BRAF/MEK Dual Inhibitors Therapy in Progressive and Anaplastic Pleomorphic Xanthoastrocytoma: Case Series and Literature Review.

Recurrent and anaplastic pleomorphic xanthoastrocytoma (r&aPXA) is a rare primary brain tumor that is challenging to treat. Two-thirds of PXA tumors harbor a BRAF gene mutation. BRAF inhibitors have been shown to improve tumor control. However, resistance to BRAF inhibition develops in most cases. Concurrent therapy with MEK inhibitors may improve tumor control and patient survival. In this study, we identified 5 patients diagnosed with BRAF-mutated PXA who received BRAF and MEK inhibitors over a 10-year interval at our institution. Patient records were evaluated, including treatments, adverse effects (AEs), outcomes, pathology, next-generation sequencing, and MRI. The median age was 22 years (range, 14-66 years), 60% male, and 60% anaplastic PXA. Median overall survival was 72 months (range, 19-112 months); 1 patient died of tumor-related hemorrhage while off therapy, and the other 4 experienced long-term disease control (21, 72, 98, and 112 months, respectively). Dual BRAF/MEK inhibitors were well tolerated, with only grade 1-2 AEs, including rash, neutropenia, fatigue, abdominal discomfort, and diarrhea. No grade 3-5 AEs were detected. A literature review was also performed of patients diagnosed with BRAF-mutated PXA and treated with BRAF and/or MEK inhibitors through August 2021, with a total of 32 cases identified. The median age was 29 years (range, 8-57 years) and the median PFS and OS were 8.5 months (range, 2-35 months) and 35 months (range, 10-80 months), respectively. The most common AEs were grade 1-2 fatigue and skin rash. Results of this case series and literature review indicate that dual-drug therapy with BRAF and MEK inhibitors for r&aPXA with BRAF V600E mutation may delay tumor progression without unexpected AEs.

Moderate aerobic exercise prevents matrix degradation and death in a mouse model of aortic dissection and aneurysm.

Thoracic aortic aneurysm and dissection (TAAD) is a deadly disease characterized by intimal disruption induced by hemodynamic forces of the circulation. The effect of exercise in patients with TAAD is largely unknown. ß-Aminopropionitrile (BAPN) is an irreversible inhibitor of lysyl oxidase that induces TAAD in mice. The objective of this study was to investigate the effect of aerobic exercise on BAPN-induced TAAD. Upon weaning, mice were given either BAPN-containing water or standard drinking water and subjected to either conventional cage activity (BAPN-CONV) or forced treadmill exercise (BAPN-EX) for up to 26 wk. Mortality was 23.5% (20/85) for BAPN-CONV mice versus 0% (0/22) for BAPN-EX mice (hazard ratio 3.8; P = 0.01). BAPN induced significant elastic lamina fragmentation and intimal-medial thickening compared with BAPN-untreated controls, and aneurysms were identified in 50% (5/10) of mice that underwent contrast-enhanced CT scanning. Exercise significantly decreased BAPN-induced wall thickening, calculated circumferential wall tension, and lumen diameter, with 0% (0/5) of BAPN-EX demonstrating chronic aortic aneurysm formation on CT scan. Expression of selected genes relevant to vascular diseases was analyzed by qRT-PCR. Notably, exercise normalized BAPN-induced increases in TGF-ß pathway-related genes Cd109, Smad4, and Tgfßr1; inflammation-related genes Vcam1, Bcl2a1, Ccr2, Pparg, Il1r1, Il1r1, Itgb2, and Itgax; and vascular injury- and response-related genes Mmp3, Fn1, and Vwf. Additionally, exercise significantly increased elastin expression in BAPN-treated animals compared with controls. This study suggests that moderate aerobic exercise may be safe and effective in preventing the most devastating outcomes in TAAD.NEW & NOTEWORTHY Moderate aerobic exercise was shown to significantly reduce mortality, extracellular matrix degradation, and thoracic aortic aneurysm and dissection formation associated with lysyl oxidase inhibition in a mouse model. Gene expression suggested a reversal of TGF-ß, inflammation, and extracellular matrix remodeling pathway dysregulation, along with augmented elastogenesis with exercise.

Endovascular Vertebral Artery Transposition Using Flow Reversal Technique for Left Subclavian Artery Stump Syndrome.

BACKGROUND: Cerebellar strokes are a rare complication related to thoracic endovascular aortic repair (TEVAR). This can manifest in an indolent manner or as a neurological catastrophe. Often it is unclear when a surgical intervention would be needed. Patients at risk for this relatively rare complication are not easily identified. CASE: We describe an endovascular option with flow reversal for left vertebral artery transposition using stent grafts for relocating arterial inflow and excluding a floating thrombus at the proximal subclavian artery (SCA) related to a previous TEVAR. CONCLUSIONS: Ligation of the subclavian artery proximal to the vertebral artery should be considered when performing a carotid subclavian bypass for elective TEVAR. This case details a unique, less invasive approach for vertebral artery transposition and thrombus exclusion in a high-risk patient with previous neck dissection.

Endovascular Reconstruction of the Hepatic Arterial System for the Management of Mycotic Pseudoaneurysm in a Liver Transplant Patient.

BACKGROUND: Hepatic artery pseudoaneurysm is a rare but very morbid complication after liver transplant. Treatment options include ligation or endovascular embolization, followed by revascularization. We describe a new endovascular approach by stent exclusion in a high-risk patient. RESULTS: A 62-year-old male who received a second liver transplant after failed allograft presented with hemobilia and was diagnosed with a hepatic artery pseudoaneurysm in the setting of infection. Given his hostile abdomen, an endovascular approach was sought. We excluded the mycotic pseudoaneurysm with multiple covered stent grafts extending from the common hepatic artery to the right and left hepatic arteries. He was discharged with long-term antibiotics. On his 6-month follow-up visit, his stent was patent and hepatic function was stable. CONCLUSIONS: Endovascular stent-graft placement for management of hepatic artery pseudoaneurysm after liver transplant should be considered as a lower morbidity alternative to surgical repair, even in the setting of infection.

Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) Not Yet Applicable for Widespread Out-of-Hospital Use: A Case of Nonsurvivable Complication from Prolonged REBOA Inflation.

BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is being considered for temporizing catastrophic hemorrhage before arriving at a specialty center for definitive surgical management. CASE: We describe the clinical case of a 72-year-old male with a ruptured infrarenal aortic abdominal aneurysm initially stabilized with REBOA at an outside facility and transferred to our care. Transport time was >100 minutes. Despite successful surgical repair of the ruptured aneurysm, the patient expired from multiple-organ failure likely related to ischemia-reperfusion injuries from prolonged balloon occlusion of the aorta. CONCLUSIONS: Ischemia-mitigating techniques and therapies need to improve drastically before the clinical application of REBOA can be effectively extended to outside the vicinity of specialty centers.

Hybrid approach to deep vein arterialization as an adjunct for patients with severe medial calcinosis.

Patients with no-option chronic limb-threatening ischemia are not candidates for conventional revascularization options and will inevitably require major amputation. Deep venous arterialization (DVA) is a potential option for these patients. A complete endovascular system to perform DVA has recently received great acclaim and US Foor and Drug Administration approval. However, patients with severe tibial medial calcinosis such as those with diabetes or renal failure may not be candidates for this because most endovascular needles cannot penetrate severe calcium. Here we describe a novel hybrid approach to DVA that provided technical success in three patients with end-stage renal disease and severe medial calcinosis.

Investigating the Role of Thrombosis, Fenestration, and False Lumen Orbital Orientation in the Hemodynamics of Type B Aortic Dissection.

While much about the fundamental mechanisms behind the initiation and progression of Type B aortic dissection (TBAD) is still unknown, predictive models based on patient-specific computational fluid dynamics (CFD) can help in risk stratification and optimal clinical decision-making. Aiming at the development of personalized treatment, CFD simulations can be leveraged to investigate the interplay between complex aortic flow patterns and anatomical features. In this study, the hemodynamics of false lumen thrombosis, a large fenestration, and the orbital orientation of the false lumen is studied through image-based CFD simulations on three TBAD patient-specific geometries. A new pipeline was developed leveraging the open-source software SimVascular and Paraview to analyze multiple patients simultaneously and to achieve large-scale parallelization in CFD results based on patients' computed tomography (CT) images. The results of this study suggest that the internal orbital orientation of the false lumen contributes to maintaining a positive luminal pressure difference ΔPTL-FL=PTL-PFL between the true lumen (TL) and the false lumen (FL), despite an impingement area in the false lumen near the entry tear. A positive and high luminal pressure difference is thought to promote TL expansion and FL compression. Moreover, it was also found that both FL thrombosis at the entry tear region, and the presence of a large fenestration in the descending thoracic aorta reduce the magnitude of the negative luminal pressure difference, which in turn may reduce FL expansion and the risk of unstable aortic growth.

LRP1 protects against excessive superior mesenteric artery remodeling by modulating angiotensin II-mediated signaling.

Vascular smooth muscle cells (vSMCs) exert a critical role in sensing and maintaining vascular integrity. These cells abundantly express the low-density lipoprotein receptor-related protein 1 (LRP1), a large endocytic signaling receptor that recognizes numerous ligands, including apolipoprotein E-rich lipoproteins, proteases, and protease-inhibitor complexes. We observed the spontaneous formation of aneurysms in the superior mesenteric artery (SMA) of both male and female mice in which LRP1 was genetically deleted in vSMCs (smLRP1-/- mice). Quantitative proteomics revealed elevated abundance of several proteins in smLRP1-/- mice that are known to be induced by angiotensin II-mediated (AngII-mediated) signaling, suggesting that this pathway was dysregulated. Administration of losartan, an AngII type I receptor antagonist, or an angiotensinogen antisense oligonucleotide to reduce plasma angiotensinogen concentrations restored the normal SMA phenotype in smLRP1-/- mice and prevented aneurysm formation. Additionally, using a vascular injury model, we noted excessive vascular remodeling and neointima formation in smLRP1-/- mice that was restored by losartan administration. Together, these findings reveal that LRP1 regulates vascular integrity and remodeling of the SMA by attenuating excessive AngII-mediated signaling.

Delayed stroke after hospitalization for coronavirus disease 2019 pneumonia from common and internal carotid artery thrombosis.

Large vessel arterial thrombosis has been reported to complicate a subset of cases of coronavirus disease 2019 (COVID-19). Thrombosis of the extracranial carotid arterial system can lead to devastating stroke in some patients with COVID-19. We have presented the case of a patient previously hospitalized with COVID-19 for oxygen supplementation who had presented after discharge with delayed stroke from a right common carotid artery and internal carotid artery thrombosis. The thrombotic occlusion resolved with antithrombotic medications and no invasive intervention. The present report highlights the complicated and heterogeneous nature of COVID-19 and provides one approach to managing the devastating complication of stroke from carotid arterial thrombosis.

Successful repair of an arteriovesical fistula as a complication after coil embolization for right hypogastric artery aneurysm.

An 84-year-old man has a history of a right hypogastric artery aneurysm that was excluded with endograft several years ago. His course was complicated by a type II endoleak with an enlarging aneurysm that required multiple attempts of coil embolization. Several years later, he presented with gross hematuria and was found to have embolization coils extruding into his bladder and an arteriovesical fistula. As seen in this case, endovascular intervention for a type II endoleak is not benign. We describe a novel complication of an arteriovesical fistula that necessitated a difficult repair and ultimate revascularization.

Treatment train approaches for the remediation of per- and polyfluoroalkyl substances (PFAS): A critical review.

Per- and polyfluoroalkyl substances (PFAS) have recently drawn great attention due to their ubiquitous presence in aquatic environments and potential toxicity to human health and the environment. A number of recent studies have demonstrated that "passive" removal approaches, such as adsorption, filtration, and reverse osmosis or "active" degradation technologies, such as enhanced photolysis, electrochemical oxidation, and sonochemical destruction, are all able to individually conduct remedial measures for PFAS contamination at some level. However, drawbacks, specifically high energy consumption, low cost-efficiency, and extreme operating conditions, are commonly observed from these studies which significantly suppress the future for commercialization of these innovative technologies. Since 2015, a new trend of PFAS remediation has emerged that uses multiple synergetic technologies simultaneously (known as treatment train processes) to effectively achieve in-situ remediation of PFAS. This paper provides new insight of the recently reported treatment train studies selected from approximately 150 different publications with regards to the remediation of PFAS and discusses their innovative designs, remediation performances, present limits, and possible improvements. Based on a comprehensive review of the current treatment train studies, this review work proposes a new design that consists of three individual technologies, namely, nanofiltration, electrochemical anodic oxidation, and electro-Fenton degradation, to maximize economic and environmental benefits of PFAS remedial measures.

Disruption of hmgA by DNA Duplication is Responsible for Hyperpigmentation in a Vibrio anguillarum Strain.

Vibrio anguillarum 531A, isolated from a diseased fish in the Atlantic Ocean, is a mixture composed of about 95 and 5% of highly pigmented cells (strain 531Ad) and cells with normal levels of pigmentation (strain 531Ac), respectively. Analysis of the V. anguillarum 531Ad DNA region encompassing genes involved in the tyrosine metabolism showed a 410-bp duplication within the hmgA gene that results in a frameshift and early termination of translation of the homogentisate 1,2-dioxygenase. We hypothesized that this mutation results in accumulation of homogentisate that is oxidized and polymerized to produce pyomelanin. Introduction in E. coli of recombinant clones carrying the V. anguillarum hppD (4-hydroxyphenylpyruvate-dioxygenase), and a mutated hmgA produced brown colored colonies. Complementation with a recombinant clone harboring hmgA restored the original color to the colonies confirming that in the absence of homogentisate 1,2-dioxygenase the intermediary in tyrosine catabolism homogentisate accumulates and undergoes nonenzymatic oxidation and polymerization resulting in high amounts of the brown pigment. Whole-genome sequence analysis showed that V. anguillarum 531 Ac and 531Ad differ in the hmgA gene mutation and 23 mutations, most of which locate to intergenic regions and insertion sequences.

Factors influencing community health centers' efficiency: a latent growth curve modeling approach.

The objective of study is to examine factors affecting the variation in technical and cost efficiency of community health centers (CHCs). A panel study design was formulated to examine the relationships among the contextual, organizational structural, and performance variables. Data Envelopment Analysis (DEA) of technical efficiency and latent growth curve modeling of multi-wave technical and cost efficiency were performed. Regardless of the efficiency measures, CHC efficiency was influenced more by contextual factors than organizational structural factors. The study confirms the independent and additive influences of contextual and organizational predictors on efficiency. The change in CHC technical efficiency positively affects the change in CHC cost efficiency. The practical implication of this finding is that healthcare managers can simultaneously optimize both technical and cost efficiency through appropriate use of inputs to generate optimal outputs. An innovative solution is to employ decision support software to prepare an expert system to assist poorly performing CHCs to achieve better cost efficiency through optimizing technical efficiency.