2 Minute Medicine Rewind January 8, 2018

Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain

Sporadic arteriovenous malformations (AVMs) of the brain are a leading cause of hemorrhagic stroke in children and young adults. While the etiology of these malformations is unclear, similar lesions are found in rare genetic disorders, such as hereditary hemorrhagic telangiectasia. As such, it has been hypothesized that somatic genetic mutations may underlie the development of sporadic AVMs in the brain. In this case-control study, tissue samples of AVMs of the brain and blood samples from 39 patients in the main study group and 33 patients in an independent validation group were whole exome-sequenced to probe for somatic genetic variants. Droplet digital PCR analysis revealed three somatic missense activating KRAS mutations in arteriovenous malformation tissue samples from 29 of the 39 patients, but in none of the 21 paired blood samples nor in 3 non-AVM vascular lesions of the brain. These results were verified in the independent validation group. KRAS is an effector molecule that acts downstream of several receptor tyrosine kinases. These tyrosine kinases activate various cell signaling networks responsible for phosphorylating target molecules, such as ERK1/2 of the MAPK-ERK signaling pathway. Researchers observed increased levels of ERK1/2 phosphorylation in endothelial cell-enriched cultures from patients with KRAS mutations, but not in control cultures. Furthermore, RNA-sequencing of human umbilical vein endothelial cells expressing plasmids for the two most common KRAS variants from the main study group analysis revealed enrichment of genes involved in angiogenesis and vascular development and proliferation. Finally, the mutant-KRAS cells exhibited abnormal elongated morphology and increased migration and motility. Altogether, these results suggest that endothelial cell somatic activating KRAS mutations may lead to dysregulation of the MAPK-ERK signaling pathway and the development of sporadic arteriovenous malformations.

Effect of Mechanically Expanded vs Self-Expanding Transcatheter Aortic Valve Replacement on Mortality and Major Adverse Clinical Events in High-Risk Patients With Aortic Stenosis: The REPRISE III Randomized Clinical Trial

Transcatheter aortic valve replacement (TAVR) for symptomatic severe aortic stenosis has become widely employed in patients at intermediate or greater surgical risk. However, TAVR devices that use self-expanding valves (SEV) have limitations in safety and effectiveness, including the risk of hemodynamic compromise during implantation and paravalvular leak (PVL). Conversely, the mechanically expanded valve (MEV) functions early during deployment, is retrievable following implantation, and has an adaptive seal to minimize PVL. In this multicenter randomized controlled trial, 912 patients were randomized in a 2:1 ratio to receive the mechanically expanded Lotus Valve System or the commercially available self-expanding CoreValve to evaluate whether MEV is noninferior to SEV in both safety and effectiveness. Researchers found that the 30-day primary safety end point (all-cause mortality, stroke, life-threatening or major bleeding, stage 2/3 acute kidney injury, and major vascular complications) occurred in 20.3% of MEV patients, and 17.2% of SEV patients (between-group difference 3.1%, 97.5% CI – to 8.3%, p=0.003 for noninferiority). The 1-year primary effectiveness end point (composite of all-cause mortality, disabling stroke, and moderate or greater PVL) occurred in 15.4% of MEV patients and 25.5% of SEV patients (between-group difference -10.1%, 97.5% CI – to -4.41%, p<0.001 for noninferiority). Moderate or severe PVL occurred in 0.9% in the MEV group and 6.9% in the SEV group (between-group difference -6.1%, 95% CI -9.6% to -2.6%, p<0.001 for superiority). Finally, valve thrombosis and the need for a new pacemaker within one year were more common in the MEV group, while disabling stroke, valve malpositioning, TAV-in-TAV deployment, and repeat procedures for valve dysfunction were less common. Limitations of this study included the use of possibly outdated noninferiority margins given rapid improvements in the TAVR procedure over time, the comparison of MEV to an early-generation SEV instead of the newer generation SEV-E, and the lack of long-term assessment of primary and secondary end points. Overall, these findings illustrate noninferiority in both safety and effectiveness of the MEV, and indicate that it may be a useful addition in the treatment of high-risk severe aortic stenosis patients undergoing TAVR.

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

Scleroderma with internal-organ involvement is a devastating autoimmune disorder, with little to no improvements in mortality due to pulmonary involvement over the past 40 years. Despite exhaustive investigations concerning the role of disease-modifying anti-rheumatic drugs and biologics, only cyclophosphamide administered over the course of 1-year has shown short-term benefit. Previous studies of autologous hematopoietic stem-cell transplantation (HSCT) showed improvement in skin sclerosis and pulmonary function. However, HSCT has not been widely adopted into clinical practice due to concerns surrounding safety and durability of response. In this phase 2 randomized controlled trial, 75 scleroderma patients with pulmonary or renal involvement were randomized to receive either 11 monthly infusions of cyclophosphamide or myeloablative CD34+ selected autologous stem-cell transplantation to study the impact on scleroderma disease manifestations and progression at 54 months. The primary end point was a global rank composite score, which compared participants to each other on the basis of a hierarchy of disease features, including death, event-free survival, forced vital capacity, the Disability Index of the Health Assessment Questionnaire score, and the modified Rodnan skin score. Based on an intention-to-treat analysis, global rank composite scores at 54 months indicated the superiority of transplantation (p=0.01). Of all pairwise comparisons in the per-protocol population, 70% favored transplantation over cyclophosphamide versus 30% at 54 months (p=0.004) and 71% versus 29% at 48 months (p=0.003) using the global rank composite score. At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored the transplantation group (p=0.03 and 0.02, respectively). Notably, treatment-related mortality was 3% and 6% in the transplantation group at 54 and 72 weeks respectively, as compared to 0% in the cyclophosphamide group. Overall, the results of this study suggest superior clinical outcomes are achieved following myeloablative autologous HSCT as compared to 12 months of cyclophosphamide for scleroderma with severe internal organ disease. These outcomes, however, did come at the cost of increased toxicity.

Effect of Hydrolyzed Infant Formula vs Conventional Formula on Risk of Type 1 Diabetes: The TRIGR Randomized Clinical Trial

Type 1 diabetes mellitus (T1DM) is a chronic disease characterized by selective loss of insulin-producing β cells in the pancreatic islets in genetically susceptible individuals. It is thought to be mediated by β-cell autoimmunity that emerges early in life, and some studies have suggested that exposure to complex dietary proteins in infancy may increase the risk of disease. Previous investigations have shown that weaning at-risk infants to an extensively hydrolyzed casein formula containing no intact proteins does not decrease the incidence of diabetes-associated autoantibodies by 7 years of age. However, the impact of this weaning strategy on the cumulative incidence of T1DM in at-risk infants is unclear. In this multicenter randomized controlled trial, 2,159 genetically at-risk newborn infants were randomized to receive either an intervention formula (extensively hydrolyzed casein-based formula) or control formula (80% intact cow’s milk protein and 20% hydrolyzed milk protein) until reaching at least 6 months of age to study the cumulative incidence of T1DM. The median follow-up period was 11.5 years. The median duration from seroconversion to clinical diabetes was 4.1 years in the intervention group and 3.9 years in the control group (between-group difference 0.2, 95% CI -0.8 to 1.1, p=0.76). The absolute risk of T1DM was 8.4% in the intervention group as compared to 7.6% in the control group (between-group difference 0.8%, 95% CI -1.6% to 3.2%, p=0.47; HR 1.1, 95% CI 0.8 to 1.5). The median age of T1DM diagnosis was 6.0 years in the intervention group and 5.8 years in the control group (between-group difference 0.2, 95% CI -0.9 to 1.2, p=0.75). The two groups did not differ significantly in the characteristics of patients who developed diabetes. This high-powered study therefore suggests that eliminating early exposure to foreign intact protein does not prevent or prolong progression to T1DM in genetically high-risk infants.

Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of biological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies

The current standard of care for adults infected with HIV-1 is lifelong antiretroviral therapy (ART) regimen, comprising two nucleoside reverse transcriptase inhibitors (NRTIs) and either a boosted protease inhibitor, an integrase strand transfer inhibitor, or a non-NRTI (NNRTI). However, patients may experience adverse effects due to toxicity and related comorbidities. As such, the development of a safe and efficacious regimen is a priority in the field of ART research. A combination of dolutegravir (an integrase strand transfer inhibitor) and rilpivirine (an NNRTI) is promising due to the clinically demonstrated safety, efficacy and specificity of these two therapies. The SWORD-1 and SWORD-2 studies were phase 3 open-label randomized controlled trials designed to evaluate safety and the proportion of participants with a plasma viral load of <50 copies per mL by week 48. A total of 1,028 stably suppressed HIV-infected patients on their first or second ART regimen were randomized to switch to dolutegravir-rilpivirine or to continue their current ART regimen (CAR). In both treatment groups, 95% of participants maintained viral loads of <50 copies per mL (adjusted treatment difference -0.2%, CI -3.0 to 2.5), confirming the noninferiority in effectiveness of dolutegravir-rilpivirine. In addition, the dolutegravir-rilpivirine group exhibited a larger reduction in bone-turnover biomarkers than the CAR group. Of participants in the dolutegravir-rilpivirine group, 77% reported at least one adverse event by week 48, while 71% of the CAR group reported at least one adverse event by week 48, and drug-related events were more frequent in the dolutegravir-rilpivirine group. The most frequent adverse events were psychiatric disorders, nasopharyngitis, and headache. It is important to note that tolerance of CAR without substantial new adverse events was expected in the CAR group, as all participants were stable on their current regimen for at least 6 months prior to screening. Overall, the results from this study suggest that dolutegravir-rilpivirine may be noninferior to alternative three-drug regimens. Planned analyses of long-term SWORD endpoints will provide further data on the safety and efficacy of dolutegravir-rilpivirine.

Image: PD

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