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.

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.

Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety as potential antitumor inhibitor.

A series of pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety were designed, synthesized and evaluated for the anti-proliferative on three cancer cell lines (A549, HepG2 and MCF-7) in vitro. Most of the compounds showed moderate to high potency. Some excellent compounds were tested for the inhibitory activity of c-Met kinase. Compound 34 (c-Met IC50 = 17 nM) was investigated the selectivity against Flt-3, c-Kit, VEGFR-2, ALK, PDGFR-ß and RON. Structure-activity relationship studies indicated that hydrogen, fluorine atom, and mono-electron-withdrawing groups (mono-EWGs, such as R2 = F) on R, R1 and R2, respectively, were beneficial for the anti-proliferative activities of the target compounds. Besides, we have took further study on the combined mode between compound 34 and c-Met kinase through molecular docking.

Development and Validation of a Clinical Risk Score to Predict Immune-mediated Liver Injury Caused by Sintilimab: Assessed for Causality Using Updated RUCAM.

Background and Aims: Immune-mediated liver injury is a fatal side effect of sintilimab. This study aimed to shed light on the associated risk factors and characteristics of this adverse event. Methods: The clinical records of 772 patients treated with sintilimab were retrospectively reviewed to investigate risk factors associated with sintilimab immune-related hepatotoxicity, as well as its incidence and outcome. The Roussel Uclaf Causality Assessment Method was used to identify cases of sintilimab-induced hepatotoxicity. Furthermore, logistic regressions were performed to compare the clinical and bloodwork characteristics of patients with and without immune-mediated liver injury caused by checkpoint inhibitors. Results: Of the 585 patients included in the study, 71 (12.1%) developed liver injury during sintilimab use. The median RUCAM score with interquartile range was 7 (6, 8). Hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were risk factors for sintilimab-related hepatotoxicity. A nomogram model was constructed for sintilimab-induced immune-mediated liver injury based on these risk factors, which had a C-index value of 0.713 and a good calibration curve. When applied to patients with grade ≥3 and ≥4 sintilimab-induced immune-mediated liver injury, it achieved C-index values of 0.752 and 0.811, respectively. The nomogram model also showed a good prediction potential in patients ≥65 years and males. Six of the patients with sintilimab-related hepatotoxicity showed improved liver function upon treatment with steroids. Conclusions: This study demonstrated that hypoproteinemia, dyslipidemia, and the presence of thyroid peroxidase antibodies were clinically feasible prognostic biomarkers to predict liver injury in patients treated with sintilimab.

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.

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.

Clinical and genetic risk factors for the prediction of hepatotoxicity induced by a docetaxel, epirubicin and cyclophosphamide regimen in breast cancer patients.

Aim: To screen clinical and genetic risk factors and examine their combined effect on docetaxel, epirubicin and cyclophosphamide (TEC) regimen-induced liver injury (TEC-ILI). Patients & methods: We enrolled 396 breast cancer patients, and TEC-ILI-associated factors were screened by logistic regression analyses. Results:SOD2 rs4880 and ABCG2 rs2231142 polymorphisms correlated with an increased risk of TEC-ILI. Multivariate analysis incorporating clinical and genetic factors revealed that ABCC1 rs246221 (CC) and SOD2 rs4880 (AG/GG) increased the risk of TEC-ILI. Patients with at least two risk factors among nonalcoholic fatty liver disease, high low-density lipoproteinemia levels and the rs246221 or rs4880 adverse genotypes exhibited a significantly increased risk of developing TEC-ILI. Conclusion: The combination of clinical and genetic risk factors had higher predictive value for TEC-ILI than the interclinical risk factors alone.

High Serum Estradiol Reduces Acute Hepatotoxicity Risk Induced by Epirubicin Plus Cyclophosphamide Chemotherapy in Premenopausal Women with Breast Cancer.

Aim: We evaluated whether acute drug-induced liver injury (DILI) caused by adjuvant chemotherapy with epirubicin plus cyclophosphamide for early breast cancer was associated with estradiol (E2), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Methods: Reproductive hormone test results of breast cancer patients were collected in the first chemotherapy cycle. E2, LH, and FSH levels were loge-transformed to normally distributed variables and were assessed using Student's t-test to determine significant differences between the case and control groups. Hormone levels were classified according to the interquartile range and analyzed by logistic regression to determine their association with DILI caused by chemotherapy. Results: Among the 915 enrolled patients (DILI group: 204; control group: 711), menopausal status, along with serum E2, LH, and FSH levels, did not substantially differ between case and control groups. However, in the premenopause subgroup (n = 483), we found a significant difference in the E2 level between the case and control groups (p = 0.001). After adjusting for age and body mass index, premenopausal patients with 152-2,813 pg/mL E2 showed a lower risk of chemotherapy-induced DILI than patients with ≤20 pg/mL E2 (odds ratio: 0.394; 95% confidence interval: 0.207-0.748). The linear trend χ2 test revealed that E2 levels in premenopausal patients with breast cancer were inversely associated with the development of DILI. Conclusion: High serum E2 levels are associated with a reduced DILI risk in premenopausal patients with breast cancer undergoing epirubicin plus cyclophosphamide adjuvant chemotherapy.

Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety.

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety were designed, synthesized and evaluated for their biological activities. The target compounds exhibited moderate to high antiproliferative activity against three cancer cell lines (A549, HepG2 and MCF-7) and several compounds (25, 27, 33, 37, 41, 43, 49 and 53) were evaluated for the activity against c-Met kinase. The most promising compound 33 (IC50 c-Met = 2.36 nM) showed excellent activity against A549, HepG2 and MCF-7 cell lines with IC50 values of 0.23 µM, 0.42 µM and 0.21 µM, respectively, which was 1.5-2.1 times of the positive control. Furthermore, compound 33 was evaluated for the activity against Flt3, PDGFR-α, PDGFR-ß, c-Kit, Flt4, ALK and EGFR kinase. Structure activity relationship studies indicated that mono-EWGs (such as R2 = F) at 4-position of moiety C was a key factor in improving the antitumor activity. In addition, further research on compound 33 was mainly including concentration dependence, apoptosis (acridine orange staining), apoptosis result analyzing and molecular docking.

Discovery of novel 7-azaindole derivatives bearing dihydropyridazine moiety as c-Met kinase inhibitors.

A series of 7-azaindole derivatives bearing the dihydropyridazine scaffold were synthesized and evaluated for their c-Met kinase inhibitory, and antiproliferative activity against 4 cancer cell lines (HT29, A549, H460, U87MG) were evaluated in vitro. Most compounds showed moderate to excellent potency. Compared to foretinib, the most promising analog 34 (c-Met IC50: 1.06 nM, a multitarget tyrosine kinase inhibitor) showed a 6.4-, 7.8-, and 3.2-fold increase in activity against HT29, A549, and H460 cell lines, respectively. Structure activity relationship studies indicated that mono-EWGs (such as R2 = F) at 4-position of moiety D was a key factor in improving the antitumor activity.