The relative risk of immune checkpoint inhibitor pneumonitis in advanced non-small- cell lung cancer: Meta-analyses of controlled clinical trials.

OBJECTIVE: Immune checkpoint inhibitor pneumonitis (CIP) is a prevalent form of immunotherapy-induced pulmonary toxicity, ranking among the leading causes of mortality associated with immune checkpoint inhibitors (ICIs). Despite its significance, the risk stratification of CIP in advanced non-small cell lung cancer (NSCLC) remains uncertain. In this study, we conducted a comprehensive analysis, comparing various factors such as histological types, treatment regimens, PD-L1 expression levels, and EGFR/ALK negativity in advanced NSCLC. Our investigation extends to evaluating the relative risk of developing CIP based on previous treatment history. This analysis aims to provide valuable insights for the identification of specific patient subgroups at higher risk, facilitating more effective risk management and precision therapy approaches. METHODS: PubMed, Embase, and Cochrane databases were systematically searched up to February 16, 2023. We conducted a screening of randomized controlled trials (RCTs) that compared ICI monotherapy or its combination with chemotherapy in advanced NSCLC. The trials were categorized based on histological type, treatment regimen, PD-L1 expression level, EGFR/ALK-negative status, and prior treatment history. Subsequently, the data were stratified into five subgroups, and the occurrences of all-grades (1-5) and high-grades (3-5) pneumonia events were extracted. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were then calculated for further analysis. RESULTS: Twenty-two RCTs, encompassing 13,725 patients with advanced NSCLC, were included in this analysis. Regardless of histology (OR = 2.47, 95% CI 1.41-4.33, P = 0.002; OR = 1.84, 95% CI 1.10-3.09, P = 0.02), treatment regimen (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.91, 95% CI 1.98-4.27, P < 0.00001), PD-L1 expression level (OR = 5.11, 95% CI 2.58-10.12, P < 0.00001; OR = 5.15, 95% CI 2.48-10.70, P < 0.0001), negative EGFR/ALK expression (OR = 4.32, 95% CI 2.22-8.41, P < 0.0001; OR = 3.6, 95% CI 1.56-8.28, P = 0.003), whether there is a history of treatment (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.74, 95% CI 1.75-4.29, P < 0.0001), ICI use was associated with a higher risk of all-grade (1-5) and high-grade (3-5) pneumonia compared to chemotherapy. Subgroup analysis revealed that the squamous group, the ICI vs. combination chemotherapy (CT) group, the PD-L1 > 50% group, and the previously untreated group had a higher risk of developing all-grade and grade 3-5 CIP (P < 0.05). CONCLUSIONS: In advanced NSCLC, ICI treatment was linked to an elevated risk of pneumonitis across all grades (1-5) as well as high-grade occurrences (3-5) compared to chemotherapy. Notably, individuals with squamous histology and high PD-L1 expression, along with those lacking a history of prior treatment, demonstrated a heightened susceptibility to developing immune-related pneumonitis of all grades (1-5) and high grades (3-5). These observations provide valuable insights for clinicians seeking to enhance the management of pulmonary toxicity associated with immunotherapy.

Enhanced Hydrogen Bonds of the (H2O)n (n = 4-8) Clusters Confined in Uranyl Peroxide Cluster Na20(UO2)20(O2)30.

Water is a basic resource and an essential component of living organisms. It often exhibits some novel properties under confinement. The water clusters (H2O)n (n = 4-8) confined in the cavity of uranyl peroxide cluster Na20(UO2)20(O2)30 (U20) have been computationally investigated by using ab initio molecular dynamics (AIMD) simulations and density functional theory (DFT) calculations in this study. The results show that the confined water clusters can form hydrogen bonds with the internal oxygen atoms (Ouranyl) of U20, and their conformations changed significantly. The average lengths (2.553-2.645 Å) of hydrogen bonds in confined (H2O)n are shorter than those (2.731-2.841 Å) in the corresponding free water clusters. Moreover, these confined hydrogen bonds show better hydrogen bond patterns according to the quantified indices. The natural bond orbital (NBO) calculations determine that there is electron transferring from the U20 to its interior (H2O)n. It is the main reason for enhancing hydrogen bond interactions among the confined water molecules because their oxygen atoms are more negatively charged and their hydrogen atoms are more positively charged. The quantum theory of atoms in molecules (QTAIM) and interacting quantum atoms (IQA) analyses indicate that the confined hydrogen bonds are more covalent, based on the significant electron density ρ(r) and local energy density H(r) at the bond critical points (BCPs), and the stronger energies of interatomic exchange interactions (Vxc). These findings may help to promote the communication of confined water clusters and enrich the understating of confined hydrogen bonds.

Arteriovenous thrombotic events in a patient with advanced lung cancer following bevacizumab plus chemotherapy: A case report.

BACKGROUND: In driver gene-negative non-small cell lung cancer patients who relapse following radical resection, combination chemotherapy using bevacizumab and platinum-based dual drugs is known to increase both progression-free and overall survival. Treatment initially includes bevacizumab, and if patients are able to tolerate it, bevacizumab can continue to be utilized until disease progression. Bevacizumab is a recombinant humanized monoclonal neutralizing antibody that acts against vascular endothelial growth factor (VEGF). Various anti-VEGF monoclonal antibodies, such as bevacizumab, can increase the risk of arterial thromboembolism. Current data indicate that VEGF-targeted treatment does not significantly increase the risk of venous thromboembolism events, except for bevacizumab. CASE SUMMARY: A 55-year-old man underwent radical resection for cancer of the right lung. Six months following surgery, multiple metastases were observed in his left lung. Subsequently, six cycles of bevacizumab combined with pemetrexed/carboplatin chemotherapy was given. Efficacy evaluation continued to be partial relief according to RECIST 1.1 standards, and no noticeable adverse reactions were noted. After three cycles of maintenance therapy using a combination of bevacizumab and pemetrexed, the patient developed dizziness and dyspnea. The patient was diagnosed with acute cerebral infarction and pulmonary embolism following head magnetic resonance imaging, computed tomography (CT) angiography, and chest enhanced CT. Although the patient received low-molecular-weight heparin anticoagulation and other treatment, the patient eventually died of respiratory failure 1 mo later. This case report may offer some insight into fatal arteriovenous embolism, which has not been previously reported. CONCLUSION: Bevacizumab combined with chemotherapy may also increase the risk of arteriovenous thromboembolism. Accordingly, patients who receive angiogenesis inhibitor therapy should be carefully selected. Furthermore, close monitoring and timely intervention are necessary in order to reduce the risk of such toxicities.

Ligands enhanced the Ac[triple bond, length as m-dash]Ac triple bond.

The multiple bonds between actinide atoms and their derivatives are computationally investigated extensively and compounds with an unsupported actinide-actinide bond, especially in low oxidation states, have attracted great attention. Herein, high level relativistic quantum chemical methods are used to probe the Ac-Ac bonding in compounds with a general formula LAcAcL (L = AsH3, PH3, NH3, H, CO, NO) at both scalar and spin-orbit coupling relativistic levels. H3AsAcAcAsH3, H3PAcAcPH3 and OCAcAcCO compounds show a type of zero valence Ac[triple bond, length as m-dash]Ac triple bond with a 1σ2g1π4u configuration, and H3AsAcAcAsH3 has been found to have the shortest Ac-Ac bond length of 3.012 Å reported so far. The Ac2 unit is very sensitive to the σ donor ligands and can form triple, double and even single bonds when suitable ligands are introduced, up to 3.652 Å with an Ac-Ac single bond in H3NAcAcNH3.

Model of lymph node metastasis posterior to the right recurrent laryngeal nerve in papillary thyroid carcinoma.

BACKGROUND: Cervical lymph node metastasis (LNM) is a prognostic factor of papillary thyroid carcinoma (PTC). The way to deal with lymph node posterior to the right recurrent laryngeal nerve (LN-prRLN) is controversial. Nevertheless, if metastatic lymph nodes are not removed during the first operation, the subsequent salvage surgery of recurrent tumor in this area would entail high risk and complication. The purpose of this study was to develop a preoperative prediction model for LN-prRLN metastasis in PTC patients using clinicopathological characteristics. PATIENTS AND METHODS: We performed a prospective study of 595 patients with PTC who underwent LN-prRLN dissection from March 2014 to June 2017. The clinicopathological data were randomly divided into derivation (n=476) and validation sets (n=119). A predictive model was initially established based upon the data of the derivation set via multivariate analyses, and the accuracy of the model was then examined with data of the validation set. The discriminative power of this model was assessed in both sets. RESULTS: Metastases of the LN-prRLN were identified in 102 (17.14%) of 595 patients. Age (odds ratio [OR] 0.971, 95% CI, 0.949-0.994, p=0.013), tumor size (OR 2.163, 95% CI, 1.431-3.270, p<0.001), capsular invasion (OR 1.934, 95% CI, 1.062-3.522, p=0.031), and right LNM (OR 3.786, 95% CI, 2.012-7.123, p<0.001) were significantly associated with LN-prRLN metastasis. The areas under the curves were 0.790 for the derivation set (sensitivity 71.95%, specificity 78.68%) and 0.878 for the validation set (sensitivity 85.00%, specificity 78.79%). CONCLUSION: We developed and validated the first model to predict LN-prRLN metastases in patients with PTC based on clinicopathological parameters.

Clinical value and indication for the dissection of lymph nodes posterior to the right recurrent laryngeal nerve in papillary thyroid carcinoma.

Lymph nodes posterior to the right recurrent laryngeal nerve (LN-prRLN) are common sites of nodal recurrence after the resection of papillary thyroid carcinoma (PTC). However, the indication for LN-prRLN dissection remains debatable. We therefore studied the relationships between LN-prRLN metastasis and the clinicopathological characteristics in 306 patients with right or bilateral PTC who underwent LN-prRLN dissection. We found that LN-prRLN metastasis occurred in 16.67% of PTC and was associated with a number of the clinicopathological features. The receiver-operator characteristic (ROC) analysis showed that the areas under the ROC curves for the prediction of LN-prRLN metastasis by the risk factors age < 35.5 years, right tumor size > 0.85 cm, lymph node (right cervical central VI-1) number > 1.5, metastatic lymph node (right cervical central VI-1) size > 0.45 cm, and lymph node number in the right cervical lateral compartment > 0.5 were 0.601, 0.815, 0.813, 0.725, and 0.743, respectively. In conclusion, the risk factors for LN-prRLN metastasis in patients suffering right thyroid lobe or bilateral PTC include age ≤ 35.5 years, right tumor size ≥ 0.85 cm, capsular invasion, metastatic lymph node (right cervical central VI-1) number ≥ 2, metastatic lymph node (right cervical central VI-1) size ≥ 0.45 cm, and metastatic lymph node number in the right cervical lateral compartment ≥ 1. In patients whose risk factors can be identified pre-operatively or intraoperatively, the dissection of LN-pr-RLN should be considered during right cervical central compartment dissection.