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Discover Oncology Jun 2022Cutaneous squamous cell carcinoma (cSCC) is a disease with globally rising incidence and poor prognosis for patients with advanced or metastatic disease.... (Review)
Review
A tEMTing target? Clinical and experimental evidence for epithelial-mesenchymal transition in the progression of cutaneous squamous cell carcinoma (a scoping systematic review).
Cutaneous squamous cell carcinoma (cSCC) is a disease with globally rising incidence and poor prognosis for patients with advanced or metastatic disease. Epithelial-mesenchymal transition (EMT) is a driver of metastasis in many carcinomas, and cSCC is no exception. We aimed to provide a systematic overview of the clinical and experimental evidence for EMT in cSCC, with critical appraisal of type and quality of the methodology used. We then used this information as rationale for potential drug targets against advanced and metastatic cSCC. All primary literature encompassing clinical and cell-based or xenograft experimental studies reporting on the role of EMT markers or related signalling pathways in the progression of cSCC were considered. A screen of 3443 search results yielded 86 eligible studies comprising 44 experimental studies, 22 clinical studies, and 20 studies integrating both. From the clinical studies a timeline illustrating the alteration of EMT markers and related signalling was evident based on clinical progression of the disease. The experimental studies reveal connections of EMT with a multitude of factors such as genetic disorders, cancer-associated fibroblasts, and matrix remodelling via matrix metalloproteinases and urokinase plasminogen activator. Additionally, EMT was found to be closely tied to environmental factors as well as to stemness in cSCC via NFκB and β-catenin. We conclude that the canonical EGFR, canonical TGF-βR, PI3K/AKT and NFκB signalling are the four signalling pillars that induce EMT in cSCC and could be valuable therapeutic targets. Despite the complexity, EMT markers and pathways are desirable biomarkers and drug targets for the treatment of advanced or metastatic cSCC.
PubMed: 35666359
DOI: 10.1007/s12672-022-00510-4 -
Computational and Mathematical Methods... 2022This research is aimed at systematically assessing the safety and effectiveness of intravenous thrombolysis (IVT) with rt-PA plus human urinary kallidinogenase (HUK) for... (Meta-Analysis)
Meta-Analysis
PURPOSE
This research is aimed at systematically assessing the safety and effectiveness of intravenous thrombolysis (IVT) with rt-PA plus human urinary kallidinogenase (HUK) for acute ischemic stroke (AIS).
METHODS
The data were obtained through rigorous searching of both domestic and foreign databases from inception to 2021.7.1. Randomized controlled trials (RCTs) were included for the comparison of the efficacy of IVT plus HUK. The Cochrane risk of bias (RoB) tool and Review Manager software 5.3 were responsible for RoB assessment and statistical analyses, respectively.
RESULTS
A total of 18 articles were retrieved, including 2676 AIS patients treated with IVT within the time window. The control group used standardized rt-PA IVT, and the test group added HUK. After 14 days of combined application of HUK, the National Institute of Health Stroke Scale (NIHSS) score was significantly better in moderate stroke patients using the combination treatment versus those with IVT alone (mean difference (MD) = -3.13; 95% confidence intervals (CI): -3.40,-2.86; < 0.00001); the NIHSS score was also statistically in severe stroke patients with combined treatment than in those with IVT alone, but the degree of recovery of patients varied greatly. After 90 days of treatment, the NIHSS (MD = -1.93; 95% CI: -2.51,-1.34; < 0.00001) and Barthel index (BI) scores (MD = 22.23; 95% CI: 18.96, 25.49; < 0.00001) of patients plus HUK were significantly better than those of patients with IVT alone, with fewer adverse events during treatment (Relative Risk (RR) = 0.66; 95% CI: 0.47, 0.92; = 0.02).
CONCLUSIONS
For AIS patients with IVT within the time window, HUK plus rt-PA IVT could significantly improve the neurological function recovery after 14 days and the quality of life after 90 days and reduce the adverse reactions of IVT. This trial is registered with CRD42021226975.
Topics: Humans; Ischemic Stroke; Kallikreins; Randomized Controlled Trials as Topic; Stroke; Thrombolytic Therapy; Tissue Plasminogen Activator
PubMed: 35620206
DOI: 10.1155/2022/1500669 -
Frontiers in Neurology 2022The available literature on mobile stroke units (MSU) has focused on clinical outcomes, rather than operational performance. Our objective was to establish normalized...
BACKGROUND
The available literature on mobile stroke units (MSU) has focused on clinical outcomes, rather than operational performance. Our objective was to establish normalized metrics and to conduct a meta-analysis of the current literature on MSU performance.
METHODS
Our MSU in upstate New York serves 741,000 people. We present prospectively collected, retrospectively analyzed data from the inception of our MSU in October of 2018, through March of 2021. Rates of transportation/dispatch and MSU utilization were reported. We also performed a meta-analysis using MEDLINE, SCOPUS, and Cochrane Library databases, calculating rates of tPA/dispatch, tPA-per-24-operational-hours ("per day"), mechanical thrombectomy (MT)/dispatch and MT/day.
RESULTS
Our MSU was dispatched 1,719 times in 606 days (8.5 dispatches/24-operational-hours) and transported 324 patients (18.8%) to the hospital. Intravenous tPA was administered in 64 patients (3.7% of dispatches) and the rate of tPA/day was 0.317 (95% CI 0.150-0.567). MT was performed in 24 patients (1.4% of dispatches) for a MT/day rate of 0.119 (95% CI 0.074-0.163). The MSU was in use for 38,742 minutes out of 290,760 total available minutes (13.3% utilization rate). Our meta-analysis included 14 articles. Eight studies were included in the analysis of tPA/dispatch (342/5,862) for a rate of 7.2% (95% CI 4.8-9.5%, I = 92%) and 11 were included in the analysis of tPA/day (1,858/4,961) for a rate of 0.358 (95% CI 0.215-0.502, I = 99%). Seven studies were included for MT/dispatch (102/5,335) for a rate of 2.0% (95% CI 1.2-2.8%, I = 67%) and MT/day (103/1,249) for a rate of 0.092 (95% CI 0.046-0.138, I = 91%).
CONCLUSIONS
In this single institution retrospective study and meta-analysis, we outline the following operational metrics: tPA/dispatch, tPA/day, MT/dispatch, MT/day, and utilization rate. These metrics are useful for internal and external comparison for institutions with or considering developing mobile stroke programs.
PubMed: 35614916
DOI: 10.3389/fneur.2022.868051 -
Journal of Gastrointestinal and Liver... Jun 2022Several studies have investigated the role of multiple proteins in nonalcoholic fatty liver disease (NAFLD); one that has recently gained attention is plasminogen... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIMS
Several studies have investigated the role of multiple proteins in nonalcoholic fatty liver disease (NAFLD); one that has recently gained attention is plasminogen activator inhibitor-1 (PAI-1). However, studies evaluating PAI-1 levels in NAFLD demonstrated conflicting results. Our objective was to understand the role of PAI-1 in NAFLD more clearly by carrying out a systematic review and meta-analysis.
METHODS
We gathered evidence by performing a systematic search on PubMed, EMBASE, and Cochrane Library, through using a predefined search string. The included studies diagnosed NAFLD through either liver biopsy, ultrasonography, computed tomography (CT), magnetic resonance spectroscopy, or using one of the latter methods with blood parameters. Studies had to fulfill predefined inclusion and exclusion criteria. To assess the quality of the studies included, we used the NHLBI quality assessment tools. The main summary outcome was the mean difference (MD) in serum PAI-1 levels reported as ng/mL Results: 33 articles involving 10,840 subjects fulfilled our inclusion criteria and were systematically reviewed. 11 studies were included in our meta-analyses. We found a significant MD in PAI-1 levels in NAFLD patients vs. controls [17.147 (95%CI: 7.720-26.574)]. Moreover, subgroup analysis evaluating PAI-1 levels in biopsy- proven NAFLD vs. controls remained significant [24.086 (95%CI: 3.812-44.361)], as well as in CT-diagnosed NAFLD [15.523 (95%CI: 7.163-23.883)]. However, no significant MD in PAI-1 levels was found in ultrasound- diagnosed NAFLD patients vs. controls [10.394 (95%CI: -13.335-34.123)]. No significant MD in PAI-1 levels in NASH patients vs. controls was observed [26.835 (95%CI: -0.879-54.549)].
CONCLUSIONS
In summary, elevated serum PAI-1 levels are associated with adult NAFLD (biopsy-proven and CT-diagnosed). However, no significant difference was found in ultrasound-diagnosed NAFLD and NASH patients. Nonetheless, the included studies have methodological variance, dictating that the obtained results should be carefully interpreted.
Topics: Adult; Biopsy; Humans; Non-alcoholic Fatty Liver Disease; Plasminogen Activator Inhibitor 1
PubMed: 35574617
DOI: 10.15403/jgld-4091 -
Frontiers in Endocrinology 2022Despite patients with thyroid dysfunction show obvious abnormal hemostatic indicators in the peripheral blood, the current research on whether and how subclinical... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Despite patients with thyroid dysfunction show obvious abnormal hemostatic indicators in the peripheral blood, the current research on whether and how subclinical hypothyroidism (SCH) influence hemostatic function (the coagulation and fibrinolytic system) still remains controversial.
OBJECTIVE
We conducted this study to evaluate how SCH influence on the coagulation and fibrinolytic system in human body.
METHODS
Prior to March 2022, Web of Science, Embase, PubMed, WanFang, CNKI data and reference lists were searched to identify eligible researches. Two of us independently extracted the data and evaluated study quality. The effect size is represented by standard mean difference (SMD). Both fixed and random-effects models were used where appropriate. Review Manager 5.3 and STATA 16.0 were used to analyze the eligible data.
RESULTS
1325 patients from twelve observational studies were involved in our research. Our study revealed that SCH changed the heamostatic balance towards hypercoagulable and hypofibrinolytic conditions accompanied by an increase in tissue fibrinogen, plasminogen activator and plasminogen activator inhibitor-1. By contrast, there was no statistically difference in acivated partial thromboplastin time (APTT) and D-Dimer in SCH group compared with that in control subjects.
CONCLUSIONS
Our study confirmed that SCH is related with a prothrombotic state, as reflected by changes in both coagulation and fibrinolysis. It is highly recommended for screening cardiovascular risk factors in combination with an adequate evaluation of SCH state.
SYSTEMATIC REVIEW REGISTRATION
[https://www.crd.york.ac.uk/prospero/#recordDetails] PROSPERO [CRD42021275313].
Topics: Blood Coagulation; Fibrinolysis; Hemostatics; Humans; Hypothyroidism; Thyroid Diseases
PubMed: 35574019
DOI: 10.3389/fendo.2022.861746 -
Frontiers in Pharmacology 2022This meta-analysis aimed to assess the efficacy and safety of ginkgo terpene lactone preparations including ginkgo diterpene lactone meglumine injection, ginkgolide...
This meta-analysis aimed to assess the efficacy and safety of ginkgo terpene lactone preparations including ginkgo diterpene lactone meglumine injection, ginkgolide injection, and ginkgolide B injection for ischemic stroke (IS). We searched the randomized controlled trials (RCTs) with publication date earlier than 31 August 2021 in PubMed, China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Journals Database (VIP), Chinese Biomedical Literature Database (CBM), Wanfang Database, Embase, and the Cochrane Library. RevMan 5.3 software was applied to analyze the data and generate the forest plot and funnel plot. Meanwhile, publication bias was also assessed by Egger's test with STATA 12 software. A total of 28 RCTs were eligible for inclusion. Among them, 23 RCTs were used to evaluate the efficacy of ginkgo terpene lactone preparations as the main treatment intervention for IS. To be specific, ginkgo diterpene lactone meglumine injection was superior to control drug in improving clinical efficacy [RR = 1.18, 95% CI (1.12, 1.24), Z = 6.36, < 0.001] and neurological function [MD = -1.42, 95% CI (-1.91, -0.93), Z = 5.66, < 0.001]. However, the effectiveness of the ginkgolide B injection group was equivalent to that of the control group. Additionally, ginkgolide injection achieved better clinical efficacy [RR = 1.10, 95% CI (1.02, 1.18), Z = 2.36, = 0.02], but the changes of neurological function deficit was not obviously different between two groups [MD = -0.43, 95% CI (-4.32, 3.46), Z = 0.22, = 0.83]. Furthermore, meta-analysis of five trials on ginkgo diterpene lactone meglumine injection combined with recombinant tissue plasminogen activator (rt-PA) thrombolytic therapy for acute IS showed that combination therapy was better in improving clinical efficacy [OR = 1.91, 95% CI (1.13, 3.22), Z = 2.41, = 0.02] and neurological function [MD = -3.31, 95% Cl (-3.64,-2.98), Z = 19.63, < 0.001]. Importantly, no serious adverse drug reactions/adverse drug events (ADRs/ADEs) were reported. Ginkgo terpene lactone preparations have good therapeutic effects on patients with IS. For acute IS, ginkgo diterpene lactone meglumine injection can be used as a complementary therapy to improve the clinical efficacy of rt-PA.
PubMed: 35392576
DOI: 10.3389/fphar.2022.821937 -
The Cochrane Database of Systematic... Apr 2022Patients with kidney failure require vascular access to receive maintenance haemodialysis (HD), which can be achieved by an arteriovenous fistula or a central venous... (Review)
Review
BACKGROUND
Patients with kidney failure require vascular access to receive maintenance haemodialysis (HD), which can be achieved by an arteriovenous fistula or a central venous catheter (CVC). CVC use is related to frequent complications such as venous stenosis and infection. Venous stenosis occurs mainly due to trauma caused by the entrance of the catheter into the venous lumen and repeated contact with the vein wall. A biofilm, a colony of irreversible adherent and self-sufficient micro-organisms embedded in a self-produced matrix of exopolysaccharides, is associated with the development of infections in patients with indwelling catheters. Despite its clinical relevance, the treatment of catheter-related bloodstream infections (CRBSIs) in patients receiving maintenance HD remains controversial, especially regarding catheter management. Antibiotic lock solutions may sterilise the catheter, treat the infection and prevent unnecessary catheter procedures. However, such treatment may also lead to antibiotic resistance or even clinical worsening in certain more virulent pathogens. Catheter removal and delayed replacement may remove the source of infection, improving infectious outcomes, but this approach may also increase vascular access stenosis, thrombosis or both, or even central vein access failure. Catheter guidewire exchange attempts to remove the source of infection while maintaining access to the same vein and, therefore, may improve clinical outcomes and preserve central veins for future access.
OBJECTIVES
To assess the benefits and harms of different interventions for CRBSI treatment in patients receiving maintenance HD through a permanent CVC, such as systemic antibiotics alone or systemic antibiotics combined with either lock solutions or catheter guidewire exchange or catheter replacement.
SEARCH METHODS
We searched the Cochrane Kidney and Transplant Register of Studies up to 21 December 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov.
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) and quasi-RCTs evaluating the management of CRBSI in permanent CVCs in people receiving maintenance HD.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies for inclusion, assessed their risk of bias, and performed data extraction. Results were expressed as risk ratios (RR) or hazard ratios (HR) for dichotomous outcomes and mean difference (MD) for continuous outcomes, with their 95% confidence intervals (CI). The certainty of the evidence was assessed using GRADE.
MAIN RESULTS
We identified two RCTs and one quasi-RCT that enrolled 760 participants addressing the treatment of CRBSIs in people (children and adults) receiving maintenance HD through CVC. No two studies compared the same interventions. The quasi-RCT compared two different lock solutions (tissue plasminogen activator (TPA) and heparin) with concurrent systemic antibiotics. One RCT compared systemic antibiotics alone and in association with an ethanol lock solution, and the other compared systemic antibiotics with different catheter management strategies (guidewire exchange versus removal and replacement). The overall certainty of the evidence was downgraded due to the small number of participants, high risk of bias in many domains, especially randomisation, allocation, and other sources of bias, and missing outcome data. It is uncertain whether an ethanol lock solution used with concurrent systemic antibiotics improved CRBSI eradication compared to systemic antibiotics alone (RR 1.61, 95% CI 1.16 to 2.23) because the certainty of this evidence is very low. There were no reported differences between the effects of TPA and heparin lock solutions on cure rates (RR 0.92, 95% CI 0.74 to 1.15) or between catheter guidewire exchange versus catheter removal with delayed replacement, expressed as catheter infection-free survival (HR 0.88, 95% CI 0.43 to 1.79). To date, no results are available comparing other interventions. Outcomes such as venous stenosis and/or thrombosis, antibiotic resistance, death, and adverse events were not reported.
AUTHORS' CONCLUSIONS
Currently, there is no available high certainty evidence to support one treatment over another for CRBSIs. The benefit of using ethanol lock treatment in combination with systemic antibiotics compared to systemic antibiotics alone for CRBSIs in patients receiving maintenance HD remains uncertain due to the very low certainty of the evidence. Hence, further RCTs to identify the benefits and harms of CRBSI treatment options are needed. Future studies should unify CRBSI and cure definitions and improve methodological design.
Topics: Adult; Catheter-Related Infections; Central Venous Catheters; Child; Heparin; Humans; Renal Dialysis; Sepsis
PubMed: 35363884
DOI: 10.1002/14651858.CD013554.pub2 -
JAMA Network Open Mar 2022Tenecteplase is being evaluated as an alternative thrombolytic agent for the treatment of acute ischemic stroke (AIS) within ongoing randomized clinical trials (RCTs).... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Tenecteplase is being evaluated as an alternative thrombolytic agent for the treatment of acute ischemic stroke (AIS) within ongoing randomized clinical trials (RCTs). In addition, nonrandomized clinical experiences with off-label use of tenecteplase vs alteplase for AIS treatment are being published.
OBJECTIVE
To evaluate the available evidence on the safety and efficacy of intravenous tenecteplase compared with intravenous alteplase provided by nonrandomized studies.
DATA SOURCES
Eligible studies were identified by searching MEDLINE and Scopus databases. No language or other restrictions were imposed. The literature search was conducted on October 12, 2021. This meta-analysis used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) proposal.
STUDY SELECTION
Nonrandomized studies (prospective or retrospective) comparing intravenous tenecteplase (at any dose) with intravenous alteplase in patients with AIS were included in the analysis.
DATA EXTRACTION AND SYNTHESIS
The crude odds ratios (ORs) and 95% CIs were calculated for the association of tenecteplase vs alteplase with the outcomes of interest and adjusted ORs were extracted if provided. Estimates using random-effects models were pooled.
MAIN OUTCOMES AND MEASURES
The primary outcome was the probability of good functional outcome (modified Rankin scale [mRS] score, 0-2) at 90 days.
RESULTS
Six studies were identified including a total of 1820 patients (618 [34%] treated with tenecteplase). Patients receiving tenecteplase had higher odds of 3-month good functional outcome (crude odds ratio [OR], 1.22; 95% CI, 0.90-1.66; adjusted OR, 1.60, 95% CI, 1.08-2.37), successful recanalization (crude OR, 2.82; 95% CI, 1.12-7.10; adjusted OR, 2.38; 95% CI, 1.18-4.81), and early neurological improvement (crude OR, 4.88; 95% CI, 2.03-11.71; adjusted OR, 7.60; 95% CI, 1.97-29.41). No significant differences were detected in 3-month excellent functional outcome proportions (mRS score 0-1; crude OR, 1.53; 95% CI, 0.81-2.91; adjusted OR, 2.51; 95% CI, 0.66- 9.49), symptomatic intracranial hemorrhage (crude OR, 0.97; 95% CI, 0.44-2.16; adjusted OR, 1.16; 95% CI, 0.13-10.50), or parenchymal hematoma (crude OR, 1.20; 95% CI, 0.24-5.95).
CONCLUSIONS AND RELEVANCE
Evidence from nonrandomized studies suggests tenecteplase is as safe as alteplase and potentially associated with improved functional outcomes compared with alteplase. Based on these findings, enrollment in the ongoing RCTs appears to be appropriate.
Topics: Brain Ischemia; Humans; Ischemic Stroke; Observational Studies as Topic; Off-Label Use; Stroke; Tenecteplase
PubMed: 35357458
DOI: 10.1001/jamanetworkopen.2022.4506 -
Journal of Clinical Medicine Feb 2022The prevalence and risk factors of hemorrhagic transformation (HT) after acute ischemic stroke HT have not been adequately delineated. We performed a systematic review...
The prevalence and risk factors of hemorrhagic transformation (HT) after acute ischemic stroke HT have not been adequately delineated. We performed a systematic review and meta-analysis to identify English-language prospective observational MEDLINE and EMBASE-listed reports of acute ischemic stroke with HT published from 1985-2017. Studies that used the ECASS-2 definitions of hemorrhagic transformation subtypes, hemorrhagic infarction (HI), and parenchymal hematoma (PH) were included. Patients treated with intravenous thrombolysis with tissue plasminogen activator (IV-tPA) were compared with those who did not receive thrombolysis. A total of 65 studies with 17,259 patients met inclusion criteria. Overall, HT prevalence was 27%; 32% in patients receiving IV-tPA vs. 20% in those without. Overall PH prevalence was 9%; 12% in IV-tPA treated patients vs. 5% in those without. HT was associated with a history of atrial fibrillation (OR 2.94) and use of anticoagulants (OR 2.47). HT patients had higher NIHSS (Hedge's-G 0.96) and larger infarct volume (diffusion-weighted MRI, Hedge's-G 0.8). In IV-tPA treated patients, PH correlated with antiplatelet (OR 3) and statin treatment (OR 4). HT (OR 3) and PH (OR 8) were associated with a poor outcome at 90-day (mRS 5-6). Hemorrhagic transformation is a frequent complication of acute ischemic stroke and is associated with poor outcome. Recognition of risk factors for HT and PH may reduce their incidence and severity.
PubMed: 35268253
DOI: 10.3390/jcm11051162 -
Stroke Mar 2022Stroke disproportionately affects racial minorities, and the level to which stroke treatment practices differ across races is understudied. Here, we performed a...
Stroke disproportionately affects racial minorities, and the level to which stroke treatment practices differ across races is understudied. Here, we performed a systematic review of disparities in stroke treatment between racial minorities and White patients. A systematic literature search was performed on PubMed to identify studies published from January 1, 2010, to April 5, 2021 that investigated disparities in access to stroke treatment between racial minorities and White patients. A total of 30 studies were included in the systematic review. White patients were estimated to use emergency medical services at a greater rate (59.8%) than African American (55.6%), Asian (54.7%), and Hispanic patients (53.2%). A greater proportion of White patients (37.4%) were estimated to arrive within 3 hours from onset of stroke symptoms than African American (26.0%) and Hispanic (28.9%) patients. A greater proportion of White patients (2.8%) were estimated to receive tPA (tissue-type plasminogen activator) as compared with African American (2.3%), Hispanic (2.6%), and Asian (2.3%) patients. Rates of utilization of mechanical thrombectomy were also lower in minorities than in the White population. As shown in this review, racial disparities exist at key points along the continuum of stroke care from onset of stroke symptoms to treatment. Beyond patient level factors, these disparities may be attributed to other provider and system level factors within the health care ecosystem.
Topics: Healthcare Disparities; Humans; Racial Groups; Stroke; Thrombectomy; Tissue Plasminogen Activator; United States
PubMed: 35105178
DOI: 10.1161/STROKEAHA.121.036263