Efficacy and Safety of Programmed Death 1/Programmed Death-Ligand 1 Plus Cytotoxic T-Lymphocyte-Associated Antigen 4 Inhibitors for Advanced or Metastatic Non-Small Cell Lung Cancer: A Meta-analysis Based on Randomized Controlled Trials.

BACKGROUND: This meta-analysis aims to investigate the efficacy and safety of programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) combined with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors for patients with advanced or metastatic non-small cell lung cancer (NSCLC). METHODS: Authors conducted a comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, Scopus, and Medline for randomized controlled trials comparing the prognosis and safety of PD-1/PD-L1 plus CTLA-4 inhibitors with other therapies for advanced or metastatic NSCLC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used as effect sizes. The primary outcomes of this study were overall survival (OS) and progression-free survival. RESULTS: A total of 4943 patients diagnosed with stage III/IV advanced or metastatic NSCLC were included in the analysis of the 6 randomized controlled trials. The results showed that patients receiving dual immunotherapy with PD-1/PD-L1 plus CTLA-4 inhibitors had a longer survival time compared with the control group (HR = 0.88, P = 0.044). However, no statistically significant difference was observed in progression-free survival (HR = 0.95, P = 0.579). Subgroup analysis revealed better OS in the interventional group for patients aged >65 years (HR = 0.88, P = 0.076), smokers (HR = 0.81, P = 0.036), and those with a tumor mutational burden (TMB) ≥20 mut/Mb (HR = 0.66, P < 0.001). Conversely, the control group demonstrated superior OS in patients with TMB <20 mut/Mb (HR = 1.14, P = 0.048). In addition, the statistical results indicated a lower incidence rate of any-grade anemia in the dual immunotherapy group compared with the control group (RR = 0.32, P = 0.04). CONCLUSIONS: This meta-analysis demonstrates the effectiveness and safety of dual immunotherapy with PD-1/PD-L1 plus CTLA-4 inhibitors for treating advanced or metastatic NSCLC. Its efficacy is influenced by certain clinical and pathological factors, such as age, smoking status, and TMB.

Efficacy of Glucagon-like Peptide-1 Receptor Agonists in Overweight/Obese and/or T2DM Adolescents: A Meta-analysis Based on Randomized Controlled Trials.

Objective: This meta-analysis aimed to investigate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on blood glucose and weight in overweight/obese and/or type 2 diabetes mellitus (T2DM) adolescents aged <18 years. Methods: Herein, we searched PubMed, Embase, Web of Science, and Cochrane Library for all randomized controlled trials (RCTs) comparing GLP-1RAs with placebo in overweight/obese and/or T2DM adolescents and extracted relevant data up to August 2023 for meta-analysis. Results: Fourteen RCTs were included in the meta-analysis with a total of 1262 participants. Results revealed that the GLP-1RAs group had a more significant reduction in glycosylated hemoglobin A1c (HbA1c; risk difference (RD)=-0.34%, P<0.001) than the control group. However, there was no difference in fasting blood glucose (FPG; RD=-2.07mg/dL, P=0.065) between the two groups. Nonetheless, the experimental group that administered exenatide showed a no significant reduction in HbA1c (P=0.253) and FPG (P=0.611) between the two groups. The GLP-1RAs group had a more significant decline in body weight (RD=-4.28kg, P=0.002) and BMI (RD=-1.63kg/m2, P=0.002) compared to the control group. The experimental group was adopted with liraglutide (RD=-2.31kg, P=0.038) or exenatide (RD=-2.70kg, P<0.001). Compared to the control group, the experimental group had a more significant drop in body weight than the control group. But for the experimental group that received liraglutide, the BMI had a no significant reduction between the two groups (RD=-0.81kg/m2, P=0.260). For the experimental group that was adopted with exenatide, BMI revealed a more significant decline in the intervention group than in the control group (RD=-1.14kg/m2, P<0.001). Conclusion: This study showed that GLP-1RAs reduced HbA1c, FPG, and weight loss in overweight/obese and/or T2DM adolescents. Liraglutide is better than exenatide in terms of glucose reduction. Nevertheless, in terms of weight control, exenatide is better than liraglutide.

The cardiac-related adverse events of PD-1/PD-L1 immunotherapy in advanced or metastatic lung cancer: a RCT-based meta-analysis.

BACKGROUND: This study aims to investigate the effect of PD-1/PD-L1 immunotherapy on cardiac-related adverse events in patients with advanced or metastatic lung cancer. METHODS: We conducted a detailed search in PubMed, Web of Science, Cochran, and Embase for articles on the application of immunotherapy for lung cancer and report cardiac-related adverse events with respect to myocardial ischemia, pericardial effusion, myocarditis, and electrophysiology. The dichotomous variables were assessed by relative risk (RR) and 95% confidence intervals (CI). RESULTS: A total of 7132 subjects were included in 12 phase III randomized controlled trials (RCTs). The results showed that under the fixed effects model, the probability of cardiac-related adverse events in pericardial effusion was higher in the experimental group than in the control group (RR 2.30, 95% CI 1.01-5.21, P = 0.05). Under the random effects model, there was no statistical difference between the two groups (RR 2.03, 95% CI 0.81-5.12, P = 0.13). No statistical difference is observed between the experimental group and the control group (under the fixed effects model and the random effects model) for other cardiac-related adverse events, including myocarditis, acute coronary syndrome, myocardial infarction, acute myocardial infarction, myocardial ischemia, unstable angina, ventricular tachycardia, supraventricular tachycardia, tachycardia, bradycardia, atrial flutter, atrial fibrillation, cardiac failure, cardiac arrest, cardiopulmonary failure, acute heart failure, cardiac arrest (all P > 0.05). CONCLUSIONS: PD-1/PD-L1 immunotherapy in advanced or metastatic lung cancer is generally safe for cardiac-related adverse events.

Venoarterial extracorporeal membrane oxygenation with intra-aortic balloon pump for postcardiotomy cardiogenic shock: A systematic review and meta-analysis.

OBJECTIVE: Intra-aortic balloon pump (IABP) is currently recommended as a strategy to address the increased afterload in patients who received venoarterial extracorporeal membrane oxygenation (VA-ECMO). The benefit of VA-ECMO with IABP in postcardiotomy cardiogenic shock is inconclusive. A systematic review and meta-analysis was conducted to assess the influence of VA-ECMO with IABP for postcardiotomy cardiogenic shock (PCS). METHODS: The Cochrane Library, PubMed, and Embase were searched for all articles published from 1 January, 1964 to July 11, 2020. Retrospective cohort studies targeting the comparison of VA-ECMO with IABP and isolated VA-ECMO were included in this study. RESULTS: We included 2251 patients in the present study (917 patients in the VA-ECMO with IABP group and 1334 patients in the isolated VA-ECMO group). Deaths occurred in 589 of 917 patients (64.2%) in the VA-ECMO with IABP group and occurred in 885 of 1334 patients (66.3%) in isolated VA-ECMO group. Pooling the results of all studies showed that VA-ECMO with IABP was not related to a reduced in-hospital mortality in patients who received VA-ECMO for PCS (RR, 0.95; 95% CI, 0.86-1.04; p = 0.231). In addition, VA-ECMO with IABP was not related to an increased rate of VA-ECMO weaning in patients who received VA-ECMO for PCS (RR, 1.28; 95% CI, 0.99-1.66; p = 0.058). CONCLUSIONS: This study indicates that VA-ECMO with IABP did not improve either in-hospital survival or weaning for VA-ECMO in postcardiotomy cardiogenic shock patients.

Extracorporeal membrane oxygenation (ECMO)-assisted surgery for traumatic bronchial rupture: a report of three cases.

Background: Traumatic tracheal rupture is a severe closed chest injury that often causes major respiratory and circulatory disturbances requiring emergency surgery. We have found that veno-venous extracorporeal membrane oxygenation (VV-ECMO) employs lung-protective ventilation strategies to facilitate lung rest, aiming to minimize the risk of ventilator-induced lung injury, while ensuring adequate oxygenation. Case Description: We presented 3 critically ill patients who presented with traumatic bronchial rupture between 2019 and 2021, and underwent emergency thoracic surgery with the help of VV-ECMO. The ECMO support time, the operative time, the duration of postoperative hospital stay, and the postoperative mechanical ventilation time were collected in this study. All patients were successfully treated and discharged home. The duration of surgery ranged from 135 to 180 min, the duration of ECMO use ranged from 98 to 123 h, the duration of postoperative ventilator use ranged from 5 to 8 days, and the duration of postoperative hospital stay ranged from 14 to 30 days. All 3 patients had good postoperative pulmonary re-expansion, with no residual tracheal or bronchial stenosis, and good physical activity following the surgery. Conclusions: We reported successful use of VV-ECMO in critically ill patients with traumatic bronchial rupture presenting in acute respiratory and circulatory failure. Performing emergency surgery with ECMO-assisted support can provide more time to stabilize the patient and ensure the safety of the procedure. However, considering the small sample size of this study, larger cohorts with long-term follow-up data are needed to further evaluate its application.

A single-arm, multicenter, phase II clinical study of tislelizumab plus albumin-bound paclitaxel/cisplatin as neoadjuvant therapy for borderline resectable esophageal squamous cell carcinoma.

Background: Esophageal cancer responds poorly to conventional radiotherapy, chemotherapy, and/or surgery. Immunotherapy works by boosting the body's immune system, and preoperative immunotherapy combined with chemotherapy may increase the survival rate of patients with esophageal cancer. Here we further explore immunotherapy's role in treating borderline resectable (BR) esophageal squamous cell carcinoma (ESCC) by combining immunotherapy with chemotherapy. Methods: In this multicenter, randomized controlled study of preoperative immunotherapy plus chemotherapy for BR ESCC, immunotherapy plus chemotherapy [i.e., tislelizumab plus albumin-bound paclitaxel (ABP)/cisplatin] will be given according to the inclusion and exclusion criteria. Patients are to be observed and recorded for various indicators, the follow-up visits are standardized, and a database is to be established for the statistical analysis, with an attempt to clarify the value of preoperative immunotherapy plus chemotherapy in improving the survival of patients with BR ESCC. The primary endpoints are disease-free survival (DFS), major pathologic response (MPR), and pathologic complete response (pCR). The secondary endpoints include the objective response rate (ORR) and overall survival (OS) in subjects with PD-L1 expression levels of <1%, ≥1%, ≥20%, and ≥50%. Discussion: The role of preoperative concurrent immunotherapy plus chemotherapy in improving the survival rates of patients with BR ESCC will be explored in this study. Given that the 5-year survival rate of BR ESCC is 10%, we hope that a reasonable immunotherapy plus chemotherapy regimen with higher efficacy and lower toxicity will further increase the pCR. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR2100051514.

Integrin α6 overexpression promotes lymphangiogenesis and lymphatic metastasis via activating the NF-κB signaling pathway in lung adenocarcinoma.

OBJECTIVE: It has been reported that tumor-associated lymphangiogenesis plays an important role in lymph node metastasis and contributes to the poor survival of lung adenocarcinoma (LUAD) patients. As yet, however, the molecular mechanism underlying LUAD-associated lymphangiogenesis has remained elusive. METHODS: Immunohistochemistry (IHC) was used to determine the expression of integrin subunit alpha 6 (ITGA6) and the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1) in clinicopathologically characterized LUAD specimens. The effect of ITGA6 overexpression on lymphangiogenesis and lymphatic metastasis was examined by tube formation, scratch wound-healing, and cell migration assays in vitro and a popliteal lymph node metastasis model in vivo. Mechanistically, overexpression of ITGA6 and activation of NF-κB signaling were examined by real-time PCR, ubiquitination and dual-luciferase reporter assays. Finally, high ITGA6 expression in LUAD tissue samples was related to copy number variation (CNV) using the TCGA database. RESULTS: We found that ITGA6 overexpression correlated with microlymphatic vessel density in LUAD specimens (p < 0.01). Importantly, by using a popliteal lymph node metastasis model, we found that ITGA6 upregulation significantly enhanced lymphangiogenesis and lymphatic metastasis in vivo (p < 0.05). In addition, we found that ITGA6 overexpression enhanced the capability of A549 and H1299 LUAD cells to induce tube formation and migration in human lymphatic endothelial cells (HLECs). Mechanistically, we found that ITGA6 sustained NF-κB activity via binding and promoting K63 polyubiquitination of TNF receptor-associated factor 2 (TRAF2). Finally, CNV analysis revealed ITGA6 amplification of 27.5% in the LUAD tissue samples in the TCGA database. CONCLUSIONS: Taken together, our results uncover a plausible role for ITGA6 in mediating lymphangiogenesis and lymphatic metastasis and may provide a basis for targeting ITGA6 to treat LUAD lymphatic metastasis.

A narrative review of primary research endpoints of neoadjuvant therapy for lung cancer: past, present and future.

OBJECTIVE: This review summarizes the current status of neoadjuvant therapy and discusses the choice of new clinical research endpoints for non-small cell lung cancer. BACKGROUND: Neoadjuvant chemotherapy is a recognized practice in patients with resectable and locally advanced lung cancer. With the introduction of molecular targeted drugs and immune checkpoint inhibitors (ICIs), the overall survival (OS) of patients with lung cancer has been significantly improved, and the original traditional clinical research endpoints are no longer suitable for existing clinical research. In order to accelerate the process of clinical trials and the development and approval of drugs, it is necessary to find suitable alternative indicators as the main indicators of clinical research. METHODS: Therefore, this article focuses on clinical trials using disease-free survival (DFS), progression free survival, and pathological evaluation indicators, pathologic complete response and major pathologic response, as surrogate endpoints. We search related literature through PubMed database and clinical trials through clinicaltrials.gov. CONCLUSIONS: Pathologic complete response and major pathologic response are recommended as surrogate endpoints in the era of neoadjuvant immunotherapy, and secondary endpoints are listed for the prediction of pathological results. In addition, the definitions of major pathological response (MPR) and PCR should be standardized, and a new pathological evaluation standard should be developed, which is applicable to all current treatment methods. KEYWORDS: Neoadjuvant therapy; resectable lung cancer; clinical research endpoint; pathological response.

Narrative review of pembrolizumab for the treatment of esophageal cancer: evidence and outlook.

OBJECTIVE: Based on the current evidence, review the efficacy and safety profile of pembrolizumab, along with its shortcomings, in an effort to define future research directions. BACKGROUND: The survival outcome of esophageal cancer (EC) is poor, especially in patients with advanced stage. Palliative surgery, chemotherapy, radiotherapy and chemoradiotherapy have limited efficacy in prolonging the survival time. Currently, immunotherapies, including adoptive cell therapy-based, antibody-based, and vaccine-based therapies, are attracting considerable attention. The mechanism of immunotherapy lies in the modification of immune response and prevention of immune escape. Immunomodulatory agents can block the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway, thereby allowing lymphocytes to attack tumor cells. This class of drugs has the potential to treat a variety of tumors and may substantially improve overall survival (OS) in some patients. Multiple clinical trials have shown that pembrolizumab has good efficacy and safety, enhances the EC treatment paradigm, and has even become the first-line treatment of choice for patients with PD-L1-positive recurrent or metastatic EC. METHODS: We reviewed the results of clinical trials of pembrolizumab for EC and gastroesophageal cancer presented at Embase, PubMed, the American Society of Clinical Oncology (ASCO) annual meetings, and the Cochrane Central Register of Controlled Trials. CONCLUSIONS: Pembrolizumab has good efficacy and tolerability profiles, and has emerged as a second-line option for the treatment of PD-L1-positive locally advanced or metastatic ESCC. Pembrolizumab has many promising applications, and further investigations into its mechanisms should be conducted.

Inter-relationship among myasthenia gravis, WHO histology, and Masaoka clinical stage and effect on surgical methods in patients with thymoma: a retrospective cohort study.

BACKGROUND: The aim of study is to analyze the inter-relationship among WHO histology, myasthenia gravis (MG) and Masaoka stage and to assess the feasibility of thoracoscopic surgery in thymoma patients. METHODS: Data from 142 consecutive thymoma patients from January 2009 to March 2016 were retrospectively reviewed in our institution. Histological classification and clinical staging were assessed by WHO histology criteria and Masaoka stage. We investigated the clinical characteristics, inter-relationship among WHO histology, MG and Masaoka stage, and compared the feasibility and safety of thoracoscopic thymectomy by comparison of open thymectomy. RESULTS: Among 142 patients, the incidence of MG was 29.6%. Compared with A and AB-type thymomas, a higher prevalence of advance clinical stage was in B1 to C-type thymomas (37/63 vs. 9/43, P<0.001), and there was an increased trend of Masaoka stage from A to C-type thymomas (P<0.001). The incidence of MG was significantly higher in AB, B1 and B2-type thymomas than other type thymomas (23/63 vs. 6/44, P=0.009) and in early Masaoka clinical stage than advanced Masaoka clinical stage (29/80 vs. 12/59, P=0.042). Thoracoscopic surgery could significantly decrease blood loss in patients with (104.06±137.36 vs. 350.91±560.79 mL, P=0.001) or without MG (91.90±77.70 vs. 266.32±292.60 mL, P=0.02), with comparable complications. Additionally, thoracoscopic surgery could achieve an equal effect on the remission of MG with open surgery (7/11 vs. 10/14, P=1.000), and Masaoka stage was significantly associated with the remission of MG after thymectomy. CONCLUSIONS: Our study suggests that WHO histology, MG, and Masaoka stage interrelate with one another, and Masaoka stage is an important prognostic factor in remission of MG after thymectomy in thymoma patients. Thoracoscopic thymectomy could achieve an equal efficacy to open thymectomy and should be recommended as a routine surgery for patients with early Masaoka stage.

Case report: acute demyelinating encephalomyelitis following viper bite.

The most serious complications of the central nervous system that occur after venomous snake bite are intracranial hemorrhage and ischemic stroke.We present a rarely seen central nervous system complication, acute demyelinating encephalomyelitis, after a treated Deinagkistrodon's viper bite.On April 5, 2015, a 50-year-old male farmer was bitten on his right leg by a Deinagkistrodon's viper. The bite rendered the victim unconscious for 14 days, during which he was treated with tetanus toxoid and polyvalent antisnake venom. Acute demyelinating encephalomyelitis (ADEM) was suspected after magnetic resonance imaging of the brain. After a high dose of methylprednisolone was used as diagnostic treatment, the patient started recovering fast.ADEM is a rare complication after snake bite, and is triggered by venom or antivenin. Magnetic resonance imaging helps in the early diagnosis of ADEM, and high-dose corticosteroid therapy appears to be effective in ADEM after viper bite or antivenin management.

[Comparison of sedative effects of propofol and midazolam on emergency critical patients on mechanical ventilation].

OBJECTIVE: To compare the sedative effects of propofol and midazolam, or combination of them on emergency critically ill patients on mechanical ventilation. METHODS: Medical records of 68 patients treated in emergency intensive care unit (EICU) receiving mechanical ventilation and sedation care from August 2007 to July 2011 were reviewed retrospectively. According to the type of sedatives used, patients were assigned to propofol group (n=28), midazolam group (n=20), combination of propofol and midazolam group (combination group, n=20). Patients in the former two groups were given a loading dose of propofol or midazolam and followed by continuous infusion of the same drugs. Those in the combination group were given a loading dose of propofol and followed by continuous infusion of propofol together with midazolam. In this study, Ramsay anesthesia score was used to evaluate the effectiveness of sedation. The patients in three groups were maintained at depth of sedation level 2-4 according to the Ramsay score, and reassessed every 1-2 hours after the initiation. The change in vital signs and respirator related parameters were observed before and after administration in three groups, and the treatment information of sedative and mechanical ventilation were recorded. RESULTS: Heart rate (HR), respiratory rate (RR), systolic blood pressure (SBP), diastolic blood pressure (DBP), tidal volume (VT) were decreased at 1 hour after treatment compared with those before treatment in all the three groups, while the blood oxygen saturation (SpO2) was increased. There were no significant differences in RR and SpO2 at 1 hour after treatment among three groups. HR, SBP, DBP at 1 hour after treatment in propofol group were significantly decreased compared with those in midazolam group and combination group (HR: 20.43 ± 13.52 bpm vs. 15.27 ± 13.71 bpm, 18.54 ± 10.07 bpm; SBP: 39.26 ± 16.64 mm Hg vs. 25.80 ± 21.09 mm Hg, 31.50 ± 28.20 mm Hg; DBP: 21.35 ± 12.91 mm Hg vs. 14.07 ± 10.53 mm Hg, 16.42 ± 13.55 mm Hg, P<0.05 or P<0.01). VT at 1 hour after beginning of the treatment in combination group was decreased significantly compared with propofol group and midazolam group (121.06 ± 96.50 ml vs. 33.36 ± 28.49 ml, 39.94 ± 33.24 ml, both P<0.01). The drug dosage in combination group was decreased significantly compared with propofol group and midazolam group (total dosage of propofol: 25.21 ± 15.33 mg/kg vs. 90.83 ± 17.42 mg/kg, total dosage of midazolam: 2.37 ± 1.87 mg/kg vs. 4.02 ± 3.62 mg/kg, both P<0.01), but there was no significant difference in sedation time among groups. EICU stay days in combination group was shortened significantly compared with propofol group and midazolam group (7.75 ± 5.20 days vs. 12.53 ± 8.24 days, 15.20 ± 8.33 days, both P<0.05), but there was no significant difference in mechanical ventilation duration among groups. CONCLUSIONS: A combination of propofol with midazolam for emergency critically ill patients on mechanical ventilation not only can achieve a good sedative effect, reduce total amount of the drug, but also alleviate the inhibitory effect of propofol on the circulation, improve the symptoms of asynchronous ventilation, and reduce stay time in EICU.