Antiprogrammed death ligand 1 therapy failed to reduce the risk of developing brain metastases in patients with extensive-stage small cell lung cancer: A retrospective analysis.

BACKGROUND: Immunotherapy (IO) has demonstrated promising results in treating extensive-stage small cell lung cancer (ES-SCLC), and the management of ES-SCLC brain metastases (BMs) is now receiving significant clinical attention. The objective of this study was to evaluate the role of IO in the clinical management of BMs. METHODS: Between January 2020 and December 2021, the study included the records of 250 patients who were diagnosed with ES-SCLC. Overall survival (OS), progression-free survival, intracranial progression-free survival, and the cumulative incidence of BMs were calculated using the Kaplan-Meier method and were compared using the log-rank test. In addition, the Cox regression model was used to analyze prognostic factors. RESULTS: In the entire group, 85 patients had baseline BMs (IO plus chemotherapy [IO + ChT], n = 38; ChT alone, n = 47), and 165 patients (IO + ChT, n = 86; ChT alone, n = 79) did not have BMs at the time of initial diagnosis. The median follow-up was 22.4 months. The OS benefit with first-line antiprogrammed death ligand 1 therapy was maintained regardless of whether patients had BMs (with BMs, 17.97 vs. 13.14 months [p = .03]; without BMs, 18.46 vs. 15.05 months [p = .047]). However, in patients without BMs, IO did not delay the median time to developing brain progression (10.84 vs. 10.74 months; p = .84), and it did not significantly reduce the risk of developing intracranial metastases (the 2-year actuarial risk of developing BMs was 57.0% vs. 50.6%, respectively). CONCLUSIONS: Antiprogrammed death ligand 1 therapy improved OS regardless of the presence of BMs. However, IO did not delay the median time to brain progression or reduce the risk of intracranial metastasis in patients without baseline BMs. The findings of this study have important clinical implications for the future management of BMs from ES-SCLC.

Immunotherapy combined with cranial radiotherapy for driver-negative non-small-cell lung cancer brain metastases: a retrospective study.

Background: This study assesses immune checkpoint inhibitors' efficacy for non-small-cell lung cancer (NSCLC) with brain metastases (BM) and explores the role of cranial radiation therapy (CRT) in the immunotherapy era. Methods: The retrospective analysis screened NSCLC patients with BMs from July 2018 to December 2021. Treatment involved chemotherapy combined with immune checkpoint inhibitors as the first-line, with patients divided into CRT and non-CRT groups. Overall survival (OS), progression-free survival and intracranial progression-free survival were calculated and compared. Results: Among 113 patients, 74 who received CRT had significantly better median OS (not reached vs 15.31 months), particularly among those with one to three BMs. Factors correlating with better OS included CRT, PD-L1 expression and diagnosis-specific graded prognostic assessment scores. Conclusion: Integrating CRT with anti-PD-1 therapy notably enhanced long-term survival in NSCLC patients with BMs.

[Box: see text].

CovBinderInPDB: A Structure-Based Covalent Binder Database.

Covalent inhibition has emerged as a promising orthogonal approach for drug discovery, despite the significant challenge in achieving target specificity. To facilitate the structure-based rational design of target-specific covalent modulators, we developed an integrated computational protocol to curate covalent binders from the RCSB Protein Data Bank (PDB). Starting from the macromolecular crystallographic information files (mmCIF) in the PDB archive, covalent bond records, which indicate the side chain modification of amino acid residue by a covalent binder, were collected and cleaned. Then, residue-binder adducts, which are products of chemical reactions between targeted residues and covalent binders, were recovered with the help of the Chemical Component Dictionary in PDB. Finally, several strategies were employed to curate the pre-reaction forms of covalent binders from the adducts. Our curated CovBinderInPDB database contains 7375 covalent modifications in which 2189 unique covalent binders target nine types of amino acid residues (Cys, Lys, Ser, Asp, Glu, His, Met, Thr, and Tyr) from 3555 complex structures of 1170 unique protein chains. This database would set a solid foundation for developing and benchmarking computational strategies for covalent modulator design and is freely accessible at https://yzhang.hpc.nyu.edu/CovBinderInPDB.

A DFT study on PBu3-catalyzed intramolecular cyclizations of N-allylic substituted α-amino nitriles for the formation of functionalized pyrrolidines: mechanisms, selectivities, and the role of catalysts.

The mechanisms and chemo- and stereo-selectivities of PBu3-catalyzed intramolecular cyclizations of N-allylic substituted α-amino nitriles leading to functionalized pyrrolidines (5-endo-trig cyclization, Mechanism A) and their competing reaction leading to another kind of pyrrolidine (5-exo-trig cyclization, Mechanism B) have been investigated using density functional theory (DFT). Multiple possible reaction pathways associated with four different isomers (RR, SR, RS, and SS) for Mechanism A, and two isomers (R and S) for Mechanism B have been studied. The calculated results indicate that the Gibbs free energy barriers of Mechanism A are remarkably lower than those of Mechanism B, and the reaction pathway leading to the RS-configured product has the lowest Gibbs free energy barrier, which is in agreement with the experiments. A C-H···π interaction has been identified to be responsible for the favorability of RS isomers by non-covalent interaction (NCI) analysis. Moreover, global reaction indexes (GRIs) and NBO analyses confirm that PBu3 acts as a Lewis base to strengthen the nucleophilicity of the reaction active site. The mechanistic insights gained in the present study should be valuable for the rational design of effective organocatalysts for this kind of reaction with high chemo- and stereo-selectivities.

Theoretical Investigations toward the Asymmetric Insertion Reaction of Diazoester with Aldehyde Catalyzed by N-Protonated Chiral Oxazaborolidine: Mechanisms and Stereoselectivity.

In recent years, the N-protonated chiral oxazaborolidine has been utilized as the Lewis acid catalyst for the asymmetric insertion reaction, which is one of the most challenging topics in current organic chemistry. Nevertheless, the reaction mechanism, stereoselectivity, and regioselectivity of this novel insertion reaction are still unsettled to date. In this present work, the density functional theory (DFT) investigation has been performed to interrogate the mechanisms and stereoselectivities of the formal C-C/H insertion reaction between benzaldehyde and methyl α-benzyl diazoester catalyzed by the N-protonated chiral oxazaborolidine. For the reaction channel to produce the R-configured C-C insertion product as the predominant isomer, the catalytic cycle can be characterized by four steps: (i) the complexation of the aldehyde with catalyst, (ii) addition of the other reactant methyl α-benzyl diazoester, (iii) the removal of nitrogen concerted with the migration of phenyl group or hydrogen, and (iv) the dissociation of catalyst from the products. Our computational results show that the carbon-carbon bond formation step is the stereoselectivity determining step, and the reaction pathways associated with [1, 2]-phenyl group migration occur preferentially to those pathways associated with [1, 2]-hydrogen migration. The pathway leading to the R-configured product is the most favorable pathway among the possible stereoselective pathways. All these calculated outcomes align well with the experimental observations. The novel mechanistic insights should be valuable for understanding this kind of reaction.

Role of Surgery in Potentially Resectable Small-Cell Lung Cancer Based on the Eighth Edition of the TNM Classification: A Population Study of the US SEER Database.

BACKGROUND: This study aimed to identify a specific SCLC population that would benefit from surgery. METHODS: This study utilized patient data retrieved from the Surveillance, Epidemiology, and End Results (SEER) database spanning 2010 to 2017. To mitigate clinical biases, the propensity score matching (PSM) technique was employed. Separate cohorts were aligned using PSM according to the AJCC 8th edition TNM classification. The Kaplan-Meier method and a competing risk model were applied to evaluate overall survival (OS) and lung cancer-specific survival (LCSS), respectively. OUTCOMES: Among the 3394 patients with potentially resectable SCLC included in the study, 3062 underwent chemoradiotherapy and 332 underwent surgical treatment with adjuvant chemotherapy. Surgery was associated with better OS (median OS: 49 months; 95% CI: 35-63 months vs. 27 months; 95% CI: 21-33 months, p < 0.001) and LCSS (SHR, 0.578; 95% CI: 0.411-0.815, p < 0.001) in stage I patients after PSM. However, there was no significant difference in OS and LCSS between the surgery and nonsurgery groups in stage II and III patients after PSM. In the entire cohort, lobectomy was associated with improved OS (median OS: 48.6 vs. 28.7 months, p < 0.0001), but not LCSS (SHR, 0.696; 95% CI: 0.466-1.040, p = 0.078) compared with sublobar resection after PSM. CONCLUSION: Surgery with adjuvant chemotherapy significantly improved the survival prognosis of patients with early-stage SCLC. However, surgical treatment should be carefully considered in patients with stage II/III disease. Lobectomy is oncologically equal to sublobar resection.

Palladium-catalyzed synthesis of 3-acylated indoles involving oxidative cross-coupling of indoles with α-amino carbonyl compounds.

A new and selective C-N bond oxidative cleavage method to 3-acylated indoles by Pd-catalyzed oxidative cross coupling of indoles with α-amino carbonyl compounds has been developed; moreover, one-pot synthesis of 3-acylated indoles from 2-ethynylanilines and α-amino carbonyl compounds has also been established. Importantly, the products 3-acylated indoles can be used to construct polyheterocyclic compound, which can be employed as efficient probes for Hg(2+) and Fe(3+).

Primary lung cancer in children and adolescents: Analysis of a surveillance, epidemiology, and end results database.

Background: The incidence of primary lung cancer (LC) in children and adolescence was rare. We analyzed data from a SEER database to better define the incidence, clinical characters, pathology, treatment, and outcomes of rare primary malignant pulmonary tumors in childhood and adolescence. Methods: Patients were chosen from the SEER database (SEER*Stat 8.4.0 software) from 2000 to 2019 and all patients were pathologically diagnosed with primary malignant tumors of the lung and bronchus. Demographic characteristics of patients (age, gender, race, primary site, laterality, location, differentiation grade, operation methods, histology, and history of radiotherapy and chemotherapy), as well as TNM stage and survival time, were collected. Results: A total of 301 cases of children ≤19 years of age with a primary malignant pulmonary tumor were reported to the SEER database from 2000 to 2019. There were 143 men (47.5%) and 158 women (52.5%). Whites represented majority of patients (79.7%), followed by Black (13.6%) and others (6.7%). As for the primary site, the main site was the lower lobe (33.2%), followed by the upper lobe (26.9%). Most of the patients (80.4%) underwent surgery. Lobectomy (39.9%) is the main operation method. Only 28 (9.3%) patients received radiotherapy and 112 (37.2) patients received chemotherapy. Carcinoid tumor was the most common histology (29.6%), followed by pulmonary blastoma (PB) (22.3%), mucoepidermoid carcinoma (MEC) (12.3%), adenocarcinoma (10.3%), neuroendocrine tumor (NET) (5.7%), squamous cell carcinoma (SCC) (5.3%), atypical carcinoma (2.3%). The mean follow-up time was 100 months. For the entire group of children and adolescents, the 1-year OS was 89.1%, and the 3-year overall survival (OS) was 79.7%. the 5-year OS was 77.9%, the 10-year OS was 75.7%, and the 15-year OS was 73.9%. And 1-year lung cancer specificity survival (LCSS) was 89.8%, and the 3-year LCSS was 80.4%. the 5-year LCSS was 79.4%, the 10-year LCSS was 77.7%, and the 15-year LCSS was 75.9%. The OS of atypical carcinoma, carcinoid tumor, and MEC were in the top three. Conclusions: Primary LC in children and adolescent were rare and histopathological diverse. Fortunately, children and adolescents with LC had an overall favorable outcome after treatment. Histology, differentiation grade, surgery, TNM stage, and therapeutic modalities have important influence on OS. The further treatment experience of each pathological type would make better evidence-based practice possible.

[Pneumonectomy for Non-small Cell Lung Cancer: Predictors of Operative Mortality and Survival].

Surgery is the most effective way to cure non-small cell lung cancer currently. Although sleeve lobectomy, with less reduction of respiratory function and a lower mortality rate, would not compromise oncological results in well-selected patients with central lung cancer, pneumonectomy is still necessary when complete resection could not be achieved by other surgical procedures. Cardiopulmonary complications are the most common complication after pneumonectomy. Fully understanding the related complications after pneumonectomy can help surgeons make a diagnosis timely, and further take relevant measures to reduce the adverse effects of postoperative complications on patients. What's more, in order to avoid postoperative complications and improve the prognosis of patients as much as possible, it is necessary to fully understand the risk factors to minimize the risk and to make the patients benefit from pneumonectomy as much as possible.

Development and validation of a nomogram prognostic model for patients with neuroendocrine tumors of the thymus.

BACKGROUND: The purpose of this study was to analyze the clinical characteristics and prognostic survival of patients with neuroendocrine tumors of the thymus (NETTs), and to develop and validate a nomogram model for predicting the prognosis of patients. METHODS: We conducted a retrospective analysis of patients with neuroendocrine tumors of the thymus in the Surveillance, Epidemiology, and End Results (SEER) database in the United States between 1988 and 2016. Cox scale risk regression analysis, the Kaplan-Meier method and log-rank test were used to carry out the significance test to determine the independent prognostic factors, from which a nomogram for NETTs was established. C-index and calibration curve were used to evaluate the prediction accuracy of the model. External validation of the nomogram was performed using data from our center. RESULTS: A total of 254 patients with NETTs were collected in the SEER database. In the multivariable analysis, T stage, tumor grade, surgery, and chemotherapy were found to be independent factors affecting the prognosis of patients (all P < 0.05). A nomogram model was constructed based on these variables, and its c-index was 0.707 (0.661-0.752). The c-index results showed that the nomogram model had better authentication capability than the eighth edition of the tumor, node, metastasis (TNM) staging system and Masaoka-Koga (MK) staging system. The calibration curve showed that the model could accurately predict patient prognosis. CONCLUSIONS: The study established a nomogram model that predicted the overall survival rate of one-, three- and five-years, and used the survival prediction model to optimize individualized therapy and prognostic follow-up through risk stratification.

Mechanistic insights into cobalt(ii/iii)-catalyzed C-H oxidation: a combined theoretical and experimental study.

Cobalt-mediated C-H functionalization has been the subject of extensive interest in synthetic chemistry, but the mechanisms of many of these reactions (such as the cobalt-catalyzed C-H oxidation) are poorly understood. In this paper, possible mechanisms including single electron transfer (SET) and the concerted metalation-deprotonation (CMD) pathways of the CoII/CoIII-catalyzed alkoxylation of C(sp2)-H bonds have been investigated for the first time using the DFT method. CoII(OAc)2 has been employed as an efficient catalyst in our previous experimental study, but the calculated results unexpectedly indicated that the intermolecular SET pathway with CoIII as the actual catalyst might be the most favorable pathway. To support this theoretical prediction, we have explored a series of Cp*CoIII(CO)I2 catalyzed C(sp2)-H bond alkoxylations, extending the application of cobalt-catalyzed functionalization of C-H bonds. Furthermore, kinetic isotope effect (KIE) data, electron paramagnetic resonance (EPR) data, and TEMPO inhibition experiments also support the SET mechanism in both the Co-catalyzed alkoxylation reactions. Thus, this work should support an understanding of the possible mechanisms of the CoII/CoIII-catalyzed C(sp2)-H functionalization, and also provide an example of the rational design of novel catalytic reactions guided by theoretical calculations.

Self-assembly of an unprecedented polyoxomolybdate anion [Mo20O66]12- in a giant peanut-like 62-core silver-thiolate nanocluster.

A polyoxometalate-templated silver thiolate nanocluster, [Ag62(S(t)Bu)40(Mo20O66)(Mo6O19)3(CH3CN)2]·(CF3SO3)4 (1), has been isolated, in which a giant peanut-like silver(i)-thiolate cluster [Ag62(S(t)Bu)40](22+) encapsulates an unprecedented [Mo20O66](12-) polyoxoanion core. It opens a new approach for the synthesis of both elusive polyoxometalates and high-nuclearity silver(i)-thiolate nanoclusters.