Comparison of immune checkpoint inhibitors related to pulmonary adverse events: a retrospective analysis of clinical studies and network meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed tumor treatment. However, the risk of pulmonary adverse events (PAEs) associated with ICI combination therapy is still unclear. We aimed to provide a PAE overview and risk ordering of ICIs used in tumor treatment. METHODS: We searched the databases of PubMed, PsycINFO, Embase, Cochrane Library, CINAHL, Web of Science, Scopus, and clinical trial websites during January 2011-April 2023 to identify phase II and III randomized clinical trials (RCTs) and single-arm clinical trials wherein at least one treatment arm received ICIs (e.g., ICI monotherapy, a combination of two ICIs, or ICIs in combination with conventional cancer therapy). We reported the results of PAEs. Additionally, we compared risks of PAEs between different drug classes using a Bayesian network meta-analysis. RESULTS: Among 143 RCTs and 24 single-arm trials, the incidence of all-grade and grade 3-4 PAEs were highest with programmed death L1 (PD-L1) plus cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and plus chemotherapy and anti-PD1 plus anti-CTLA4, the lowest with targeted therapy drug plus chemotherapy and anti-PD1 plus anti-PDL1. Anti-PD1 plus anti-CTLA4 and plus chemotherapy was the intervention with the highest risk for all-grade and 3-4 grade PAEs, and the intervention with the lowest risk was chemotherapy and anti-PD1 plus anti-PDL1. In terms of all-grade PAEs, chemotherapy was safer than ICI monotherapy. Except for the anti-PD1 plus anti-PDL1 regimen, no significant difference in the risk of grade 3-4 PAEs was detected between dual-ICIs and single-ICIs. Furthermore, the risk of PAEs associated with nivolumab, pembrolizumab, and atezolizumab may be dose dependent. CONCLUSIONS: In the single-drug regimen, anti-PD1 caused the greatest incidence of PAEs. The risk of PAEs was higher with all single-ICIs than with chemotherapy. However, no significant difference in the risk of PAEs was detected between single-ICIs. In the combined regimen, anti-PD1 plus anti-CTLA4 and plus chemotherapy showed the greatest risk of PAEs, but there were no significant differences in risk between dual-ICIs and single-ICIs.

Pulmonary Toxicity Associated with Immune Checkpoint Inhibitors-Based Therapy: Current Perspectives and Future Directions.

Immune checkpoint inhibitors (ICIs) have shown efficacy in tumor therapy. However, the risk of pulmonary toxicity from ICI-based treatment regimens remains unknown. We searched multiple databases and clinical trial websites from January 2015 to December 2021 and summarized the pulmonary toxicity profile and risk ranking of ICI-based treatments in cancer patients. We included a Phase III randomized clinical trial (RCT) in which the treatment group received at least one ICI and experienced pulmonary adverse events (PAEs). Our study, which included 104 RCTs, found the highest incidence of grades 1-2 and 3-5 treatment-associated PAEs (Tr-PAEs) in programmed death 1 (PD-1)+ chemotherapy and PD-1+ cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), respectively. The first incidence rates of grades 1-2 and 3-5 immune-mediated PAEs (Im-PAEs) were PD1+CTLA-4+ chemotherapy and PD-L1 + CTLA4, respectively. Cytotoxic T lymphocyte-associated antigen 4 + chemotherapy regimen and PD-L1+ targeted therapy drug (TTD)+ chemotherapy regimen had the highest risk of developing grades 1-2 and 3-5 Tr-PAEs. Programmed death-L1+ CTLA-4 has a higher risk of grade 3-5 Tr-PAEs than PD-L1. The risk of grade 1-2 pulmonary toxicity was significantly different in the high-dose and low-dose groups of nivolumab and atezolizumab. Nivolumab and atezolizumab induced dose-dependent grade 1-2 pulmonary toxicity. Among single-agent regimens, PD-1 showed the greatest grade 1-2 pulmonary toxicity. Programmed death-L1+ TTD+ chemotherapy showed the greatest grade 3-5 pulmonary toxicity in combination therapy. PD-L1+ TTD+ chemotherapy was associated with a higher risk of grade 3-5 Tr-PAEs and a lower risk of Im-PAEs. We recommend a targeted approach to managing PAE.

Identifying Migration Routes of Wild Asian Elephants in China Based on Ecological Networks Constructed by Circuit Theory Model.

Humans overlap with Asian elephants, resulting in frequent costly human-elephant conflicts, which disturb and even threaten local residents. In this study, we treat provincial and national nature reserves where Asian elephants still exist and other alternative habitats suitable for Asian elephants in southern Yunnan, China, as ecological patches. By using this approach, we can treat the terrain and surface state factors that hinder the migration of Asian elephants as a form of ecological resistance surface. We can then use a circuit theory model and remote sensing data to construct an ecological network, which allows us to identify ecological corridors and ecological pinch points. Herein, the possible migration routes of wild Asian elephants were identified. The main results are as follows: (1) In the study area, dense forests with steep slopes and high altitudes, cultivated land, and building land have greater migration resistance, while the gently undulating shrubs, bamboo forests, and grasslands far away from the city have less migration resistance. (2) There are three ecological corridor groups in the study area, mainly composed of shrub and grassland. The ecological corridors identified in this paper are the most likely migration routes of wild Asian elephants in China, and areas with higher simulated current densities reflect a higher probability of Asian elephants passing through. (3) According to the analysis, the ecological pinch points in the study area are 602 km2 in total, and woodland and grassland account for 89.2% of the total ecological pinch area. The areas where the pinch points are located have a high probability of Asian elephants passing through and a narrow space. Our findings can provide suggestions and solutions for the current conservation of wild Asian elephant species, alleviate human-elephant conflicts, promote the harmonious coexistence between humans and nature, and provide reference for biological protection and biological reserve planning.

Hepatotoxicity of immune checkpoint inhibitors: What is Currently Known.

BACKGROUND: This systematic review and network meta-analysis aimed to provide a complete hepatotoxicity profile, hepatotoxicity spectrum, and safety ranking of immune checkpoint inhibitor drugs for cancer treatment. METHODS: PubMed, Embase, Scopus, CINAHL, Web of Science, psycINFO, Cochrane Library, and ClinicalTrials.gov. websites were searched, and a manual search of relevant reviews and trials up to January 1, 2022, was undertaken. Head-to-head III randomized controlled trials comparing any 2 or 3 of the following treatments or different doses of the same immune checkpoint inhibitor drug were included: programmed death 1 (PD-1), programmed death ligand 1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors and conventional therapy. We included 106 randomized trials (n=164,782) containing 17 treatment arms. RESULTS: The overall incidence of hepatotoxicity was 4.06%. The rate of fatal liver adverse events was 0.07%. The programmed death ligand 1 inhibitor+targeted therapy drug+chemotherapy group had the highest risk of treatment-related increases in all-grade alanine aminotransferase and aspartate aminotransferase levels, and the differences were significant. For immune-related hepatotoxicity, no significant difference was found between PD-1 and CTLA-4 inhibitors for all-grade hepatotoxicity; however, CTLA-4 inhibitors were associated with a higher risk of grade 3-5 hepatotoxicity than PD-1 inhibitors. CONCLUSIONS: The highest incidence of hepatotoxicity and fatality was observed with triple therapy. The overall incidence of hepatotoxicity was similar between different dual regimens. For immune checkpoint inhibitor monotherapy, the overall risk of immune-mediated hepatotoxicity related to CTLA-4 inhibitors did not differ significantly from that of PD-1 inhibitors. There was no direct relationship between the risk of liver injury and drug dose, whether monotherapy or combination therapy was used.

Efficacy of non-pharmacological interventions in pain relief and opioid consumption after cardiac surgery: A systematic review and Bayesian network meta-analysis.

OBJECTIVE: To investigate and rank the evidence for the efficacy of non-pharmacological interventions in relieving pain after cardiac surgery using comprehensive comparisons. BACKGROUND: Although several previous systematic reviews and meta-analyses showed that non-pharmacological interventions effectively control and reduce pain after cardiac surgery, none quantitatively compared the effect of these different types of interventions. DESIGN: Systematic review and Bayesian network meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Network Meta-Analysis guidelines. METHODS: Six databases were searched from inception to April 2021 to collect all published evidence from randomised clinical trials. One author extracted the relevant information from the eligible trials; a second author independently reviewed the data. Before analysing the extracted data, two investigators independently assessed the quality of the included studies. Conventional meta-analysis was conducted using either fixed- or random-effects models according to statistical heterogeneity. The Bayesian network meta-analysis was conducted using the consistency model. RESULTS: We identified 42 randomised clinical trials comparing 14 groups with 4253 patients. Transcutaneous electrical nerve stimulation, acupressure, music and massage were effective for pain relief, with transcutaneous electrical nerve stimulation being associated with the best probability of successful pain relief after cardiac surgery (cumulative ranking curve surface, 0.97; probability, 77.03%). Acupressure (cumulative ranking curve surface, 0.79; probability, 30.69%) was the second-best option. However, there was no evidence that any pair-up intervention significantly reduced opioid use or anxiety. CONCLUSIONS: These findings suggest that transcutaneous electrical nerve stimulation, acupressure, music and massage may effectively alleviate postoperative cardiac pain, with transcutaneous electrical nerve stimulation representing the best choice for pain relief. RELEVANCE TO CLINICAL PRACTICE: The results of this network meta-analysis can guide patients after cardiac surgery and healthcare providers to make optimal decisions in managing postoperative cardiac pain. TRIAL REGISTRATION: PROSPERO CRD42021246183.

Cardiotoxicity of immune checkpoint inhibitors: A frequency network meta-analysis.

Immune checkpoint inhibitors (ICIs) in combination withother anti-cancer treatments have been approved for a variety of cancers. While the difference in the incidence of cardiovascular adverse events has not been fully investigated. We aimed to assess the the differences in cardiotoxicity among cancer patients receiving different ICI therapies. PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov. websites were searched for all randomized controlled trials (RCTs) of ICI. The primary outcomes were any grade cardiotoxicity and Grade 3-5 cardiotoxicity, the secondary outcomes were any grade myocarditis and Grade 3-5 myocarditis, with sub-analyses based on cancer type and does of ICI. A systematic review and frequency network meta-analysis were then performed for cardiotoxicity events. 91 RCTs (n=52247) involving 12 treatment arms were finally included. We observed that PD-L1 + CTLA-4 had the highest risk among all therapies inducing any grade cardiotoxicity, and the differences were significant except PD-1 + CTLA-4, PD-1 + TTD and PD-L1 + TTD. In addition, CTLA-4 had a higher risk of Grade 3-5 cardiotoxicity than PD-1 and anit-PD-L1. For Grade 1-5 myocarditis and Grade 3-5 myocarditis, no significant difference was found among differences therapies. No differences were observed in subgroup analyses according to does and cancer type. There were differences in the incidence of cardiotoxicity among different ICI therapies. For ICI monotherapy, CTLA-4 may be linked to Grade 3-5 cardiotoxicity than PD-1 or PD-L1. For dual therapy, the cardiotoxicity of dual ICI therapy seems to be higher than that of chemotherapy or targeted therapy.

Effects of eHealth Interventions on Quality of Life and Psychological Outcomes in Cardiac Surgery Patients: Systematic Review and Meta-analysis.

BACKGROUND: Patients undergoing heart surgery may experience a range of physiological changes, and the postoperative recovery time is long. Patients and their families often have concerns about quality of life (QoL) after discharge. eHealth interventions may improve patient participation, ensure positive and effective health management, improve the quality of at-home care and the patient's quality of life, and reduce rates of depression. OBJECTIVE: The purpose of this study was to evaluate the effects of eHealth interventions on the physiology, psychology, and compliance of adult patients after cardiac surgery to provide a theoretical basis for clinical practice. METHODS: We conducted systematic searches of the following 4 electronic databases: PubMed, Embase, CINAHL, and the Cochrane Central Register of Controlled Trials. Mean (SD) values were used to calculate the pooled effect sizes for all consecutive data, including QoL, anxiety, and depression. Where the same results were obtained using different instruments, we chose the standardized mean difference with a 95% CI to represent the combined effect size; otherwise, the mean difference (MD) with a 95% CI was used. Odds ratios were used to calculate the combined effect size for all dichotomous data. The Cohen Q test for chi-square distribution and an inconsistency index (I2) were used to test for heterogeneity among the studies. We chose a fixed-effects model to estimate the effect size if there was no significant heterogeneity in the data (I2≤50%); otherwise, a random-effects model was used. The quality of the included studies was assessed using the Cochrane risk-of-bias tool for randomized trials (RoB 2). RESULTS: The search identified 3632 papers, of which 19 met the inclusion criteria. In terms of physical outcomes, the score of the control group was lower than that of the intervention group (MD 0.15, 95% CI 0.03-0.27, I2=0%, P=.02). There was no significant difference in the mental outcomes between the intervention and control groups (MD 0.10, 95% CI -0.03 to 0.24, I2=46.4%, P=.14). The control group's score was lower than that of the intervention group for the depression outcomes (MD -0.53, 95% CI -0.89 to -0.17, I2=57.1%, P=.004). Compliance outcomes improved in most intervention groups. The results of the sensitivity analysis were robust. Nearly half of the included studies (9/19, 47%) had a moderate to high risk of bias. The quality of the evidence was medium to low. CONCLUSIONS: eHealth improved the physical component of quality of life and depression after cardiac surgery; however, there was no statistical difference in the mental component of quality of life. The effectiveness of eHealth on patient compliance has been debated. Further high-quality studies on digital health are required. TRIAL REGISTRATION: PROSPERO CRD42022327305; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=327305.