Citations

Abstract Metastasis accounts for the overwhelming majority of cancer deaths. In prostate cancer and many other solid tumors, progression to metastasis is associated with drastically reduced survival outcomes, yet the mechanisms behind this progression remain largely unknown. ATPase family AAA domain containing 2 (ATAD2) is an epigenetic reader of acetylated histones that is overexpressed in multiple cancer types and usually associated with poor patient outcomes. However, the functional role of ATAD2 in cancer progression and metastasis has been relatively understudied. Here, we employ genetically engineered mouse models of prostate cancer bone metastasis, as well as multiple independent human cohorts, to show that ATAD2 is highly enriched in bone metastasis compared with primary tumors and significantly associated with the development of metastasis. We show that ATAD2 expression is associated with MYC pathway activation in patient datasets and that, at least in a subset of tumors, MYC and ATAD2 can regulate each other’s expression. Using functional studies on mouse bone metastatic cell lines and innovative organ-on-a-chip bone invasion assays, we establish a functional role for ATAD2 inhibition in reducing prostate cancer metastasis and growth in bone. Implications: Our study highlights ATAD2 as a driver of prostate cancer progression and metastasis and suggests it may constitute a promising novel therapeutic target.

Background/Objectives: Hypertrophic cardiomyopathy (HCM) is a common heart disorder characterized by the thickening of the heart muscle, particularly in the left ventricle, which increases the risk of cardiac complications. This study aims to analyze the expression of apoptosis-regulating genes (CASP8, CASP9, CASP3, BAX, and BCL2) in blood samples from HCM patients, to better understand their potential as biomarkers for disease progression. Methods: Quantitative real-time PCR (qPCR) was used to evaluate gene expression in blood samples from 93 HCM patients. The correlation between apoptosis-regulating genes was conducted and clinical parameters were integrated for feature importance and clustering analysis. Results: Most patients exhibited significant downregulation of CASP8, CASP9, and CASP3. In contrast, BAX expression was elevated in 71 out of 93 patients, while BCL2 was increased in 55 out of 93 patients. Correlation analysis revealed weak negative correlations between the BAX/BCL2 ratio and CASP gene expression. Conclusions: These findings suggest that reduced expression of apoptotic genes may indicate a protective cellular mechanism, which could serve as a biomarker for disease progression. Further studies are needed to investigate the potential for therapeutic modulation of these pathways to improve patient outcomes.

Here we have shown for the first time altered expression of the vascular smooth muscle (VSM) KATP channel subunits in segments of the human internal mammary artery (HIMA) in patients with type-2 diabetes mellitus (T2DM). Functional properties of vascular KATP channels in the presence of T2DM, and the interaction between its subunits and endogenous ligands known to relax this vessel, were tested using the potassium (K) channels opener, pinacidil. HIMA is the most commonly used vascular graft in cardiac surgery. Previously it was shown that pinacidil relaxes HIMA segments through interaction with KATP (SUR2B/Kir6.1) vascular channels, but it is unknown whether pinacidil sensitivity is changed in the presence of T2DM, considering diabetes-induced vascular complications commonly seen in patients undergoing coronary artery bypass graft surgery (CABG). KATP subunits were detected in HIMA segments using Western blot and immunohistochemistry analyses. An organ bath system was used to interrogate endothelium-independent vasorelaxation caused by pinacidil. In pharmacological experiments, pinacidil was able to relax HIMA from patients with T2DM, with sensitivity comparable to our previous results. All three KATP subunits (SUR2B, Kir6.1 and Kir6.2) were observed in HIMA from patients with and without T2DM. There were no differences in the expression of the SUR2B subunit. The expression of the Kir6.1 subunit was lower in HIMA from T2DM patients. In the same group, the expression of the Kir6.2 subunit was higher. Therefore, KATP channels might not be the only method of pinacidil-induced dilatation of T2DM HIMA. T2DM may decrease the level of Kir6.1, a dominant subunit in VSM of HIMA, altering the interaction between pinacidil and those channels.

Background: Acute kidney injury (AKI) increases the risk of hospital readmission, chronic kidney disease, and death. Therefore, effective communication in discharge summaries is essential for safe transitions of care. Objective: The objectives of this study were to determine the quality of discharge summaries in AKI survivors and identify predictors of higher quality discharge summaries. Design: Retrospective chart review. Setting: Tertiary care academic center in Ontario, Canada. Patients: We examined the discharge summary quality of 300 randomly selected adult patients who survived a hospitalization with AKI at our tertiary care hospital, stratified by AKI severity. We included 150 patients each from 2015 to 2016 and 2018 to 2019, before and after introduction of a post-AKI clinic in 2017. Measurements: We reviewed charts for 9 elements of AKI care to create a composite score summarizing discharge summary quality. Methods: We used multivariable logistic regression to identify predictors of discharge summary quality. Results: The median discharge summary composite score was 4/9 (interquartile range, 2-6). The least frequently mentioned elements were baseline creatinine (n = 55, 18%), AKI-specific follow-up labs (n = 66, 22%), and medication recommendations (n = 80, 27%). The odds of having a higher quality discharge summary (composite score ≥4/9) was greater for every increase in baseline creatinine of 25 μmol/L (adjusted odds ratio [aOR]: 1.27; 95% confidence interval [CI]: 1.03, 1.56), intrarenal etiology (aOR: 2.32; 95% CI: 1.26, 4.27), and increased AKI severity (stage 2 aOR: 2.57; 95% CI: 1.35, 4.91 and stage 3 aOR: 3.36; 95% CI: 1.56, 7.22). There was no association between discharge summary quality and the years before and after introduction of a post-AKI clinic (aOR: 0.77; 95% CI: 0.46, 1.29). Limitations: The single-center study design limits generalizability. Conclusions: Most discharge summaries are missing key AKI elements, even in patients with severe AKI. These gaps suggest several opportunities exist to improve discharge summary communication following AKI.

Background: Despite the well-established potent benefit of mechanical thrombectomy (MT) for large vessel occlusion (LVO) stroke, access to MT has not been studied globally. We conducted a worldwide survey of countries on 6 continents to define MT access (MTA), the disparities in MTA, and its determinants on a global scale. Methods: Our survey was conducted in 75 countries through the Mission Thrombectomy 2020+ global network between November 22, 2020, and February 28, 2021. The primary end points were the current annual MTA, MT operator availability, and MT center availability. MTA was defined as the estimated proportion of patients with LVO receiving MT in a given region annually. The availability metrics were defined as ([current MT operators×50/current annual number of estimated thrombectomy-eligible LVOs]×100 = MT operator availability) and ([current MT centers×150/current annual number of estimated thrombectomy-eligible LVOs]×100= MT center availability). The metrics used optimal MT volume per operator as 50 and an optimal MT volume per center as 150. Multivariable-adjusted generalized linear models were used to evaluate factors associated with MTA. Results: We received 887 responses from 67 countries. The median global MTA was 2.79% (interquartile range, 0.70–11.74). MTA was <1.0% for 18 (27%) countries and 0 for 7 (10%) countries. There was a 460-fold disparity between the highest and lowest nonzero MTA regions and low-income countries had 88% lower MTA compared with high-income countries. The global MT operator availability was 16.5% of optimal and the MT center availability was 20.8% of optimal. On multivariable regression, country income level (low or lower–middle versus high: odds ratio, 0.08 [95% CI, 0.04–0.12]), MT operator availability (odds ratio, 3.35 [95% CI, 2.07–5.42]), MT center availability (odds ratio, 2.86 [95% CI, 1.84–4.48]), and presence of prehospital acute stroke bypass protocol (odds ratio, 4.00 [95% CI, 1.70–9.42]) were significantly associated with increased odds of MTA. Conclusions: Access to MT on a global level is extremely low, with enormous disparities between countries by income level. The significant determinants of MT access are the country’s per capita gross national income, prehospital LVO triage policy, and MT operator and center availability.

Objectives/HypothesisThe purpose of this study is to develop consensus on key points that would support the use of systemic bevacizumab for the treatment of recurrent respiratory papillomatosis (RRP), and to provide preliminary guidance surrounding the use of this treatment modality.Study DesignDelphi method‐based survey series.MethodsA multidisciplinary, multi‐institutional panel of physicians with experience using systemic bevacizumab for the treatment of RRP was established. The Delphi method was used to identify and obtain consensus on characteristics associated with systemic bevacizumab use across five domains: 1) patient characteristics; 2) disease characteristics; 3) treating center characteristics; 4) prior treatment characteristics; and 5) prior work‐up.ResultsThe international panel was composed of 70 experts from 12 countries, representing pediatric and adult otolaryngology, hematology/oncology, infectious diseases, pediatric surgery, family medicine, and epidemiology. A total of 189 items were identified, of which consensus was achieved on Patient Characteristics (9), Disease Characteristics (10), Treatment Center Characteristics (22), and Prior Workup Characteristics (18).ConclusionThis consensus statement provides a useful starting point for clinicians and centers hoping to offer systemic bevacizumab for RRP and may serve as a framework to assess the components of practices and centers currently using this therapy. We hope to provide a strategy to offer the treatment and also to provide a springboard for bevacizumab's use in combination with other RRP treatment protocols. Standardized delivery systems may facilitate research efforts and provide dosing regimens to help shape best‐practice applications of systemic bevacizumab for patients with early‐onset or less‐severe disease phenotypes.Level of Evidence5 Laryngoscope, 131:E1941–E1949, 2021

Objective: The overall risk of ischemic stroke from a chronically occluded internal carotid artery (COICA) is around 5%-7% per year despite receiving the best medical therapy. We propose a radiographic classification of COICA that can be used as a guide to determine the technical success and safety of endovascular recanalization for symptomatic COICA. Methods: The radiographic images of 100 consecutive subjects with COICA were analyzed. A new classification of COICA was proposed based on the morphology, location of occlusion, and presence or absence of reconstitution of the distal ICA. The classification was used to predict successful revascularization in 32 symptomatic COICAs in 31 patients. Patients were included in the study if they had a COICA with ischemic symptoms refractory to medical therapy. Results: Four types (A-D) of radiographic COICA were identified. Types A and B were more amenable to safe revascularization than types C and D. Recanalization was successful at a rate of 68.75% (22/32 COICAs; type A: 8/8; type B: 8/8; type C: 4/8; type D: 2/8). The perioperative complication rate was 18.75% (6/32; type A: 0/8 [0%]; type B: 1/8 [12.50%]; type C: 3/8 [37.50%], type D: 2/8 [25.00%]). None of these complications led to permanent morbidity or death. Twenty (64.52%) of 31 subjects had improvement in their symptoms at the 2-6 months' follow-up. A statistically significant decrease in systolic blood pressure (SBP) was noted in 17/21 (80.95%) patients who had successful revascularization, which persisted on follow-up (p = 0.0001). The remaining 10 subjects in whom revascularization failed had no significant changes in SBP (p = 0.73). Conclusions: The pilot study suggested that our proposed classification of COICA may be useful as an adjunctive guide to determine the technical feasibility and safety of revascularization for symptomatic COICA using endovascular techniques. Additionally, successful revascularization may lead to a significant decrease in SBP postprocedure. A Phase 2b trial in larger cohorts to assess the efficacy of endovascular revascularization using our COICA classification is warranted.

OBJECTIVE The overall risk of ischemic stroke from a chronically occluded internal carotid artery (COICA) is around 5%–7% per year despite receiving the best available medical therapy. Here, authors propose a radiographic classification of COICA that can be used as a guide to determine the technical success and safety of endovascular recanalization for symptomatic COICA and to assess the changes in systemic blood pressure following successful revascularization. METHODS The radiographic images of 100 consecutive subjects with COICA were analyzed. A new classification of COICA was proposed based on the morphology, location of occlusion, and presence or absence of reconstitution of the distal ICA. The classification was used to predict successful revascularization in 32 symptomatic COICAs in 31 patients, five of whom were female (5/31 [16.13%]). Patients were included in the study if they had a COICA with ischemic symptoms refractory to medical therapy. Carotid artery occlusion was defined as 100% cross-sectional occlusion of the vessel lumen as documented on CTA or MRA and confirmed by digital subtraction angiography. RESULTS Four types (A–D) of radiographic COICA were identified. Types A and B were more amenable to safe revascularization than types C and D. Recanalization was successful at a rate of 68.75% (22/32 COICAs; type A: 8/8; type B: 8/8; type C: 4/8; type D: 2/8). The perioperative complication rate was 18.75% (6/32; type A: 0/8 [0%]; type B: 1/8 [12.50%]; type C: 3/8 [37.50%], type D: 2/8 [25.00%]). None of these complications led to permanent morbidity or death. Twenty (64.52%) of 31 subjects had improvement in their symptoms at the 2–6 months’ follow-up. A statistically significant decrease in systolic blood pressure (SBP) was noted in 17/21 (80.95%) patients who had successful revascularization, which persisted on follow-up (p = 0.0001). The remaining 10 subjects in whom revascularization failed had no significant changes in SBP (p = 0.73). CONCLUSIONS The pilot study suggested that our proposed classification of COICA may be useful as an adjunctive guide to determine the technical feasibility and safety of revascularization for symptomatic COICA using endovascular techniques. Additionally, successful revascularization may lead to a significant decrease in SBP postprocedure. A Phase 2b trial in larger cohorts to assess the efficacy of endovascular revascularization using our COICA classification is warranted.