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     

Effects of cancer screening restart strategies after COVID-19 disruption

Background Many breast, cervical, and colorectal cancer screening programmes were disrupted due to the COVID-19 pandemic. This study aimed to estimate the effects of five restart strategies after the disruption on required screening capacity and cancer burden.Methods Microsimulation models simulated five restart strategies for breast, cervical, and colorectal cancer screening. The models estimated required screening capacity, cancer incidence, and cancer-specific mortality after a disruption of 6 months. The restart strategies varied in whether screens were caught up or not and, if so, immediately or delayed, and whether the upper age limit was increased.Results The disruption in screening programmes without catch-up of missed screens led to an increase of 2.0, 0.3, and 2.5 cancer deaths per 100 000 individuals in 10 years in breast, cervical, and colorectal cancer, respectively. Immediately catching-up missed screens minimised the impact of the disruption but required a surge in screening capacity. Delaying screening, but still offering all screening rounds gave the best balance between required capacity, incidence, and mortality.Conclusions Strategies with the smallest loss in health effects were also the most burdensome for the screening organisations. Which strategy is preferred depends on the organisation and available capacity in a country.Subject terms: Health policy, Population screening, Cancer screening, Cancer screening     

Chromosome 1q21 abnormalities in multiple myeloma

Gain of chromosome 1q (+1q) is one of the most common recurrent cytogenetic abnormalities in multiple myeloma (MM), occurring in approximately 40% of newly diagnosed cases. Although it is often considered a poor prognostic marker in MM, +1q has not been uniformly adopted as a high-risk cytogenetic abnormality in guidelines. Controversy exists regarding the importance of copy number, as well as whether +1q is itself a driver of poor outcomes or merely a common passenger genetic abnormality in biologically unstable disease. Although the identification of a clear pathogenic mechanism from +1q remains elusive, many genes at the 1q21 locus have been proposed to cause early progression and resistance to anti-myeloma therapy. The plethora of potential drivers suggests that +1q is not only a causative factor or poor outcomes in MM but may be targetable and/or predictive of response to novel therapies. This review will summarize our current understanding of the pathogenesis of +1q in plasma cell neoplasms, the impact of 1q copy number, identify potential genetic drivers of poor outcomes within this subset, and attempt to clarify its clinical significance and implications for the management of patients with multiple myeloma.Subject terms: Cancer genomics, Myeloma, Myeloma     

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.     

Analysis of Stroke Detection during the COVID-19 Pandemic Using Natural Language Processing of Radiology Reports

BACKGROUND AND PURPOSE:The coronavirus disease 2019 (COVID-19) pandemic has led to decreases in neuroimaging volume. Our aim was to quantify the change in acute or subacute ischemic strokes detected on CT or MR imaging during the pandemic using natural language processing of radiology reports.MATERIALS AND METHODS:We retrospectively analyzed 32,555 radiology reports from brain CTs and MRIs from a comprehensive stroke center, performed from March 1 to April 30 each year from 2017 to 2020, involving 20,414 unique patients. To detect acute or subacute ischemic stroke in free-text reports, we trained a random forest natural language processing classifier using 1987 randomly sampled radiology reports with manual annotation. Natural language processing classifier generalizability was evaluated using 1974 imaging reports from an external dataset.RESULTS:The natural language processing classifier achieved a 5-fold cross-validation classification accuracy of 0.97 and an F1 score of 0.74, with a slight underestimation (−5%) of actual numbers of acute or subacute ischemic strokes in cross-validation. Importantly, cross-validation performance stratified by year was similar. Applying the classifier to the complete study cohort, we found an estimated 24% decrease in patients with acute or subacute ischemic strokes reported on CT or MR imaging from March to April 2020 compared with the average from those months in 2017–2019. Among patients with stroke-related order indications, the estimated proportion who underwent neuroimaging with acute or subacute ischemic stroke detection significantly increased from 16% during 2017–2019 to 21% in 2020 (P = .01). The natural language processing classifier performed worse on external data.CONCLUSIONS:Acute or subacute ischemic stroke cases detected by neuroimaging decreased during the COVID-19 pandemic, though a higher proportion of studies ordered for stroke were positive for acute or subacute ischemic strokes. Natural language processing approaches can help automatically track acute or subacute ischemic stroke numbers for epidemiologic studies, though local classifier training is important due to radiologist reporting style differences.

There is much concern regarding the impact of the coronavirus disease 2019 (COVID-19) pandemic on the quality of stroke care, including issues with hospital capacity, clinical resource re-allocation, and the safety of patients and clinicians.^1,2 Previous reports have shown that there have been substantial decreases in stroke neuroimaging volume during the pandemic.^3,4 In addition, acute ischemic infarcts have been found on neuroimaging studies in many hospitalized patients with COVID-19, though the causal relationship is unclear.^5,6 Studies like these and other epidemiologic analyses usually rely on the creation of manually curated databases, in which identification of cases can be time-consuming and difficult to update in real-time. One way to facilitate such research is to use natural language processing (NLP), which has shown utility for automated analysis of radiology report data.⁷ NLP algorithms have been developed previously for the classification of neuroradiology reports for the presence of ischemic stroke findings and acute ischemic stroke subtypes.^8,9 Thus, NLP has the potential to facilitate COVID-19 research.In this study, we developed an NLP machine learning model that classifies radiology reports for the presence or absence of acute or subacute ischemic stroke (ASIS), as opposed to chronic stroke. We used this model to quantify the change in ASIS detected on all CT or MR imaging studies performed at a large comprehensive stroke center during the COVID-19 pandemic in the United States. We also evaluated NLP model generalizability and different training strategies using a sample of radiology reports from a second stroke center.