 2017, a further 29 received a VAD from 2018 to 2023. The most common MD was a dystrophinopathy (Becker, Duchenne, intermediate or affected carrier), followed by Emery-Dreifuss, Limb girdle and other MD. The median age at implant was 16.8 years (range 9.2-31.7). Seven (21%) patients were implanted as a bridge to transplant, 6 of whom survived to transplant. Of patients implanted as bridge to decision or destination therapy, 87% were alive at 1 year and 82% at 2 years. The overall frequencies of positive outcome (transplanted or alive on device) at 1 year and 2 years were 84% and 80%, respectively. Major complications included stroke (6%), sepsis (15%), tracheostomy (3%), and severe right heart failure requiring right-sided VAD (9%). Other common but not severe complications included other major infection (21%), bleeding (30%, although none required surgical intervention), and arrhythmias requiring cardioversion (15%). Longest follow-up in this cohort is now greater than 5 years on device. VADs are being increasingly utilized in the MD population and implantation can be successful, with similar complication rates to non-MD patients. Ongoing work in patient selection, assessing quality of life, and further surgical/medical optimization is needed. [ABSTRACT FROM AUTHOR]

An 8-year-old boy with known ACTA1 -associated congenital myopathy marked by mild symmetric distal weakness, myalgias and easy fatigability, presented with sudden cardiac arrest. He collapsed suddenly while participating in gym. Bystander cardio-pulmonary resuscitation was begun. Upon emergency responder arrival, he was found to be in ventricular tachycardia (VT) and was successfully defibrillated. Subsequent cardiac imaging demonstrated basilar left ventricular hypertrophy meeting criteria for hypertrophic cardiomyopathy (HCM), with continued atrial arrhythmias. Expanded genetic testing revealed a variant of unknown significance in MYH7 , which was not felt to be explanatory. He received an implantable cardioverter defibrillator and is doing well with no progression of his neuromuscular disease. Seven additional patients with pathogenic ACTA1 mutations who are followed at our institution were reviewed. Of these, three had never undergone cardiac testing, including one with a severe phenotype who passed away at age 2y secondary to respiratory complications. One patient had a history of VT found on ambulatory rhythm monitor, HCM, and subsequent cardiac dysfunction all prior to age 18 years. He died at age 29 from respiratory complications. Three other patients received cardiac screening with no major cardiac disease nor arrhythmia. In prior large case series of more than 200 patients, CM was found to be rare. However, multiple individual case reports with multiple CM phenotypes and sudden death have been reported. Our small, single-center series demonstrates disease in 2 of 5 studied patients, or 2 of 8 total patients. This may suggest a higher prevalence of cardiac disease in this population using modern screening. Additionally, it is possible previously idiopathic sudden death episodes may be attributable to ACTA1 congenital myopathy. Regular cardiac screening in this population should be considered. [ABSTRACT FROM AUTHOR]

Demonstrating the impact of increasing therapeutic options and the improvement in standards of care on mortality for Muscular Dystrophy (MD) in the US has been limited by challenges in broad data collection with long-term follow-up. We assessed whole-population overall survival (OS) among males with MD in the US using National Center for Health Statistics (NCHS, which completely captures deaths in the US) and birth data (1979–2021). OS was estimated using the Kaplan-Meier method applied to survival times inferred from estimated MD births and reported deaths associated with MD by year and age at death. Bayesian analysis was used to estimate 95% credible intervals (CrI) accounting for uncertainty in MD incidence. From 1979 to 2021, 30,242 deaths with MD in males were recorded. Median OS was 25 years (95% CrI 23, 27). Compared to the 1979-1989 birth cohort, males born later experienced a lower hazard of death by 17.8% (3.6%, 20.5%) for those born 1990-2000, by 48.7% (41.8%, 50.0%) for those born 2001-2011 and by 60.6% (55.2%, 61.6%) for those born 2012-2021. Across these birth cohorts, increasing proportions survived to age 20 years (0.63, 0.71, 0.79, n/a) and to age 30 years (0.25, 0.30, n/a, n/a). Of all deaths, nearly 1/2 were coded with respiratory failure, and nearly 1/3 with heart failure. Proportions of deaths coded with respiratory, or heart failure were similar across birth cohorts after accounting for age at death. The substantial MD survival gains observed over recent decades in this whole-population study are consistent with findings from smaller cohort studies and recent meta-analyses. Despite these improvements, male MD survival falls short of the general population. As the MD care and research community continues to invest in innovation and broader adoption of care standards and therapeutics, our findings support continued use of NCHS data to benchmark impacts on whole-population MD survival and cause of death. [ABSTRACT FROM AUTHOR]

Left ventricular anatomic substrates predisposing the development of congestive heart failure in infants with atrial left-to-right shunting after aortic coarctation repair were characterized. Mitral valve, but not aortic or left ventricular, hypoplasia correlated with the development of heart failure and the need for atrial defect closure shortly after coarctation repair. [ABSTRACT FROM AUTHOR]

Cardiac disease results in significant morbidity and mortality in patients with muscular dystrophy (MD). Single centers have described their ventricular assist device (VAD) experience in this population, however broader applicability and outcomes remain unknown. We examined outcomes of all patients with MD and dilated cardiomyopathy implanted with a VAD at Advanced Cardiac Therapies Improving Outcomes Network (ACTION) centers 9/2012-9/2020. A total of 19 VADs were implanted in 18 patients across 10 ACTION sites. The median duration of support was 252 days (range 11-1681 days). The majority of pts had dystrophinopathy (66%) and the median age at implant was 17.2 years (Table). Device strategy was bridge to transplant in 5 (27.8%), 4 of whom survived to transplant. The frequency of a positive outcome (transplanted or alive on device) at 6 months and 1 year were 89% and 84%, respectively (Figure). A single patient suffered a stroke (hemorrhagic), 2 patients developed sepsis, 1 patient developed respiratory failure requiring tracheostomy and 4 patients patient developed right heart failure (1 of whom required temporary right VAD). In selected MD patients, VADs can serve as effective bridges to HT and chronic therapy. Right heart failure and infectious complications were relatively common, while stroke and respiratory failure were rare. Further research is needed to understand the patients who may benefit most from VAD therapy in terms of survival and quality of life and how to mitigate the risks the of the adverse events identified in the current report. [ABSTRACT FROM AUTHOR]

Current trials in Duchenne muscular dystrophy (DMD) have focused on the distance traveled using the 6-min walk test (6MWT). As a primary efficacy outcome for clinical trials it can be quantified over a continuous scale. Limitations include a self-selected walking speed irrespective of encouragement and weakness predisposing to falls. We predicted that a monetary incentive of $50 could improve same-day 6MWT performance. Nine DMD boys (mean age 7.7) were instructed to walk quickly, not run. Encouragement was permitted throughout the test. Subjects were then stratified into an above or below 350 m group and randomly assigned to either the incentivized (IN) or non-incentivized (non-IN) group. A second 6MWT was completed after a rest period during which the following instructions were provided. The IN was told “If you walk faster on this repeat 6MWT you will receive $50. Remember to walk quickly and safely.” The non-IN were told “You are repeating the 6MWT and remember to walk quickly and safely.” The same evaluator conducted both tests, was blinded to group, and provided the same encouragement during each 6MWT. Current data is available in 9 boys, however data on a cohort of 36 will be presented. The boys in the IN ( n = 5, mean age = 7.7) walked an average of 44 m (11%, max: 105 m) farther on the second 6MWT. The non-IN ( n = 4, mean age = 7.6) walked an average of 5.1 m (2%, max: 16 m) farther. The increase in distance in IN was most distinct in the above 350 m (75 m or 17%) compared to the below 350 m (24 m or 7%) group. Our pilot data suggest that a financial incentive results in a measurable increase in within-day 6MWT distance in DMD. This variance is more pronounced in the above 350 m group which is the typical target for clinical trials. This data suggests that external motivators have a significant impact on the 6MWT and should be considered in the design and interpretation of clinical trials. [ABSTRACT FROM AUTHOR]