Meta-analysis of optimal timing of coronary intervention in non-ST-elevation acute coronary syndrome.

OBJECTIVES: We conducted a meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of early versus delayed invasive management of non-ST-elevation acute coronary syndrome (NSTE-ACS). BACKGROUND: Coronary angiography is recommended for patients with NSTE-ACS, however, the optimal timing for this remains controversial. METHODS: Literature search of Pubmed/MEDLINE, Cochrane Library, and Embase for all RCTs that compared early with delayed invasive approaches in treating NSTE-ACS was conducted by two independent authors. Primary outcome was major adverse cardiovascular events (MACE), while the secondary outcomes included cardiovascular mortality, all-cause mortality, myocardial infarction (MI), and bleeding events. The Mantel-Haenszel random-effects model was used to calculate risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: We included 14 RCTs (9,637 patients, mean age 65.4, 67% males). The early invasive strategy was associated with a lower incidence of MACE compared with the delayed invasive strategy (RR 0.65, 95%CI 0.49-0.87; p = .003). Subgroup analysis according to GRACE score showed a lower incidence of MACE with early invasive strategies in GRACE >140 patients (p for interaction = .002). Furthermore, recurrent ischemia was lower in patients with an early invasive strategy (RR 0.42, 95%CI 0.26-0.69; p < .0005). In contrast, there were no significant differences in all-cause mortality, cardiovascular mortality, MI, or bleeding events between groups (all p > .05). CONCLUSIONS: Among patients with NSTE-ACS, an early invasive strategy was associated with lower incidence of MACE and recurrent ischemia compared with delayed invasive strategy. There were no significant differences in all-cause mortality, cardiovascular mortality, MI, or bleeding events between groups.

Noninvasive Oxygenation Strategies in Immunocompromised Patients With Acute Hypoxemic Respiratory Failure: A Pairwise and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Acute hypoxemic respiratory failure (AHRF) is a leading cause of intensive care unit (ICU) admission among immunocompromised patients. Invasive mechanical ventilation is associated with increased morbidity and mortality. OBJECTIVE: To evaluate the efficacy of various oxygenation strategies including noninvasive ventilation (NIV), high-flow nasal cannula (HFNC), and conventional oxygen therapy in immunocompromised patients with AHRF. METHODS: Electronic databases including PubMed, Embase, and the Cochrane Library were reviewed from inception to December 2018. We included all randomized controlled trials (RCTs) comparing different modalities of initial oxygenation strategies in immunocompromised patients with AHRF. Our primary outcome was the need for intubation and invasive mechanical ventilation while secondary outcomes were ICU acquired infections and short- and long-term mortality. Data were extracted separately and independently by 2 reviewers. We performed a Bayesian network meta-analysis to calculate odds ratio (OR) and Bayesian 95% credible intervals (CrIs). RESULTS: Nine RCTs were included (1570 patients, mean age 61.1 ± 13.8 years with 64% male). Noninvasive ventilation was associated with a significantly reduced intubation rate compared with standard oxygen therapy (OR: 0.53; 95% CrI: 0.26-0.91). There were no significant reductions of intubation between NIV versus HFNC (OR: 0.83; 95% CrI: 0.35-2.11) or HFNC versus standard oxygen therapy (OR: 0.65; 95% CrI: 0.26-1.24). There were no significant differences between all groups regarding short-term (28-day or ICU) mortality or long-term (90-day or hospital) mortality or ICU-acquired infections (P > 0.05). CONCLUSION: Among immunocompromised patients with AHRF, NIV was associated with a significant reduction of intubation compared with standard oxygen therapy. There were no significant differences among all oxygenation strategies regarding mortality and ICU-acquired infections.

Extended duration of thromboprophylaxis for medically ill patients: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The benefit of extended-duration thromboprophylaxis in patients hospitalised for acute medical illness beyond hospital stay remains controversial. AIMS: To perform a meta-analysis of randomised controlled trials (RCT) in order to examine the efficacy and safety of extended-duration anticoagulation for venous-thromboembolism (VTE) prophylaxis in this high-risk population. METHODS: An electronic database search was conducted to include all RCT comparing between extended-duration versus short-duration prophylactic anticoagulation in medically ill patients. The primary efficacy outcome was the composite events of asymptomatic deep vein thrombosis (DVT), symptomatic VTE and death from VTE-related causes. RESULTS: Five RCT were included totalling 40 124 patients, with a mean age of 71 years and 51% were male. In comparison to standard-duration therapy, extended-duration thromboprophylaxis was associated with a significant reduction in the primary efficacy outcome (risk ratio (RR) 0.75; 95% confidence interval (CI) 0.67-0.85; P < 0.01), symptomatic VTE (RR 0.53; 95% CI 0.33-0.84; P < 0.01) and asymptomatic DVT (RR 0.81; 95% CI 0.71-0.94; P < 0.01). However, there were no significant differences between both groups with regard to VTE-related death (RR 0.81; 95% CI 0.60-1.10; P = 0.18) or all-cause death (RR 0.97; 95% CI 0.88-1.08; P = 0.64). In contrast, extended-duration thromboprophylaxis was associated with an increased risk of major bleeding (RR 2.04; 95% CI 1.42-2.91; P < 0.01) and non-major clinically relevant bleeding (RR 1.81; 95% CI 1.29-2.53; P < 0.01). CONCLUSIONS: Among hospitalised medically ill patients, prolonging venous thromboprophylaxis was associated with a decreased risk of composite events of the primary efficacy outcome and increased risk of bleeding with no significant difference in VTE-related death.

Personalized antiplatelet therapy in patients with coronary artery disease undergoing percutaneous coronary intervention: A network meta-analysis of randomized clinical trials.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of genotype- and phenotype-guided intensified antiplatelet therapy compared with conventional therapy in patients undergoing stent implantation. BACKGROUND: Although potent P2Y12 receptor inhibitors are recommended for percutaneous coronary intervention (PCI)-treated acute coronary syndrome, their usage is limited by a high bleeding risk. Therefore, personalized antiplatelet therapy could provide a valuable foundation for selection of antiplatelet therapy in this population. METHODS: We conducted a Bayesian network meta-analysis for all randomized clinical trials (RCTs) that evaluated genotype- and/or phenotype-guided therapy in PCI-treated coronary artery disease. RESULTS: Thirteen RCTs were included with a total of 6,845 patients. The results showed no significant differences in major adverse cardiovascular events (MACE) between the treatment options ((genotype guided vs. standard of care; OR 0.64; 95% CI: 0.38-1.05) and (phenotype vs. standard of care; OR 0.93; 95% CI: 0.54-1.37)). In addition, no significant differences were demonstrated in bleeding events ((genotype guided vs. standard of care; OR 0.73; 95% CI: 0.45-1.25) and (phenotype vs. standard of care; OR 0.90; 95% CI: 0.62-1.39)). CONCLUSIONS: In this mixed treatment meta-analysis of RCTs, neither genotype- nor phenotype-guided antiplatelet therapy in patients with PCI-treated coronary artery disease was superior to conventional therapy.

CYP2C19 pharmacogenetics versus standard of care dosing for selecting antiplatelet therapy in patients with coronary artery disease: A meta-analysis of randomized clinical trials.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of personalized genotype-guided selection of antiplatelet therapy versus standard of care in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Clopidogrel is the most frequently used P2Y12 receptor antagonist in patients with coronary artery disease. However, genetic variations of clopidogrel are associated with inter-individual response variability which could limit its efficacy. METHODS: Electronic databases were searched for all randomized clinical trials (RCTs) evaluating genotype-guided therapy versus standard of care in patients undergoing stent implantation. Aggregated risk ratios (RRs) and 95% CIs were calculated using a random-effects model. RESULTS: We included 6 RCTs with a total of 2,371 patients. When compared with standard of care, the use of genotype-guided therapy did not significantly reduce major adverse cardiovascular events (MACE) (RR 0.67; 95% CI: 0.35-1.27; P = 0.22). However, MACE was significantly reduced in the subset of trials which enrolled only acute coronary syndromes (ACS) (P < 0.01). In addition, there was a significant reduction in myocardial infarction in the genotype-guided group (RR 0.44; 95% CI: 0.28-0.70; P < 0.01; I2 = 0%). Other clinical outcomes were not significantly different: cardiovascular mortality (RR 0.68; 95% CI: 0.27-1.74; P = 0.42), stroke (RR 0.62; 95% CI: 0.23-1.65; P = 0.34), stent thrombosis (RR 0.37; 95% CI: 0.13-1.06; P = 0.06), and bleeding (RR 0.68; 95% CI: 0.43-1.06; P = 0.09). CONCLUSION: In patients undergoing stent implantation, MACE with genotype-guided therapy was not significantly reduced; however, there was a signal towards reduction of MACE in ACS patients, as well as a lower rate of MI, though this will require further confirmation in adequately powered trials.

Restrictive versus liberal red blood cell transfusion for cardiac surgery: a systematic review and meta-analysis of randomized controlled trials.

Patients undergoing cardiac surgery are among the most common recipients of allogeneic red blood cell (RBC) transfusions. However, whether restrictive RBC transfusion strategies for cardiac surgery achieve a similar clinical outcome in comparison with liberal strategies remains unclear. We searched electronic databases from inception to December 2017 for randomized controlled trials (RCTs). We calculated the risk ratios (RRs) and weighted-mean difference (MD) using a random-effects model. We included 9 RCTs with a total of 9005 patients. There was no significant difference in mortality between groups [RR 1.03; 95% confidence interval (CI) 0.74-1.45; P = 0.86]. In addition, there were no significant differences between groups in the clinical outcomes of infections (RR 1.09; 95% CI 0.94-1.26; P = 0.26), stroke (RR 0.98; 95% CI 0.72-1.35; P = 0.91), respiratory morbidity (RR 1.05; 95% CI 0.89-1.24; P = 0.58), renal morbidity (RR 1.02; 95% CI 0.94-1.09; P = 0.68), myocardial infarction (RR 1.00; 95% CI 0.80-1.24; P = 0.99), cardiac arrhythmia (RR 1.05; 95% CI 0.88-1.26; P = 0.56), gastrointestinal morbidity (RR 1.93; 95% CI 0.81-4.63; P = 0.14), or reoperation (RR 0.90; 95% CI 0.67-1.20; P = 0.46). There was a significant difference in the intensive care unit length of stay (h) (MD 4.29; 95% CI 2.19-6.39, P < 0.01) favoring the liberal group. However, there was no significant difference in the hospital length of stay (days) (MD 0.15; 95% CI - 0.18 to 0.48; P = 0.38). In conclusion, this meta-analysis showed that restrictive strategies for RBC transfusion are as safe as liberal strategies in patients undergoing cardiac surgery with regards to short-term clinical outcomes.

Clopidogrel and aspirin after ischemic stroke or transient ischemic attack: an updated systematic review and meta-analysis of randomized clinical trials.

Recurrent stroke is common immediately following a transient ischemic attack (TIA) or ischemic stroke. Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin may provide greater protection against subsequent stroke than monotherapy. Electronic databases were searched for randomized clinical trials (RCTs) comparing DAPT with monotherapy in ischemic stroke/TIA. Sixteen RCTs with a total of 29,032 patients were included. Compared with monotherapy, DAPT was associated with significantly lower rates of any stroke (risk ratio [RR] 0.80; 95% confidence interval [CI] 0.72-0.89) and ischemic stroke (RR 0.75; 95% CI 0.66-0.85) during any follow-up period. Although significant increases in intracranial bleeding (RR 1.55; 95% CI 1.20-2.01) and major bleeding (RR 1.90; 95% CI 1.33-2.72) were associated with DAPT, especially with long-term follow-up, the number needed to harm was 258 and 113, respectively. Nevertheless, short-duration DAPT (≤ 1 month) started during the early acute ischemic phase was associated with less bleeding than longer DAPT and greater reduction of recurrent strokes compared with monotherapy. In contrast, long DAPT and DAPT started later after the index event (≥ 1 month) were associated with similar rates of any stroke and increased risks of bleeding compared with monotherapy. Other clinical outcomes were essentially similar between the two groups and included recurrent TIA (RR 0.88; 95% CI 0.72-1.07), myocardial infarction (RR 1.04; 95% CI 0.84-1.29), vascular death (RR 0.99; 95% CI 0.82-1.19), and any death (RR 1.12; 95% CI 0.88-1.42). Similar findings were observed in patients who presented with minor stroke/TIA. Conclusions: Among patients who presented with ischemic stroke/TIA, short-course clopidogrel plus aspirin immediately following the index event appears to be more effective than and as safe as monotherapy for secondary stroke prevention.

Tenecteplase versus alteplase for management of acute ischemic stroke: a pairwise and network meta-analysis of randomized clinical trials.

Tenecteplase is a genetically mutated variant of alteplase with superior pharmacodynamic and pharmacokinetic properties. However, its efficacy and safety in acute ischemic strokes are limited. Hence, we conducted a study to evaluate the efficacy and safety of tenecteplase compared with alteplase in acute ischemic stroke. Electronic databases were searched for randomized clinical trials (RCTs) comparing tenecteplase with alteplase in acute ischemic stroke patients eligible for thrombolysis. We evaluated various efficacy and safety outcomes using random-effects models for both pairwise and Bayesian network meta-analyses along with meta-regression analyses. We included 5 RCTs with a total of 1585 patients. Compared with alteplase, tenecteplase treatment was associated with significantly greater complete recanalization (odd ratio [OR] 2.01; 95% confidence interval [CI] 1.04-3.87; p = 0.04) and early neurological improvement (OR 1.43; 95% CI 1.01-2.03; p = 0.05). There were no differences between the two thrombolytics in terms of excellent recovery (modified Rankin Scale [mRS] 0-1; OR 1.17; 95% CI 0.95-1.44; p = 0.13), functional independence (mRS 0-2; OR 1.24; 95% CI 0.78-1.98), poor recovery (mRS 4-6; OR 0.78; 95% CI 0.49-1.25; p = 0.31), complete/partial recanalization (OR 1.51; 95% CI 0.70-3.26; p = 0.30), any intracerebral hemorrhage (OR 0.81; 95% CI 0.56-1.17; p = 0.26), symptomatic intracerebral hemorrhage (OR 0.98; 95% CI 0.52-1.83; p = 0.94), or mortality (OR 0.83; 95% CI 0.54-1.26; p = 0.38). In network meta-analysis, there were better efficacy and imaging-based outcomes with tenecteplase 0.25 mg/kg without increased risk of safety outcomes. Our results demonstrate that in acute ischemic stroke, thrombolysis with tenecteplase is at least as effective and safe as alteplase.

Ticagrelor versus clopidogrel after fibrinolytic therapy in patients with ST-elevation myocardial infarction: a systematic review and meta-analysis of randomized clinical trials.

Dual antiplatelet therapy with aspirin and clopidogrel are recommended as adjuncts to fibrinolytic-treated patients with ST-elevation myocardial infarction (STEMI). However, the role of switching to ticagrelor within 24 h of fibrinolytics compared with clopidogrel continuation in this setting is uncertain. Hence, we conducted a comprehensive search of electronic databases for all randomized clinical trials (RCTs) that evaluated the safety and efficacy of ticagrelor versus clopidogrel after fibrinolytic therapy in patients with STEMI. A random-effects model was used to calculate the risk ratios (RRs) and 95% confidence intervals (CIs). A total of 5 RCTs that evaluated the efficacy of ticagrelor post-fibrinolysis were identified. We included 3 RCTs with 3999 total patients for our meta-analysis. The results showed similar short-term clinical outcomes between ticagrelor and clopidogrel with regard to rates of Bleeding Academic Research Consortium (BARC) type ≥ 2 bleeding (RR 0.94; 95% CI 0.56-1.60; P = 0.83), major adverse cardiovascular events (RR 0.87; 95% CI 0.49-1.52; P = 0.62), mortality (RR 0.92; 95% CI 0.53-1.59; P = 0.77), myocardial infarction (RR 0.76; 95% CI 0.43-1.36; P = 0.36), and stroke (RR 0.93; 95% CI 0.50-1.73; P = 0.82). Our results demonstrate that in STEMI patients treated with fibrinolytic therapy, switching to ticagrelor was associated with similar bleeding and ischemic outcomes compared with clopidogrel continuation.

Real-World Multicenter Study of PD-1 Blockade in HIV-Associated Classical Hodgkin Lymphoma Across the United States.

BACKGROUND: Despite a higher risk of classical Hodgkin lymphoma (cHL) in people with HIV and the demonstrated safety and efficacy of PD-1 blockade in cHL, there are limited data on the use of these agents in HIV-associated cHL (HIV-cHL). PATIENTS/METHODS: We retrospectively identified patients with HIV-cHL from the "Cancer Therapy using Checkpoint inhibitors in People with HIV-International (CATCH-IT)" database who received nivolumab or pembrolizumab, alone or in combination with other agents, and reviewed records for demographics, disease characteristics, immune-mediated adverse events (imAEs), and treatment outcomes. Changes in CD4+ T-cell counts with treatment were measured via Wilcoxon signed-rank tests. Overall response rate (ORR) was defined as the proportion of patients with partial or complete response (PR/CR) per 2014 Lugano classification. RESULTS: We identified 23 patients with HIV-cHL who received a median of 6 cycles of PD-1 blockade: 1 as 1st-line, 6 as 2nd-line, and 16 as ≥3rd-line therapy. Seventeen (74%) patients received monotherapy, 5 (22%) received nivolumab plus brentuximab vedotin, and 1 received nivolumab plus ifosfamide, carboplatin, and etoposide. The median baseline CD4+ T-cell count was 155 cells/µL, which increased to 310 cells/µL at end-of-treatment (P = .009). Three patients had grade 3 imAEs; none required treatment discontinuation. The ORR was 83% with median duration of response of 19.7 months. The median progression-free survival was 21.2 months and did not differ between patients with <200 versus ≥200 CD4+ cells/µL (P = .95). CONCLUSION: Our findings support the use of PD-1 blockade in HIV-cHL for the same indications as the general population with cHL.

A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic Graft-Versus-Host Disease.

Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells, as well as in vivo mouse studies. These and other preclinical studies implicated hyper-reactive B-cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD, as well as examining alterations in B-cell compartments with treatment. This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was used to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over 3 years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in 1 patient 2 years after the end of therapy. In the prophylaxis arm, 1 of 5 patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77%, with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure-free survival was 69% (95% confidence interval, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD-CD38hi plasmablast-like cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B-cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation.

Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium.

PURPOSE: Compared with people living without HIV (PWOH), people living with HIV (PWH) and cancer have traditionally been excluded from immune checkpoint inhibitor (ICI) trials. Furthermore, there is a paucity of real-world data on the use of ICIs in PWH and cancer. METHODS: This retrospective study included PWH treated with anti-PD-1- or anti-PD-L1-based therapies for advanced cancers. Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates (ORRs) were measured per RECIST 1.1 or other tumor-specific criteria, whenever feasible. Restricted mean survival time (RMST) was used to compare OS and PFS between matched PWH and PWOH with metastatic NSCLC (mNSCLC). RESULTS: Among 390 PWH, median age was 58 years, 85% (n = 331) were males, 36% (n = 138) were Black; 70% (n = 274) received anti-PD-1/anti-PD-L1 monotherapy. Most common cancers were NSCLC (28%, n = 111), hepatocellular carcinoma ([HCC]; 11%, n = 44), and head and neck squamous cell carcinoma (HNSCC; 10%, n = 39). Seventy percent (152/216) had CD4+ T cell counts ≥200 cells/µL, and 94% (179/190) had HIV viral load <400 copies/mL. Twenty percent (79/390) had any grade immune-related adverse events (irAEs) and 7.7% (30/390) had grade ≥3 irAEs. ORRs were 69% (nonmelanoma skin cancer), 31% (NSCLC), 16% (HCC), and 11% (HNSCC). In the matched mNSCLC cohort (61 PWH v 110 PWOH), 20% (12/61) PWH and 22% (24/110) PWOH had irAEs. Adjusted 42-month RMST difference was -0.06 months (95% CI, -5.49 to 5.37; P = .98) for PFS and 2.23 months (95% CI, -4.02 to 8.48; P = .48) for OS. CONCLUSION: Among PWH, ICIs demonstrated differential activity across cancer types with no excess toxicity. Safety and activity of ICIs were similar between matched cohorts of PWH and PWOH with mNSCLC.

Meta-analysis and systematic review of randomized controlled trials assessing the role of thromboprophylaxis after vascular surgery.

BACKGROUND: Venous thromboembolism (VTE) is a well-known complication associated with surgical procedures. The implementation of thromboprophylaxis in this population has become a vital aspect of perioperative care to decrease VTE-associated morbidity and mortality risk. However, data assessing the role of thromboprophylaxis for patients undergoing vascular surgery are sparse. Assessing the role of thromboprophylaxis by low-molecular-weight heparin or unfractionated heparin in vascular surgery. METHODS: We searched MEDLINE, Embase, and the Cochrane Collaboration Central Register of Controlled Trials from inception until December 2020, for randomized controlled trials assessing the role of thromboprophylaxis in vascular surgery. RESULTS: Eight randomized controlled trials met inclusion criteria, including 3130 patients, with a mean age of 55.35 years and 45% were females. Compared with placebo, anticoagulant use was associated with a decrease in deep venous thrombosis (DVT) (risk ratio [RR], 0.34; 95% confidence interval [CI], 0.11-1.05; P = .06; I2 = 68%) and pulmonary embolism (PE) (RR, 0.17; 95% CI, 0.02-1.22; P = .08; I2 = 41%), but this trend did not attain statistical significance. There was no difference for bleeding outcomes between anticoagulants and placebo (RR, 0.90; 95% CI, 0.05-15.01; P = .94; I2 = 76%). There was no significant difference in outcomes when low-molecular-weight heparin was compared directly with unfractionated heparin. In a sensitivity analysis, anticoagulant use was associated with a significant decrease in DVT or PE in patients undergoing venous surgeries, but was not associated with a significant decrease in DVT or PE in patients undergoing arterial surgeries, although this analysis was limited by the small number of studies in each group. CONCLUSIONS: Among patients undergoing vascular surgery, thromboprophylaxis with anticoagulants showed a trend toward a lesser incidence of VTE when compared with placebo, although this difference was not statistically significant. Bleeding outcomes were comparable between both treatment groups.

Meta-Analysis of the Role of Intermittent Pneumatic Compression of the Lower Limbs to Prevent Venous Thromboembolism in Critically Ill Patients.

Critically ill patients (patients treated in a medical or surgical intensive care unit) are at high risk of venous thromboembolism (VTE) development (deep vein thrombosis [DVT] and/or pulmonary embolism). Multiple thromboprophylaxis strategies have been used for the prevention of VTE in this population with various outcomes. Therefore, we aimed to evaluate the efficacy of intermittent pneumatic compression (IPC) prophylaxis in the lower limb compared with no treatment, anticoagulant use, or their combinations in reducing risk. A comprehensive electronic database search was conducted for all randomized clinical trials (RCTs) comparing the clinical outcomes of IPC versus anticoagulants or no treatment or their combinations for the prevention of VTE for critically ill patients. The primary outcome was VTE. The secondary outcome was DVT. We performed a Bayesian network meta-analysis to calculate odds ratios (ORs) and 95% credible intervals (CrIs). We included 5 RCTs with 3133 total patients, represented by a mean age of 49.61 ± 18 years, while 60.28% were male. There was a significant reduction of the primary outcome (incidence of VTE events) when no treatment was compared with IPC (OR = 0.36; 95% CrI = 0.18-0.71), anticoagulation alone (OR = 0.30; 95% CrI = 0.12-0.68), or anticoagulation with IPC (OR = 0.34; 95% CrI = 0.13-0.81). In addition, there was a significant reduction in DVT when no treatment was compared with IPC (OR = 0.45; 95% CrI = 0.21-0.9), anticoagulation alone (OR = 0.16; 95% CrI = 0.03-0.66), or anticoagulation with IPC (OR = 0.18; 95% CrI = 0.03-0.84). However, there were no significant differences between other comparisons (IPC vs anticoagulation alone, anticoagulation alone vs anticoagulation with IPC, or anticoagulation with IPC vs IPC alone) regarding VTE or DVT incidence. Among critically ill patients, IPC alone, anticoagulation alone, and IPC with anticoagulation were associated with a significant reduction of VTE and DVT incidence compared with no treatment. However, there was no significant difference between these modalities when compared together. Therefore, further larger studies comparing those different thromboprophylaxis modalities and their combinations are needed to provide more robust results for future clinical recommendations.

Identification of a Germline Pyrin Variant in a Metastatic Melanoma Patient With Multiple Spontaneous Regressions and Immune-related Adverse Events.

The mechanisms underlying tumor immunosurveillance and their association with the immune-related adverse events (irAEs) associated with checkpoint inhibitor immunotherapies remain poorly understood. We describe a metastatic melanoma patient exhibiting multiple episodes of spontaneous disease regression followed by the development of several irAEs during the course of anti-programmed cell death protein 1 antibody immunotherapy. Whole-exome next-generation sequencing studies revealed this patient to harbor a pyrin inflammasome variant previously described to be associated with an atypical presentation of familial Mediterranean fever. This work highlights a potential role for inflammasomes in the regulation of tumor immunosurveillance and the pathogenesis of irAEs.

Tumor-intrinsic NLRP3-HSP70-TLR4 axis drives premetastatic niche development and hyperprogression during anti-PD-1 immunotherapy.

The tumor-intrinsic NOD-, LRR- and pyrin domain-containing protein-3 (NLRP3) inflammasome-heat shock protein 70 (HSP70) signaling axis is triggered by CD8+ T cell cytotoxicity and contributes to the development of adaptive resistance to anti-programmed cell death protein 1 (PD-1) immunotherapy by recruiting granulocytic polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Here, we demonstrate that the tumor NLRP3-HSP70 axis also drives the accumulation of PMN-MDSCs into distant lung tissues in a manner that depends on lung epithelial cell Toll-like receptor 4 (TLR4) signaling, establishing a premetastatic niche that supports disease hyperprogression in response to anti-PD-1 immunotherapy. Lung epithelial HSP70-TLR4 signaling induces the downstream Wnt5a-dependent release of granulocyte colony-stimulating factor (G-CSF) and C-X-C motif chemokine ligand 5 (CXCL5), thus promoting myeloid granulopoiesis and recruitment of PMN-MDSCs into pulmonary tissues. Treatment with anti-PD-1 immunotherapy enhanced the activation of this pathway through immunologic pressure and drove disease progression in the setting of Nlrp3 amplification. Genetic and pharmacologic inhibition of NLRP3 and HSP70 blocked PMN-MDSC accumulation in the lung in response to anti-PD-1 therapy and suppressed metastatic progression in preclinical models of melanoma and breast cancer. Elevated baseline concentrations of plasma HSP70 and evidence of NLRP3 signaling activity in tumor tissue specimens correlated with the development of disease hyperprogression and inferior survival in patients with stage IV melanoma undergoing anti-PD-1 immunotherapy. Together, this work describes a pathogenic mechanism underlying the phenomenon of disease hyperprogression in melanoma and offers candidate targets and markers capable of improving the management of patients with melanoma.