Pooled Meta-analysis Research Articles

A Multi-Center Case Series, Systematic Review and Meta-Analysis of Neonatal Hemophagocytic Lymphohistiocytosis

Background Hemophagocytic lymphohistiocytosis (HLH) is an increasingly recognized life-threatening syndrome characterized by excessive inflammation and immune dysregulation. However, little is known about HLH presenting in neonates. Methods To describe the phenotype, etiology, and efficacy of therapy for infants presenting within 28 days of birth and diagnosed with HLH prior to 90 days of life, a retrospective multi-center study was conducted identifying 13 previously unreported cases from 8 centers. A systematic literature review identified 58 additional cases that were sufficiently similar to allow pooling for meta-analysis (n=71). Results Presenting symptoms and laboratory findings of HLH were non-specific and indistinguishable from other neonatal critical illnesses. More than 85% of patients demonstrated hepatomegaly, splenomegaly, hyperferritinemia, transaminitis, hypoalbuminemia, and severe thrombocytopenia. Notably, liver dysfunction appears more common in neonatal HLH compared to published reviews of HLH cases across the age spectrum. Genetic testing was pursued in 60% of the cohort with pathogenic variants identified in a third of patients (PRF1 in 15, UNC13D in 8). Ten additional cases occurred with a family history of HLH, for a total of 46% (33/71) of cases of presumed familial HLH. Seventeen cases (24%) represented secondary HLH with an identified trigger for immune dysregulation (e.g. infection or non-HLH disease) in the absence of an HLH-associated genetic mutation or family history. Twenty-one (30%) neonatal HLH cases were of unknown etiology. Two-year survival from presentation was low at 27%, with a trend toward superior 2-year overall survival for those with secondary HLH at 65% (unknown etiology 21%, familial HLH 18%, p=0.06; Figure). Ten patients (n=6 familial HLH, n=4 unknown etiology) underwent allogeneic hematopoietic cell transplantation (HCT) at a median of 4.8 months of age. HCT was associated with improved 2-year overall survival (OS) from HLH diagnosis (78% with HCT versus 11% without HCT, p<0.01). Infants proceeding to HCT trended toward older age at diagnosis with less severe lung and liver disease. Suspecting disease severity and/or lethality to confound treatment choice and prohibit proceeding to HCT, a landmark analysis of survival was conducted including only those surviving to 100 days of life. While this landmark analysis attenuated the survival benefit of HCT (78% with HCT versus 28% without HCT, p=0.09), the attenuation was driven by inclusion of secondary HLH cases (2-year OS 78% with HCT versus 0% without HCT when secondary HLH excluded, p<0.01). Conclusion Liver dysfunction in a severely ill neonate should prompt consideration of HLH as an etiology. Our study supports consideration of HCT for any neonate with HLH, except those with an identified trigger and absence of an HLH-associated gene mutation prompting classification as secondary HLH. Early lethality combined with superior HCT outcomes when HLH is well-controlled additionally highlight the need for novel HLH therapies to bridge to HCT. Further studies to better elucidate details of pre-HCT therapy, HCT conditioning regimens and how best to navigate multi-organ failure at HLH presentation are needed. Figure Disclosures No relevant conflicts of interest to declare.

The impact of delayed treatment of uncomplicated P. falciparum malaria on progression to severe malaria: A systematic review and a pooled multicentre individual-patient meta-analysis.

BackgroundDelay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as ‘test-and-treat’ policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM.Methods and findingsA search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case–control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle–Ottawa scale, and all studies were ranked as ‘Good’, scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07–1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92–4.06; p < 0.001) for a delay of 2–3 days and 5.46 (95% CI: 3.49–8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24–4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70–9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify.ConclusionsOur results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.

Remote ischemic preconditioning in isolated valve intervention. A pooled meta-analysis

ObjectiveRecent studies have shown no benefits from remote ischemic preconditioning (RIPC) in patients undergoing coronary artery bypass surgery. One possible explanation is that given previous exposure to angina and ischemia/reperfusion injury these patients, may be already ‘naturally preconditioned’. The role of RIPC in a context of isolated valve intervention, both surgical and particularly transcatheter is less clear and remains under investigated, with few high-quality studies. MethodsA systematic literature review identified 8 candidate studies that met the meta-analysis criteria. We analyzed outcomes of 610 subjects (312 RIPC and 298 SHAM) with random effects modeling. Each study was assessed for heterogeneity. The primary outcome was the extent of periprocedural myocardial injury, as reflected by the area under the curve for serum troponin concentration. Secondary endpoints included relevant intra- and post-operative outcomes; sensitivity and high-quality subgroup analysis was also carried out. ResultsSix and two studies reported the effect of RIPC in surgical and transcatheter valve intervention. There was a significant difference between-group in terms of periprocedural Troponin release (standardized mean difference (SMD: 0.74 [95% CI: 0.52; 0.95], p = 0.02) with no heterogeneity (χ2 2.40, I2 0%, p = 0.88). RIPC was not associated with any improvement in post-operative outcomes. No serious adverse RIPC related events were reported. ConclusionsRIPC seems to elicit overall periprocedural cardioprotection in patients undergoing valvular intervention, yet with no benefit on early clinical outcomes.

Genetic associations between CYP24A1 polymorphisms and predisposition of cancer: A meta-analysis.

CYP24A1 polymorphisms may affect predisposition of cancer, but the results of published studies remain inconclusive. Therefore, the authors conducted this meta-analysis to more robustly assess relationships between CYP24A1 polymorphisms and the predisposition of cancer by pooling the findings of published studies. A comprehensive literature search of PubMed, Embase, Web of Science, Wanfang, and CNKI was endorsed by the authors to identify eligible studies; 17 studies were finally found to be eligible for pooled meta-analysis. The pooled meta-analysis results showed that genotypic frequencies of the rs4809960 polymorphism among cancerous patients and controls of Caucasian ethnicity differed significantly, and genotypic frequencies of the rs6022999 polymorphism among cancerous patients and controls of Asian ethnicity also differed significantly. Moreover, we found that genotypic frequencies of the rs2585428 polymorphism among patients with prostate cancer and controls differed significantly, and genotypic frequencies of the rs6068816 polymorphism among patients with prostate cancer/breast cancer and controls also differed significantly. This meta-analysis suggests that the rs4809960 polymorphism may affect the predisposition of cancer in Caucasians, and the rs6022999 polymorphism may affect the predisposition of cancer in Asians. Moreover, the rs2585428 polymorphism may affect the predisposition of prostate cancer, while the rs6068816 polymorphism may affect the predisposition of prostate cancer and breast cancer.

Natural Language Processing in Surgery: A Systematic Review and Meta-analysis.

The aim of this study was to systematically assess the application and potential benefits of natural language processing (NLP) in surgical outcomes research. Widespread implementation of electronic health records (EHRs) has generated a massive patient data source. Traditional methods of data capture, such as billing codes and/or manual review of free-text narratives in EHRs, are highly labor-intensive, costly, subjective, and potentially prone to bias. A literature search of PubMed, MEDLINE, Web of Science, and Embase identified all articles published starting in 2000 that used NLP models to assess perioperative surgical outcomes. Evaluation metrics of NLP systems were assessed by means of pooled analysis and meta-analysis. Qualitative synthesis was carried out to assess the results and risk of bias on outcomes. The present study included 29 articles, with over half (n = 15) published after 2018. The most common outcome identified using NLP was postoperative complications (n = 14). Compared to traditional non-NLP models, NLP models identified postoperative complications with higher sensitivity [0.92 (0.87-0.95) vs 0.58 (0.33-0.79), P < 0.001]. The specificities were comparable at 0.99 (0.96-1.00) and 0.98 (0.95-0.99), respectively. Using summary of likelihood ratio matrices, traditional non-NLP models have clinical utility for confirming documentation of outcomes/diagnoses, whereas NLP models may be reliably utilized for both confirming and ruling out documentation of outcomes/diagnoses. NLP usage to extract a range of surgical outcomes, particularly postoperative complications, is accelerating across disciplines and areas of clinical outcomes research. NLP and traditional non-NLP approaches demonstrate similar performance measures, but NLP is superior in ruling out documentation of surgical outcomes.

LncRNA growth arrest-special 5 polymorphisms and predisposition to cancer: A meta-analysis.

The lncRNA growth arrest-special 5 (GAS5) is a critical tumor suppressor lncRNA, and its expression level has been found to be decreased in many types of cancers. So GAS5 polymorphisms are also likely to influence predisposition to many types of malignant diseases. Nevertheless, the relationships between GAS5 polymorphisms and cancer are still controversial. Thus, the authors designed this meta-analysis to get a more statistically reliable conclusion. The authors searched PubMed, Embase, and Web of Science for eligible studies. A total of 12 eligible studies involving 8693 cancer cases and 10,805 controls were pooled and analyzed in this meta-analysis. Among GAS5 polymorphisms, only GAS5 rs145204276 insertion/deletion polymorphism could be analyzed in a meta-analysis with regard to predisposition to cancer since no any other GAS5 polymorphisms were explored by at least two individual genetic association studies. All eligible studies were found to be of Asian origin. Although the overall pooled meta-analysis results did not show any significant associations between rs145204276 insertion/deletion polymorphism and a predisposition to cancer, rs145204276 insertion/deletion polymorphism was demonstrated to be significantly associated with a predisposition to gastric cancer (dominant comparison: P<0.0001; recessive comparison: P=0.005; over-dominant comparison: P=0.0003; over-dominant comparison: P<0.0001) in Asians in further subgroup analyses. This meta-analysis demonstrated that GAS5 rs145204276 insertion/deletion polymorphism was associated with a predisposition to gastric cancer in Asians. Nevertheless, considering that this positive finding was only based on three eligible studies from the same area, future studies with larger sample sizes in other populations are still warranted to test the robustness of our findings.

Effect of action observation therapy on motor function in children with cerebral palsy: a systematic review of randomized controlled trials with meta-analysis

Objective: To evaluate the evidence of using Action Observation Therapy in the rehabilitation of children with Cerebral Palsy. Study design: Systematic review with meta-analysis of Randomised Controlled Trials. Methods: For the purpose of identifying relevant studies, six databases were searched from inception until July 2020. The methodological quality was assessed by Physiotherapy Evidence Database scale. The outcomes were classified within the framework of the International Classification of Functioning. A pooled meta-analysis was performed on studies that demonstrated homogeneity. Results: Twelve randomised controlled trials with 307 participants were included with six of them were included in the meta-analysis. Non-significant difference between the groups was demonstrated by meta-analysis. Results of capacity assessed in post treatment and follow up evaluation were (0.06, –0.22 to 0.34, 95% (CI); P = 0.69 and (–0.35, –0.96 to 0.27, 95% (CI); P = 0.27); respectively. Actual performance in post-treatment and follow up were (0.10, –0.22 to 0.48, 95% (CI); P = 0.62) and (0.01, –0.40 to 0.41, 95% (CI); P = 0.97); respectively. Perceived performance evaluated using (ABILHAND-KIDS) were (0.30, –0.28 to 0.89, 95% (CI); P = 0.31) and (0.15, –0.43 to 0.73, 95% (CI); P = 0.61) for post treatment and follow up; respectively. Overall effect on activity domain was (0.08, –0.11 to 0.28, 95% (CI); P = 0.86) immediately and (0.04, –0.33 to 0.26, 95% (CI); P = 0.49) at follow-up; respectively. Conclusion: No evidence of benefit had been found to draw a firm conclusion regarding the effectiveness of action observation therapy in the rehabilitation of children with cerebral palsy due to limitations in methodological quality and variations between studies.

Improvement of Burn Scars Treated With Fractional Ablative CO2 Lasers-A Systematic Review and Meta-analysis Using the Vancouver Scar Scale.

Fractional ablative CO2 laser is being used increasingly to treat burn scars; however, objective measures of outcome success vary widely. This systematic review and meta-analysis extracts and pools available data to assess the outcomes of patients with burn scars treated with fractional ablative CO2 laser. A search of MEDLINE, EMBASE, and the gray literature was performed. The review included studies that reported patients with a confirmed diagnosis of scarring as a result of a burn injury, who were treated with fractional ablative CO2 laser and whose progress was recorded using the Vancouver Scar Scale (VSS). Eight studies were included in the systematic review and meta-analysis. Treatment regimens varied amongst studies, as did patient outcomes. Pooled data revealed an average VSS improvement of 29% across 282 patients following fractional CO2 ablative laser treatment. Although the heterogeneity of treatment regimens across studies limits this systematic review's ability to provide specific treatment recommendations, the overall trend towards improvement of burns scars treated with fractional CO2 laser based on the VSS encourages further exploration of this modality as a therapeutic tool.

Association of Alopecia Areata with VitaminD and Calcium Levels: A Systematic Review and Meta-analysis.

IntroductionTo investigate the associations of alopecia areata (AA) with serum vitamin D and calcium levels.MethodsA systematic review of all relevant articles published up to February 2020 in PubMed, Embase, and Cochrane Library databases was conducted. Primary endpoints were serum 25-hydroxyvitamin D [25(OH)D] levels and vitamin D deficiency, and the secondary endpoint was serum calcium level. Odds ratio (OR) and standardized mean difference (SMD) with 95% CI across studies were analyzed.ResultsData on 1585 patients with AA and 1114 controls from 16 case–control studies and three cross-sectional studies were included in this meta-analysis. A pooled meta-analysis was conducted using the random-effects model because of inter-study heterogeneity (vitamin D level, I2 = 87.90%; vitamin D deficiency, I2 = 81.10%; serum calcium level, I2 = 83.80%). A combined analysis revealed that patients with AA had significantly lower mean serum 25(OH)D level compared with control (WMD − 9.08, 95% CI − 11.65, − 6.50, p < 0.001), and were more likely to have vitamin D deficiency (OR 4.14, 95% CI 2.34, 7.35, p < 0.001). However, the pooled analysis revealed that patients with AA did not have significantly lower serum calcium levels compared with control (WMD − 0.17, 95% CI − 0.40, 0.06, p = 0.143). Subgroup analysis suggested that matched control, mean age, and country might contribute to the heterogeneity of serum vitamin D level, while study design, matched control, and country might contribute to the heterogeneity of vitamin D deficiency.ConclusionDeficiency of serum 25(OH)D level, rather than calcium level, was present in patients with AA. Screening for vitamin D deficiency and vitamin D supplementation may be beneficial in the treatment of patients with AA.Electronic supplementary materialThe online version of this article (10.1007/s13555-020-00433-4) contains supplementary material, which is available to authorized users.

Intracerebral hemorrhage outcomes in patients using direct oral anticoagulants versus vitamin K antagonists: a meta-analysis

Background: The objective of this paper is to assess the clinical outcomes between non-traumatic intracerebral hemorrhage(ICH) in patients using direct oral anticoagulants(DOAC) versus vitamin K antagonists(VKA) for non-valvular atrial fibrillation. We also evaluated the predictors of the poor post-ICH outcomes.Methods: We have performed pooled meta-analysis to assess long-term clinical outcomes in patients with DOAC-ICH as compared to those with VKA-ICH. A systematic literature search was conducted by searching the full-text English literature in PubMed, EMBASE, and Cochrane databases for observational studies reporting outcomes on interest. MOOSE guidelines were used to collect data till December 31, 2019 and random effects analysis was carried out to account for heterogeneity. For outcomes, risk ratios(RR) and the mean differences were pooled using a random-effects model and weighted mean differences (WMDs), respectively.Results: Seventeen studies met the inclusion criteria (n = 25,354 patients; DOAC-ICH arms = 5,631; VKA-ICH arm = 19,273). Patients with DOAC-ICH had smaller hematoma volumes (WMD=-9.59; 95%CI=-15.33--3.85; I2 = 68.6%) and reduced mortality rate at discharge (RR = 0.82; 95%CI = 0.71-0.96; I2 = 9.4%). There was no significant difference between the two groups in rate of hematoma expansion (RR = 0.79; 95%CI = 0.56-1.11; I2 = 50.9%), unfavorable functional outcome(Modified Rankin Scale) at discharge (RR = 0.82; 95%CI = 0.56-1.18; I2 = 80.2%), unfavorable outcome at 3-months (RR = 0.77; 95%CI = 0.56-1.06; I2 = 63.9), and mortality at 3-months (RR = 0.90; 95%CI = 0.73-1.10; I2 = 35∙8%). Multivariate meta-regression revealed that the average age of patient population had a significantly negative correlation with(RR=-0.202; p = 0.017) hematoma expansion.Conclusion: We conclude that use of DOAC is associated with reduced hematoma volume and mortality rate at discharge. Age is a predictor of the poor outcome of hematoma expansion.

Health promotion interventions to improve oral health of adolescents: A systematic review and meta-analysis.

To evaluate the effectiveness of health promotion interventions on oral health knowledge, behaviour and status of healthy adolescents. This review included randomized controlled trials (RCTs) of oral health promotion interventions targeting adolescents. Primary clinical outcomes (gingival health, plaque scores, caries) and secondary proxy outcomes were evaluated. Meta-analysis of primary outcomes was conducted where possible, with subgroup analysis based on intervention (comprehensive health promotion and education-only). Thirty-seven eligible publications reporting on 28 unique RCTs of oral health promotion interventions were included. Quality appraisal of studies ranged from 48% to 96%. Interventions reported ranged from single-session interventions to community-wide programmes, including clinical preventive procedures and take-home products. Half used a health behaviour change theory to inform their intervention. The meta-analysis pooling of results favoured the intervention over control for all clinical outcomes, except DMFS in the education-only subgroup. Stronger intervention effects were seen in the comprehensive intervention subgroup than the education-only subgroup for DMFS (P=.02). This effect was slight, but not as clear in all other clinical categories. The majority of studies reported improvements in oral health knowledge, attitudes and behaviours. More positive outcomes were found with longer programmes, especially for dental caries outcomes. Oral health promotion programmes targeting adolescents have the ability to improve clinical oral health outcomes in the short and long term. Programmes should use more behavioural theory-based interactive and strategic methods, including self-awareness and the use of the wider community and peers for oral health promotion activities over a longer intervention duration.

Cell Therapy Improves Cardiac Function in Anthracycline-Induced Cardiomyopathy Preclinical Models: A Systematic Review and Meta-Analysis.

Although anthracycline (ANT)-based treatment strongly contributes to cancer survivorship, the use of these agents is limited by the risk of cardiotoxicity. For those patients who evolve to heart failure, myocardial regenerative approaches are of particular interest, and a growing body of preclinical studies has been investigating the use of cell therapy for ANT-induced cardiomyopathy (AIC). However, since animal models and modalities of cell therapy are highly heterogeneous between studies, the efficacy of cell therapy for AIC is not clear. Thus, we conducted a systematic review and meta-analysis of experimental studies reporting the use of cell therapy with mesenchymal stromal cells (MSC) or bone marrow mononuclear cells (BMMNC) in animal models of AIC with regard to global cardiac function. The Medline, EMBASE, and Web of Science databases were searched from inception to November 2019. Two reviewers independently extracted data on study quality and the results of left ventricular ejection fraction (LVEF) and fractional shortening (FS) obtained by echocardiography. The quality of outcomes was assessed using the Cochrane, Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES), and SYRCLE bias risk tools. Pooled random-effects modeling was used to calculate pooled mean differences (MD) and 95% confidence intervals (CIs). Twenty-two studies comprising 381 small animals (rabbits and rodents) were included. A pooled meta-analysis of all treatments showed that cell therapy increased LVEF by 9.87% (95% CI 7.25-12.50, P < 0.00001) and FS by 7.80% (95% CI 5.68-9.92, P < 0.00001) in small animals with AIC. Cell therapy with MSC/BMMNC is effective to mitigate the deleterious effects of ANT on cardiac function in preclinical models. Nevertheless, due to the small number of studies and considerable heterogeneity, future translational studies must be designed to diminish between-study discrepancies and increase similarity to the clinical landscape.

Effect of Concomitant Therapy With Steroids and Tumor Necrosis Factor Antagonists for Induction of Remission in Patients With Crohn’s Disease: A Systematic Review and Pooled Meta-analysis

It is not clear whether concomitant therapy with corticosteroids and anti-tumor necrosis factor (TNF) agents is more effective at inducing remission in patients with Crohn's disease (CD) than anti-TNF monotherapy. We aimed to determine whether patients with active CD receiving corticosteroids during induction therapy with anti-TNF agents had higher rates of clinical improvement than patients not receiving corticosteroids during induction therapy. We systematically searched the MEDLINE, Embase, and CENTRAL databases, through January 20, 2016, for randomized trials of anti-TNF agents approved for treatment of CD and identified 14 trials (5 of adalimumab, 5 of certolizumab, and 4 of infliximab). We conducted a pooled meta-analysis of individual patient and aggregated data from these trials. We compared data from participants who continued oral corticosteroids during induction with anti-TNF therapy to those treated with anti-TNF agents alone. The endpoints were clinical remission (CD activity index [CDAI] scores <150) and clinical response (a decrease in CDAI of 100 points) at the end of induction (weeks 4-14 of treatment). We included 4354 patients who received induction therapy with anti-TNF agents, including 1653 [38.0%] who were receiving corticosteroids. The combination of corticosteroids and an anti-TNF agent induced clinical remission in 32.0% of patients, whereas anti-TNF monotherapy induced clinical remission in 35.5% of patients (odds ratio [OR], 0.93; 95% CI, 0.74-1.17). The combination of corticosteroids and an anti-TNF agent induced a clinical response in 42.7% of patients, whereas anti-TNF monotherapy induced a clinical response in 46.8% (OR 0.84; 95% CI, 0.73-0.96). These findings did not change with adjustment for baseline CDAI scores and concurrent use of immunomodulators. Based on a meta-analysis of data from randomized trials of anti-TNF therapies in patients with active CD, patients receiving corticosteroids during induction therapy with anti-TNF agents did not have higher rates of clinical improvement compared with patients not receiving corticosteroids during induction therapy. Given these findings and the risks of corticosteroid use, clinicians should consider early weaning of corticosteroids during induction therapy with anti-TNF agents for patients with corticosteroid-refractory CD.

Efficacy and Safety of Recanalization Therapy for Acute Ischemic Stroke With Large Vessel Occlusion: A Systematic Review.

The optimal recanalization strategy for acute ischemic stroke with large vessel occlusion continues to be an area of active interest. Network meta-analysis can provide insight when direct comparative evidence is lacking. A systematic review of the literature using PubMed, Embase, the Cochrane Central Register of Controlled Trials, and SinoMed was performed, and a search was conducted for clinical trials on ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, and StrokeCenter.org. Four independent reviewers conducted the study selection, data abstraction, and quality assessments. The literature review identified 17 trials including 3236 patients and 8 ongoing clinical trials. Sample sizes ranged from 7 to 656 participants. Intravenous thrombolysis (IVT) was the most common intervention, followed by IVT plus mechanical thrombectomy (MT), IVT plus intraarterial thrombolysis, intraarterial thrombolysis alone, and MT alone. In the pooled network meta-analysis, IVT+MT was associated with a higher rate of independent functioning. In contrast, IVT was ranked as the most ineffective treatment strategy with respect to neurological functions, while direct MT was ranked as the least safe intervention with respect to all-cause mortality. Also, irrespective of assessment tools, endovascular treatment plus IVT led to higher successful recanalization rate than thrombolysis alone. Compared with other recanalization treatments, IVT+MT seems to be the most effective strategy, without increasing detrimental effects, for thrombolysis-eligible patients with large vessel occlusion-acute ischemic stroke. To improve the current evidentiary basis for recanalization treatment, future trials and real-world studies are warranted and should use unified definitions of symptomatic intracranial hemorrhage and recanalization.

Ramucirumab in patients with advanced HCC and elevated alpha-fetoprotein (AFP): Outcomes by treatment-emergent ascites.

4644 Background: REACH and REACH-2 investigated ramucirumab (RAM) vs placebo (PL) in patients (pts) with advanced HCC following sorafenib, with REACH-2 enrolling only pts with baseline AFP ≥400 ng/mL. Ascites is common in HCC and associated with poorer outcomes. An exploratory analysis of outcomes by treatment-emergent (TE)-ascites was done. Methods: Pts with HCC, Child-Pugh A, ECOG PS ≤1, prior sorafenib, and no clinically meaningful ascites were randomized (REACH 1:1; REACH-2 2:1) to RAM 8 mg/kg or PL Q2W. A pooled meta-analysis of independent pt data (stratified by study) from REACH-2 and REACH (AFP ≥400 mg/mL) was done. OS and PFS were evaluated by Kaplan-Meier estimator and Cox models. Prognosis of TE-ascites in OS was evaluated by multivariate Cox models (adjusted for baseline ECOG PS, AFP, macrovascular invasion (MVI), and treatment [trt]). Results: Baseline characteristics were generally balanced between TE-ascites and non-ascites pts; however, more pts with ascites had MVI at baseline. Any-grade ascites was reported at a higher rate in RAM than PL (66 [21%] vs 33 [15%] pts, respectively), with most being low grade. Rate of Gr ≥3 ascites was similar between arms (15 [5%] vs 9 [4%] pts). Median time to onset (43 vs 47 days) and median duration of ascites (13 vs 18 days) were similar in RAM vs PL, with furosemide (22%) and spironolactone (19%) as most common trt and paracentesis (18%) as most common procedure for ascites in both arms. Ascites trended as a prognostic factor for OS after adjustment (with vs without; HR=1.3, 95% CI: 0.99, 1.62). Ascites was more commonly linked with hypoalbuminemia (odds ratio 4.9, 95% CI: 2.5, 9.3), but was not associated with proteinuria or hypertension. TEAEs occurred more frequently in pts with ascites in both arms. The most frequent Gr ≥3 TEAE in pts with ascites was hypertension. One RAM pt discontinued trt due to ascites. RAM trt was beneficial irrespective of presence of ascites (Table), and pts with ascites received more post-discontinuation therapy on RAM than PL (18% vs 6%). Conclusions: Acknowledging limitations of sample size, RAM provided a survival benefit in pts who did or did not experience TE-ascites. RAM was well tolerated and no new safety findings were observed. Clinical trial information: NCT011400347; NCT02435433 . [Table: see text]

The Association Between Nonalcoholic Fatty Liver Disease and Risk of Cardiovascular Disease, Stroke, and Extrahepatic Cancers

Although primarily a disease with liver-specific complications, nonalcoholic fatty liver disease (NAFLD) is a systemic disease with extrahepatic complications. We aim to evaluate the association between NAFLD and cardiovascular disease (CVD), stroke and cerebrovascular disease, and extrahepatic cancers. We searched MEDLINE, EMBASE, and Cochrane Systematic Review Database from January 1, 2000 to July 1, 2019 to identify peer-reviewed English language literature using predefined keywords for NAFLD, CVD, stroke and cerebrovascular disease, and extrahepatic cancers among adults. Two reviewers independently selected studies for inclusion. Measures of association between NAFLD and CVD, stroke and cerebrovascular disease, and extrahepatic cancers were extracted. Quality assessed using Newcastle-Ottawa scale and Grading of Recommendations Assessment, Development and Evaluation (GRADE). Thirty studies were included evaluating CVD, 16 studies evaluating stroke or cerebrovascular disease, and 13 studies evaluating extrahepatic cancers. On pooled meta-analysis assessment, NAFLD was associated with increased risk of CVD (risk ratio [RR]: 1.78; 95% confidence interval [CI]: 1.52-2.08) and stroke or cerebrovascular disease (RR: 2.08, 95% CI: 1.72-2.51). Significant heterogeneity in assessing extrahepatic cancers prevented applying meta-analysis methods, but NAFLD seemed to be associated with increased risk of breast and colorectal cancers. Overall level of quality of studies were very low by GRADE. NAFLD is associated with increased risks of CVD and stroke or cerebrovascular disease among adults. There appears to be increased risk of breast and colorectal cancers. Given low quality of evidence, it is premature to make any strong conclusions to modify CVD, stroke, or cancer screening policies in patients with NAFLD.

Corrigendum to 'Mortality in trials on transcatheter aortic valve implantation versus surgical aortic valve replacement: a pooled meta-analysis of Kaplan-Meier-derived individual patient data' Eur J Cardiothorac Surg 2020;58:221-9.

Corrigendum to 'Mortality in trials on transcatheter aortic valve implantation versus surgical aortic valve replacement: a pooled meta-analysis of Kaplan-Meier-derived individual patient data' Eur J Cardiothorac Surg 2020;58:221-9.

Mortality in trials on transcatheter aortic valve implantation versus surgical aortic valve replacement: a pooled meta-analysis of Kaplan-Meier-derived individual patient data.

This meta-analysis of Kaplan-Meier-estimated individual patient data was designed to evaluate the effects of transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) on the long-term all-cause mortality rate, to examine the potential time-varying effect and to model their hazard ratios (HRs) over time. Moreover, we sought to compare traditional meta-analytic tools and estimated individual patient data meta-analyses. Trials comparing TAVI versus SAVR were identified through Medline, Embase, Cochrane databases and specialist websites. The primary outcome was death from any cause at follow-up. Enhanced secondary analyses of survival curves were performed estimating individual patient time-to-event data from published Kaplan-Meier curves. Treatments were compared with the random effect Cox model in a landmark framework and fully parametric models. We identified 6 eligible trials that included 6367 participants, randomly assigned to undergo TAVI (3252) or SAVR (3115). According to the landmark analysis, the incidence of death in the first year after implantation was significantly lower in the TAVI group [risk-profile stratified HR 0.85, 95% confidence interval (CI) 0.73-0.99; P = 0.04], whereas there was a reversal of the HR after 40 months (risk-profile stratified HR 1.31, 95% CI 1.01-1.68; P = 0.04) favouring SAVR over TAVI. This time-varying trend of HRs was also confirmed by a fully parametric time-to-event model. Traditional meta-analytic tools were shown to be biased because they did not intercept heterogeneity and the time-varying effect. The mortality rates in trials of TAVI versus SAVR are affected by treatments with a time-varying effect. TAVI is related to better survival in the first months after implantation whereas, after 40 months, it is a risk factor for all-cause mortality.

CTLA-4 polymorphisms and predisposition to digestive system malignancies: a meta-analysis of 31 published studies

BackgroundThe results of genetic association studies regarding cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) polymorphisms and digestive system malignancies were controversial. The authors designed this meta-analysis to more precisely estimate relationships between CTLA-4 polymorphisms and digestive system malignancies by pooling the results of related studies.MethodsThe authors searched PubMed, Embase, Web of Science, and CNKI for eligible studies. Thirty-one eligible studies were pooled analyzed in this meta-analysis.ResultsThe pooled meta-analysis results showed that genetic distributions of rs231775, rs4553808, and rs733618 polymorphisms among patients with digestive system malignancies and controls differed significantly. Moreover, genotypic distribution differences were also observed for rs231775 polymorphism among patients with colorectal cancer/pancreatic cancer and controls, for rs4553808 and rs5742909 polymorphisms among patients with gastric cancer and controls, for rs3087243 polymorphism among patients with liver cancer and controls, and for rs733618 polymorphism among patients with colorectal cancer and controls in pooled meta-analyses.ConclusionsThis meta-analysis suggested that rs231775 polymorphism was associated with predisposition to colorectal cancer and pancreatic cancer, rs4553808 and rs5742909 polymorphisms were associated with predisposition to gastric cancer, rs3087243 polymorphism was associated with predisposition to liver cancer, and rs733618 polymorphism was associated with predisposition to colorectal cancer.

The efficacy and toxicity of induction chemotherapy plus concurrent chemoradiotherapy in locoregionally advanced nasopharyngeal carcinoma: A meta-analysis of randomized controlled trials.

A systemic review and meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy, toxicity and safety of concurrent chemoradiotherapy (CCRT) with or without induction chemotherapy (IC) for locoregionally advanced nasopharyngeal carcinoma (NPC). Research searching was performed in Web of Science, PubMed, The Cochrane Library, Embase, Chinese Biomedical Database, Chinese National Knowledge Infrastructure, Chongqing VIP Database for Chinese Technical Periodicals and Wanfang Database. RCTs including patients diagnosed with locoregionally advanced NPC without metastasis and randomly treated with IC plus CCRT and CCRT alone were included. Survival and outcome data were extracted and meta-analysis was performed using the Revman 5.3.0 software. Ten RCTs (2280 patients) were selected and used for pooled meta-analysis. In comparison with CCRT, IC plus CCRT treatment significantly improved the overall survival (OS; HR = 0.70, 95%CI 0.56-0.87, P = .002), progression-free survival (PFS; HR = 0.75, 95%CI 0.65-0.87, P < .0001), distant metastasis failure-free survival (DMFS; HR = 0.71, 95%CI 0.58-0.85, P = .0003) and loco-regional failure-free survival (LFES; HR = 0.72, 95%CI 0.59-0.88, P = .002) of patients with locoregionally advanced NPC. Patients treated with IC and CCRT had higher incidence of grade 3-4 leucopenia and thrombocytopenia than patients treated with CCRT alone (P < .0001). No significant difference in other grade 3-4 adverse events and radiation toxicity was observed between the two groups. IC combined with CCRT improved the survival of patients with locoregionally advanced NPC. Combined IC and CCRT therapy was an efficacy treatment regimen for locoregionally advanced NPC.