Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells

There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies. Our findings demonstrate that co-targeting LSD1 and one of these co-dependencies exerted synergistic in vitro lethality in AML and post-MPN sAML cells. Co-treatment with LSD1i and the JAKi ruxolitinib was also synergistically lethal against post-MPN sAML cells. LSD1i pre-treatment induced GFI1, PU.1 and CEBPα but depleted c-Myc, overcoming nongenetic resistance to ruxolitinib, or to BETi in post-MPN sAML cells. Co-treatment with LSD1i and BETi or ruxolitinib exerted superior in vivo efficacy against post-MPN sAML cells. These findings highlight LSD1i-based combinations that merit testing for clinical efficacy, especially to overcome nongenetic therapy-resistance in AML and post-MPN sAML.Subject terms: Acute myeloid leukaemia, Targeted therapies     

Long-term Implications of Tracheostomy in Cardiac Surgery Patients: Decannulation and Mortality

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The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAF^V600, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, p = 0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.Subject terms: CNS cancer, Metastasis, Melanoma, Tumour biomarkers, Cancer     

Postprocedural Antiplatelet Treatment after Emergent Carotid Stenting in Tandem Lesions Stroke: Impact on Stent Patency beyond Day 1

BACKGROUND AND PURPOSE:Postprocedural dual-antiplatelet therapy is frequently withheld after emergent carotid stent placement during stroke thrombectomy. We aimed to assess whether antiplatelet regimen variations increase the risk of stent thrombosis beyond postprocedural day 1.MATERIALS AND METHODS:Retrospective review was undertaken of all consecutive thrombectomies for acute stroke with tandem lesions in the anterior circulation performed in a single comprehensive stroke center between January 9, 2011 and March 30, 2020. Patients were included if carotid stent patency was confirmed at day 1 postprocedure. The group of patients with continuous dual-antiplatelet therapy from day 1 was compared with the group of patients with absent/discontinued dual-antiplatelet therapy.RESULTS:Of a total of 109 tandem lesion thrombectomies, 96 patients had patent carotid stents at the end of the procedure. The early postprocedural stent thrombosis rate during the first 24 hours was 14/96 (14.5%). Of 82 patients with patent stents at day 1, in 28 (34.1%), dual-antiplatelet therapy was either not initiated at day 1 or was discontinued thereafter. After exclusion of cases without further controls of stent patency, there was no significant difference in the rate of subacute/late stent thrombosis between the 2 groups: 1/50 (2%) in patients with continuous dual-antiplatelet therapy versus 0/22 (0%) in patients with absent/discontinued dual-antiplatelet therapy (P = 1.000). In total, we observed 88 patient days without any antiplatelet treatment and 471 patient days with single antiplatelet treatment.CONCLUSIONS:Discontinuation of dual-antiplatelet therapy was not associated with an increased risk of stent thrombosis beyond postprocedural day 1. Further studies are warranted to better assess the additional benefit and optimal duration of dual-antiplatelet therapy after tandem lesion stroke thrombectomy.

In around 15% of endovascular procedures for anterior circulation stroke,¹ there is a tight stenosis or occlusion of the cervical carotid artery in addition to the intracranial artery occlusion. The optimal endovascular management of tandem lesions has yet to be defined; however, there is mounting evidence^2,3 that emergent stent placement in the carotid artery associated with at least 1 antiplatelet agent could lead to better recanalization rates and improved clinical outcomes. A more definitive answer should be provided by the Thrombectomy In TANdem lesions (TITAN) randomized multicenter trial,⁴ designed to assess the safety and efficacy of emergent internal carotid artery stent placement in tandem lesion thrombectomy. This study recently enrolled the first patient in early 2020.In patients undergoing emergent carotid stent placement, there is no consensus regarding the optimal periprocedural antiplatelet therapy. Many groups^5,6 chose to avoid dual-antiplatelet therapy (DAPT) during the first 24 hours in an attempt to reduce the risk of hemorrhagic transformation. Conversely, less aggressive antiplatelet regimens might increase the risk of carotid stent thrombosis.Stent thrombosis was recently identified as a predictor of unfavorable clinical outcome.^7,8 To date, available data regarding stent patency rates remain scarce. Most case series of endovascular management for tandem lesions^5,9-11 do not report postprocedural stent patency, while some publications^12-15 offer partial data for a subgroup of patients for whom carotid imaging controls were available. Reported rates of stent thrombosis ranged between 1.2% and 22.0%.^{6-8,12-14,16,17}To date, no study has attempted to differentiate between early (first 24 hours) and subacute/late postprocedural stent thrombosis. During the first 24 hours, protection against stent thrombosis is conferred by antiplatelet agents administered during the procedure (periprocedural antiplatelets). Beyond 24 hours, the recommended antiplatelet regimen is DAPT for 4–12 weeks,^9,17 but in reality, antiplatelets are often tailored in view of neurological and extra-neurological hemorrhagic events. It is currently unknown whether discontinuation of DAPT is associated with an increased risk of late stent thrombosis.Thus, we aimed to describe the variations in the postprocedural antiplatelet regimen in a large consecutive cohort of tandem lesion thrombectomies with emergent carotid artery stent placement and to assess whether discontinuation of DAPT was associated with an increased risk of carotid stent thrombosis.     

Anatomic Snuffbox (Distal Radial Artery) and Radial Artery Access for Treatment of Intracranial Aneurysms with FDA-Approved Flow Diverters

BACKGROUND AND PURPOSE:Transradial access for neurointerventional procedures has been proved a safer and more comfortable alternative to femoral artery access. We present our experience with transradial (distal radial/anatomic snuffbox and radial artery) access for treatment of intracranial aneurysms using all 3 FDA-approved flow diverters.MATERIALS AND METHODS:This was a high-volume, dual-center, retrospective analysis of each institution’s data base between June 2018 and June 2020 and a collection of all patients treated with flow diversion via transradial access. Patient demographic information and procedural and radiographic data were obtained.RESULTS:Seventy-four patients were identified (64 female patients) with a mean age of 57.5 years with a total of 86 aneurysms. Most aneurysms were located in the anterior circulation (93%) and within the intracranial ICA (67.4%). The mean aneurysm size was 5.5 mm. Flow diverters placed included the Pipeline Embolization Device (Flex) (PED, n = 65), the Surpass Streamline Flow Diverter (n = 8), and the Flow-Redirection Endoluminal Device (FRED, n = 1). Transradial access was successful in all cases, but femoral crossover was required in 3 cases (4.1%) due to tortuous anatomy and inadequate support of the catheters in 2 cases and an inability to navigate to the target vessel in a patient with an aberrant right subclavian artery. All 71 other interventions were successfully performed via the transradial approach (95.9%). No access site complications were encountered. Asymptomatic radial artery occlusion was encountered in 1 case (3.7%).CONCLUSIONS:Flow diverters can be successfully placed via the transradial approach with high technical success, low access site complications, and a low femoral crossover rate.

The transradial access (TRA), including distal radial artery (dRA) access in the anatomic snuffbox and radial artery (RA) access at the palmar surface of the wrist, is being increasingly used as primary vascular access for neurointerventional procedures. In prior years, large randomized trials in the field of interventional cardiology and more recent articles in neurointerventional surgery have shown higher patient preference for the TRA, cost reduction, as well as lower morbidity and mortality compared with the traditional transfemoral access (TFA).^1-11 Reduction in access site complications has been a particular advantage of wrist over femoral access and is an important consideration for vascular access choice in the treatment of intracranial aneurysms using flow diversion. Patients undergoing flow diversion are required to take dual-antiplatelet agents and receive heparin during the procedure, all of which increase the risk of bleeding from the access site.¹² Also, flow diverters (FDs) may require large-bore catheter assemblies for delivery and deployment, which may increase the risk of radial artery occlusion, access site bleeding, or vascular injury.^13,14To date, only a limited number of case reports and case series have described the safety and feasibility of TRA for the treatment of intracranial aneurysms using flow diverters.^15-22Recently, a large, retrospective multicenter study reported the safety of TRA for flow diversion, showing a lower access site (P = .039) and overall complication rate (P = .035).¹² This study, however, did not cover catheter systems, patient functional outcome, and aneurysm occlusion. Here, we report our experience with TRA (dRA [anatomic snuffbox] and RA) for the treatment of intracranial aneurysms using all 3 FDA-approved flow diverters, including technical feasibility, procedural safety, patient outcome, and aneurysm occlusion on follow-up. Additionally, we reviewed the current literature on use of flow diverters via TRA.     

Rapid behavioral assessment of barriers and opportunities to improve vaccination coverage among displaced Rohingyas in Bangladesh,January 2018

Background

In November 2017, the World Health Organization received initial reports of suspected diphtheria cases in camps established for displaced Rohingyas in Cox’s Bazar district, Bangladesh. By January 11, 2018, over 4,000 suspected cases of diphtheria and 30 deaths were reported. The Bangladesh government and partners implemented a diphtheria vaccination campaign in December 2017. Outbreak response staff reported anecdotal evidence of vaccine hesitancy. Our assessment aimed to understand vaccination barriers and opportunities to enhance vaccine demand among displaced Rohingyas in Bangladesh.

Mind the gap: Teachers’ conceptions of student-staff partnership and its potential to enhance educational quality

Abstract

Introduction: Student-staff partnerships as a concept to improve medical education have received a growing amount of attention. Such partnerships are collaborations in which students and teachers seek to improve education by each adding their unique contribution to decision-making and implementation processes. Although previous research has demonstrated that students are favourable to this concept, teachers remain hesitant. The present study investigated teachers’ conceptions of student-staff partnerships and of the prerequisites that are necessary to render such partnerships successful and enhance educational quality.

Method: We conducted semi-structured interviews with 14 course coordinators who lead course design teams and also teach in 4 bachelor health programmes, using Bovill and Bulley’s levels of student participation as sensitising concepts during data analysis.

Results: The results pointed to three different conceptions of student-staff partnerships existing among teachers: Teachers teach and students study; teachers teach and value students’ feedback; and teachers and students co-create. The prerequisites for effective co-creation teachers identified were: Teachers must be open to involve students and create dialogues; students must be motivated and have good communication skills; the organisation must be supportive; and teachers should have the final say.

Conclusion: We conclude that teachers’ conceptions are consistent with Bovill and Bulley’s levels of student participation. Under certain conditions, teachers are willing to co-create and reach the highest levels of student participation.     

Managing invasive aspergillosis in haematological patients in the era of resistance polymerase chain reaction and increasing triazole resistance: A modelling study of different strategies

Objectives

Triazole resistance in Aspergillus spp. is emerging and complicates prophylaxis and treatment of invasive aspergillosis (IA) worldwide. New polymerase chain reaction (PCR) tests on broncho-alveolar lavage (BAL) fluid allow for detection of triazole resistance at a genetic level, which has opened up new possibilities for targeted therapy. In the absence of clinical trials, a modelling study delivers estimates of the added value of resistance detection with PCR, and which empiric therapy would be optimal when local resistance rates are known.