Genomic Characterization of a Carbapenem-Resistant Raoultella planticola Strain Co-Harboring blaIMP-4 and blaSHV-12 Genes.

Raoultella planticola is an emerging bacterial pathogen responsible for causing infections in both humans and animals. Unfortunately, sporadic reports of carbapenem-resistant R. planticola (CRRP) have been documented worldwide. Here we first reported the complete genome sequence of a CRRP isolate RP_3045 co-carrying blaIMP-4 and blaSHV-12, recovered from a patient in China, and its genetic relatedness to 82 R. planticola strains deposited in the NCBI GenBank database, sourced from humans, animals, and the environment. Whole-genome sequencing was performed using the Illumina NovaSeq 6000 and Oxford Nanopore MinION platforms. Phylogenetic analysis was also performed and visualized using a single nucleotide polymorphism (SNP)-based strategy. The complete genome of R. planticola strain RP_3045 was determined to be 6,312,961 bp in length, comprising five contigs that included one chromosome and four plasmids. RP_3045 was found to be multidrug-resistant and harbored several antimicrobial resistance genes, including both blaIMP-4 and blaSHV-12 genes located on a single plasmid. The most closely related strain was hkcpe63, recovered from humans in Hong Kong, China, in 2014, with 506 SNP differences. R. planticola strains were distributed globally and exhibited strong associations among isolates obtained from different sectors. This study provides evidence for the potential of R. planticola to disseminate carbapenem resistance across different sectors, highlighting the critical need for active and continuous surveillance of CRRP.

Continuous flow biocatalysis: synthesis of purine nucleoside esters catalyzed by lipase TL IM from Thermomyces lanuginosus.

Purine nucleoside ester is one of the derivatives of purine nucleoside, which has antiviral and anticancer activities. In this work, a continuous flow synthesis of purine nucleoside esters catalyzed by lipase TL IM from Thermomyces lanuginosus was successfully achieved. Various parameters including solvent, reaction temperature, reaction time/flow rate and substrate ratio were investigated. The best yields were obtained with a continuous flow microreactor for 35 min at 50 °C with the substrate ratio of 1 : 5 (nucleosides to vinyl esters) in the solvent of tert-amyl alcohol. 12 products were efficiently synthesized with yields of 78-93%. Here we reported for the first time the use of lipase TL IM from Thermomyces lanuginosus in the synthesis of purine nucleoside esters. The significant advantages of this methodology are a green solvent and mild conditions, a simple work-up procedure and the highly reusable biocatalyst. This research provides a new technique for rapid synthesis of anticancer and antiviral nucleoside drugs and is helpful for further screening of drug activity.

Inter-organ steroid hormone signaling promotes myoblast fusion via direct transcriptional regulation of a single key effector gene.

Steroid hormones regulate tissue development and physiology by modulating the transcription of a broad spectrum of genes. In insects, the principal steroid hormones, ecdysteroids, trigger the expression of thousands of genes through a cascade of transcription factors (TFs) to coordinate developmental transitions such as larval molting and metamorphosis. However, whether ecdysteroid signaling can bypass transcriptional hierarchies to exert its function in individual developmental processes is unclear. Here, we report that a single non-TF effector gene mediates the transcriptional output of ecdysteroid signaling in Drosophila myoblast fusion, a critical step in muscle development and differentiation. Specifically, we show that the 20-hydroxyecdysone (commonly referred to as "ecdysone") secreted from an extraembryonic tissue, amnioserosa, acts on embryonic muscle cells to directly activate the expression of antisocial (ants), which encodes an essential scaffold protein enriched at the fusogenic synapse. Not only is ants transcription directly regulated by the heterodimeric ecdysone receptor complex composed of ecdysone receptor (EcR) and ultraspiracle (USP) via ecdysone-response elements but also more strikingly, expression of ants alone is sufficient to rescue the myoblast fusion defect in ecdysone signaling-deficient mutants. We further show that EcR/USP and a muscle-specific TF Twist synergistically activate ants expression in vitro and in vivo. Taken together, our study provides the first example of a steroid hormone directly activating the expression of a single key non-TF effector gene to regulate a developmental process via inter-organ signaling and provides a new paradigm for understanding steroid hormone signaling in other developmental and physiological processes.

Recovery and genetic characterization of clinically-relevant ST2 carbapenem-resistant Acinetobacter baumannii isolates from untreated hospital sewage in Zhejiang Province, China.

The global transmission of carbapenem-resistant Acinetobacter baumannii (CRAB) poses a significant and grave threat to human health. To investigate the potential relationship between hospital sewage and the transmission of CRAB within healthcare facilities, isolates of Acinetobacter spp. obtained from untreated hospital sewage samples were subjected to antimicrobial susceptibility tests, genome sequencing, and bioinformatic and phylogenetic tree analysis, and that data were matched with those of the clinical isolates. Among the 70 Acinetobacter spp. sewage isolates tested, A. baumannii was the most prevalent and detectable in 5 hospitals, followed by A. nosocomialis and A. gerneri. Worryingly, 57.14 % (40/70) of the isolates were MDR, with 25.71 % (18/70) being resistant to carbapenem. When utilizing the Pasteur scheme, ST2 was the predominant type among these CRAB isolates, with Tn2006 (ΔISAba1-blaOXA-23-ATPase-yeeB-yeeA-ΔISAba1) and Tn2009 (ΔISAba1-blaOXA-23-ATPase-hp-parA-yeeC-hp-yeeB-ΔISAba1) being the key mobile genetic elements that encode carbapenem resistance. Seven A. gerneri isolates which harbored Tn2008 (ISAba1-blaOXA-23 -ATPase) and the blaPER-1 gene were also identified. Besides, an A. soil isolate was found to exhibit high-level of meropenem resistance (MIC ≥128 mg/L) and harbor a blaNDM-1 gene located in a core genetic structure of ISAba125-blaNDM-1-ble-trpF-dsbC-cutA. To investigate the genetic relatedness between isolates recovered from hospital sewage and those collected from ICUs, a phylogenetic tree was constructed for 242 clinical isolates and 9 sewage isolates. The results revealed the presence of two evolutionary clades, each containing isolates from both ICU and sewage water, suggesting that CRAB isolates in untreated sewage water were also the transmission clones or closely related evolutionary isolates recoverable in hospital settings. Findings in this work confirm that hospital sewage is a potential reservoir of CRAB.

Development of a green, concise synthesis of nicotinamide derivatives catalysed by Novozym® 435 from Candida antarctica in sustainable continuous-flow microreactors.

An increasing number of studies have shown that many nicotinamide derivatives exhibited extensive biological activities, such as anti-inflammatory and antitumor activity. In this paper, a green, concise synthesis of nicotinamide derivatives in sustainable continuous-flow microreactors catalysed by Novozym® 435 from Candida antarctica has been developed. Application of an easily obtainable and reusable lipase in the synthesis of nicotinamide derivatives from methyl nicotinate and amines/benzylamines reacted for 35 min at 50 °C led to high product yields (81.6-88.5%). Environmentally friendly tert-amyl alcohol was applied as a reaction medium. Substantially shorter reaction times as well as a significant increase in the product yield were obtained as compared to the batch process. This innovative approach provides a promising green, efficient and rapid synthesis strategy for pharmaceutical synthesis and further activity research of novel nicotinamide derivatives.

Monitoring the long-term spatiotemporal transmission dynamics and ecological surveillance of multidrug-resistant Salmonella enterica serovar Goldcoast: A multicenter genomic epidemiology study.

The emergence of multidrug-resistant Salmonella enterica serovar Goldcoast poses a significant threat to the effective treatment and control of salmonellosis within the ecological environment. Here, we conducted a genomic epidemiological study delineate the global dissemination scenarios of the multidrug-resistant S. Goldcoast originated from 11 countries for over 20 years. The population structure and evolutionary history of multidrug-resistant S. Goldcoast was investigated through phylogenomic and long-term spatiotemporal transmission dynamic analysis. ST358 and ST2529 are the predominant lineages of S. Goldcoast. Multidrug-resistant S. Goldcoast strains have mainly been identified in the ST358 lineage from human and the ST2529 lineage from livestock. ST358 S. Goldcoast was estimated to have emerged in the United Kingdom in 1969, and then spread to China, with both countries serve as centers for the global dissemination of the ST358 lineage. After its emergence and subsequent spread in Chinese clinical and environmental samples, occasional instances of this lineage have been reported in Canada, the United Kingdom, and Ireland. Clonal transmission of ST358 and ST2529 S. Goldcoast have occurred not only on an international and intercontinental scale but also among clinical, environmental and livestock samples. These data indicated that international circulation and local transmission of S. Goldcoast have occurred for over a decade. Continued surveillance of multidrug-resistant S. Goldcoast from a global "One Health" perspective is urgently needed to facilitate monitoring the spread of the antimicrobial resistant high-risk clones.

Global Phylogeography and Genomic Epidemiology of Carbapenem-Resistant blaOXA-232-Carrying Klebsiella pneumoniae Sequence Type 15 Lineage.

Prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) has compromised antimicrobial efficacy against severe infections worldwide. To monitor global spread, we conducted a comprehensive genomic epidemiologic study comparing sequences from 21 blaOXA-232-carrying CRKP isolates from China with K. pneumoniae sequence type (ST) 15 strains from 68 countries available in GenBank. Phylogenetic and phylogeographic analyses revealed all blaOXA-232-carrying CRKP isolates belonged to ST15 lineage and exhibited multidrug resistance. Analysis grouped 330 global blaOXA-232-carrying ST15 CRKP strains into 5 clades, indicating clonal transmission with small genetic distances among multiple strains. The lineage originated in the United States, then spread to Europe, Asia, Oceania, and Africa. Most recent common ancestor was traced back to 2000; mutations averaged ≈1.7 per year per genome. Our research helps identify key forces driving global spread of blaOXA-232-carrying CRKP ST15 lineage and emphasizes the importance of ongoing surveillance of epidemic CRKP.

Molecular epidemiology and genomic characterization of a plasmid-mediated mcr-10 and blaNDM-1 co-harboring multidrug-resistant Enterobacter asburiae.

Colistin is considered as one of the last-resort antimicrobial agents for treating multidrug-resistant bacterial infections. Multidrug-resistant E. asburiae has been increasingly isolated from clinical patients, which posed a great challenge for antibacterial treatment. This study aimed to report a mcr-10 and blaNDM-1 co-carrying E. asburiae clinical isolate 5549 conferred a high-level resistance against colistin. Antibiotic susceptibility testing was performed using the microdilution broth method. Transferability of mcr-10 and blaNDM-1-carrying plasmids were investigated by conjugation experiments. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was used to identify modifications in lipid A. Whole genome sequencing and phylogenetic analysis between strain 5549 and a total of 301 E. asburiae genomes retrieved from NCBI database were performed. The genetic characteristics of mcr-10 and blaNDM-1-bearing plasmids were also analyzed. Our study indicated that strain 5549 showed extensively antibiotic-resistant trait, including colistin and carbapenem resistance. The mcr-10 and blaNDM-1 were carried by IncFIB/IncFII type p5549_mcr-10 (159417 bp) and IncN type p5549_NDM-1 (63489 bp), respectively. Conjugation assays identified that only the blaNDM-1-carrying plasmid could be successfully transferred to E. coli J53. Interestingly, mcr-10 did not mediate colistin resistance when it was cloned into E. coli DH5α. Mass spectrometry analysis showed the lipid A palmitoylation of the C-lacyl-oxo-acyl chain to the chemical structure of lipid A at m/z 2063 in strain 5549. In summary, this study is the first to report a mcr-10 and blaNDM-1 co-occurrence E. asburiae recovered from China. Our investigation revealed the distribution of different clonal lineage of E. asburiae with epidemiology perspective and the underlying mechanisms of colistin resistance. Active surveillance is necessary to control the further dissemination of multidrug-resistant E. asburiae.

Genomic epidemiology of mcr carrying multidrug-resistant ST34 Salmonella enterica serovar Typhimurium in a one health context: The evolution of a global menace.

The rapid global dissemination of Salmonella enterica sequence type 34 (ST34) has sparked significant concern due to its resistance to critical antimicrobials and its ability to spread across various sectors. In order to investigate the evolution and transmission dynamics of this epidemic clonal lineage, as well as the horizontal transfer of mcr-carrying plasmids within the One Health framework, we conducted a comprehensive genomic epidemiological study. This study focused on the 11 mcr-carrying S. enterica isolates obtained from clinical settings in China, while also considering 2337 publicly available genomes of mcr-carrying S. enterica collected from 20 countries and diverse sources spanning over a 22-year period. Among the mcr-positive Salmonella isolates, ST34 was found to be the predominant lineage, comprising 30.12 % (704/2337) of the total collection. These isolates were identified as either serovar Typhimurium or its monophasic variant, which were obtained from both clinical and non-clinical sources. Phylogeographic analyses traced the global spread of the mcr-carrying ST34 lineage, which was divided into three distinct clusters, with 83.10 % of them carrying mcr-1 or/and mcr-9 genes. Notably, the mcr-1 positive ST34 isolates were primarily found in China (190/298, 63.76 %), with only four from the United States. Conversely, mcr-9 positive ST34 isolates were predominantly identified in the United States (261/293, 89.08 %), while none were observed in China. The mcr-1 positive ST34 isolates was predicted to have originated from clinical sources in United Kingdom, whereas mcr-9 positive ST34 isolates was likely derived from environmental sources in Germany. The most recent common ancestor for mcr-1 and mcr-9 carrying ST34 S. enterica was estimated to have emerged around 1983 and 1951. These findings provided thorough and intuitive insights into the intercontinental spread of mcr-carrying S. enterica ST34 lineage in a One Health context. Ongoing surveillance is crucial for effectively monitoring the worldwide dissemination of this multidrug-resistant high-risk clone.

Genomic and Phylogenetic Analysis of a Multidrug-Resistant blaNDM-carrying Klebsiella michiganensis in China.

Objective: Klebsiella michiganensis is an emerging hospital-acquired bacterial pathogen. However, there is a dearth of knowledge on the antimicrobial resistance and transmission of K. michiganensis. Here, we characterized the microbiological and genomic features of a carbapenem-resistant K. michiganensis strain harboring the blaNDM-1 gene in China. Methods: K. michiganensis strain 2563 was recovered from the sputum sample of a hospitalized patient with pulmonary infection. Whole-genome sequencing of K. michiganensis strain 2563 was conducted using both the short-read Illumina and long-read MinION platforms to thoroughly characterize the genetic context of blaNDM-carrying plasmid in K. michiganensis 2563. Furthermore, BacWGSTdb server was utilized to perform in silico multilocus sequence typing (MLST), identify antimicrobial resistance genes, and conduct genomic epidemiological analyses of the closely related isolates deposited in the public database. Results: K. michiganensis 2563 was resistant to piperacillin, aztreonam, meropenem, imipenem, amoxicillin-clavulanic acid, ampicillin, cefotaxime, cefazolin, ampicillin/sulbactam, cefepime, piperacillin-tazobactam, and ceftazidime. It belonged to sequence type (ST) 43, and the blaNDM-1 gene was found to be located on the plasmid p2563_NDM (54,035 bp). This plasmid showed remarkable similarity to other blaNDM-1-encoding plasmids found in various Enterobacterium species in the public database. The occurrence of global ST43 K. michiganensis was primarily sporadic, and the closest relative of K. michiganensis 2563 was another ST43 isolate 12,084 recovered from China in 2013, which differed by 171 SNPs. Conclusion: Our study reports the genome characteristics of a carbapenem-resistant K. michiganensis strain carrying the blaNDM-1 gene in China, highlighting the need for ongoing surveillance of this pathogen in clinical settings.

Docosahexaenoic acid alleviates the excessive degradation of extracellular matrix in the nucleus pulposus by reducing the content of lncRNA NEAT1 to prevent the progression of intervertebral disc degeneration.

The pathogenesis of intervertebral disc degeneration (IVDD), as a multifactorial disease, has not been fully elucidated. However, damage to the stress-bearing system in the intervertebral disc (IVD) mediated by the excessive decomposition of extracellular matrix (ECM) in nucleus pulposus (NP) cells caused by local stimulation is widely considered the core pathological process underlying IVDD. Docosahexaenoic acid (DHA) plays a protective role in various chronic diseases. However, whether it can have such effects in IVDD has not been clearly reported. In recent years, in-depth research on the role of long non-coding RNA (lncRNA) nuclear-enriched transcript 1 (NEAT1) in various diseases has continuously emerged, but such research in the field of IVD is not sufficient. In this study, tert-butyl hydroperoxide (TBHP) was used to induce oxidative stress in human NP cells and construct a cell model of excessive ECM decomposition in vitro. A plasmid over-expressing lncRNA NEAT1 was introduced into human NP cells to establish an NP cell model. For this specific experiment, Cell Counting Kit 8 was used to explore the timing and concentration of DHA and TBHP activity. A common gene chip platform was also used to select potential lncRNAs. Western blot and immunofluorescence assays were used to detect the expression of ECM-related proteins in NP cells in each group. Quantitative real-time polymerase chain reaction was used to detect the expression of lncRNA NEAT1 in NP cells in each group. On this basis, we proved that DHA alleviates excessive degradation of the ECM in NP cells in response to oxidative stress by reducing the content of lncRNA NEAT1. In conclusion, our study reveals the mechanism through which DHA relieves excessive ECM decomposition in NP cells and provides a potential new idea for the treatment of IVDD in clinical practice.

Global population structure and genomic surveillance framework of carbapenem-resistant Salmonella enterica.

Due to the frequent international and intercontinental transmission of multidrug-resistant bacteria, it is imperative to understand the epidemiology, phylogeography, and population structure of carbapenem-resistant Salmonella enterica (CRSE) across the globe. During the period of 2015-2022, two blaNDM-carrying S. enterica strains were recovered from 3695 Salmonella strains in four hospitals in China. The global phylogenetic framework and geographical distribution of CRSE were defined by our recently updated bacterial whole genome sequence typing and source tracking database BacWGSTdb 2.0 to measure the diversity and evolutionary relatedness in context with epidemiological metadata. Phylogeny for all carbapenemase gene-harboring plasmids in S. enterica based on the pairwise Mash differences was also constructed to evaluate the potential transmission of these plasmids in a global context. A large-scale phylogenetic analysis grouped global CRSE into nine distinct clades. The small genetic distance (< 20 SNPs) between 198 pairs of CRSE suggested the presence of clonal transmission. Global CRSE have significant geographical variations, which was associated with the clonal lineages and carbapenemase genes. Carbapenemase gene-carrying plasmids with a high degree of similarity have surfaced in various hosts and countries. The widespread of multiple-replicon plasmids that offer a great capacity to accommodate multiple antimicrobial resistance genes is continuously enhancing the potential risk of CRSE isolates to propagate globally. Both clonal spread of strains and horizontal transfer of carbapenemase gene-harboring plasmids contribute to the global dissemination of CRSE. Our findings on the worldwide spread and transmission dynamics of this emerging bacterium has increased the knowledge of its global epidemics. Continued epidemiological surveillance is necessary to prevent global outbreak of multidrug-resistant Salmonella infections.

Genomic Characterization of a Multidrug-Resistant Escherichia coli Isolate Co-Carrying bla NDM-5 and bla CTX-M-14 Genes Recovered from a Pediatric Patient in China.

Background: Public health is seriously threatened by the rise of carbapenem-resistant Enterobacterales (CRE). However, the genomic characteristics of CRE detected in pediatric patients are largely unknown. Here, we reported the genomic characteristics of a multidrug-resistant Escherichia coli strain containing the plasmid-borne bla NDM-5 and bla CTX-M-14 genes recovered from a Chinese pediatric patient. Methods: The genome sequence of E. coli strain B379 was determined using Illumina NovaSeq 6000 and Oxford Nanopore MinION. Multiple bioinformatics tools were used to annotate the genome sequence, identify antimicrobial resistance genes and plasmid replicons and perform the in silico multilocus sequence typing (MLST) analysis. Using BacWGSTdb 2.0 server, a core genome MLST (cgMLST) comparison was made between E. coli B379 and all ST746 E. coli strains downloaded from the public database. Results: The E. coli B379 genome sequence is comprised of six contigs totaling 5,152,502 bp, including one chromosome and five plasmids. Nineteen antimicrobial resistance genes were predicted. The bla NDM-5, which is located on a 46,161 bp IncX3 plasmid and the bla CTX-M-14 gene which is located on a 147,204 bp IncFII/IncFIA/IncFIB plasmid are two examples of these 19 genes. E. coli B379 was resistant to ampicillin, ampicillin/sulbactam, ceftriaxone, ceftazidime, imipenem, cefepime, ciprofloxacin, ertapenem, trimethoprim-sulfamethoxazole. This isolate belonged to ST746 and the closest relative was another one originating from a human material specimen in Denmark, which differed by 273 cgMLST alleles. Conclusion: Our study reports the emergence of a multidrug-resistant E. coli strain co-carrying bla NDM-5 and bla CTX-M-14 recovered from a pediatric patient in China. These data would help us better understand the prevalence, genetic characteristics, and mechanisms of antimicrobial resistance of this recently identified multidrug-resistant bacteria in children.

The efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as first-line treatment for extensive-stage small cell lung cancer: A Chinese multicenter real-world study.

Background: Patients with extensive-stage small-cell lung cancer (ES-SCLC) have high recurrence rates and bleak prognosis. This multicenter real-world study aimed to explore the efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment of ES-SCLC. Methods: Pathologically confirmed ES-SCLC patients receiving anlotinib plus platinum-etoposide chemotherapy as the first-line treatment were enrolled in this retrospective study. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions. The Cox regression analyses were employed to investigate the independent prognostic factors for OS and PFS of these individuals. Results: In total, 58 patients were included in this study. The median PFS was 6.0 months [95% confidence interval (CI): 3.5-8.5], and the median OS was 10.5 months (95%CI 8.7-12.3). Thirty-four patients achieved partial response (PR), 18 patients achieved stable disease (SD), and 6 patients achieved progressive disease (PD). The ORR and DCR were 58.6% and 89.6%. The main treatment-related adverse reactions were generally tolerated. Myelosuppression (44.8%) was the most common adverse reaction, followed by hypertension (41.4%), fatigue (34.5%), gastrointestinal reaction (32.7%), and hand-foot syndrome (24.1%). Multivariate analysis showed that post-medication hand-foot syndrome [PFS 8.5 vs. 5.5 months, Hazards Ratio (HR)=0.23, 95%CI 0.07-0.72, P =0.012] was the independent predictor of PFS, and hypertension (OS 15.9 vs. 8.3 months, HR=0.18, 95%CI 0.05-0.58, P =0.005) was the independent predictor of OS. Conclusion: Anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC appears to be effective and well-tolerated in the real-world. Well-designed large-scale prospective studies are urgently needed in the future to verify our findings.

Genomic Characterization of a Clinical Listeria monocytogenes ST1 Isolate Recovered from the Blood Sample of a Woman with Third Trimester Stillbirth.

Background: Listeria monocytogenes is a foodborne gram-positive bacterium which causes adverse pregnancy outcomes. Here, the genomic and phylogenetic characteristics of a L. monocytogenes isolate obtained from blood sample of a third trimester pregnant woman with stillbirth are investigated. Methods: Whole genome DNA of L. monocytogenes ST1 was sequenced with HiSeq X Ten platform. The NCBI Prokaryotic Genome Annotation Pipeline was used to annotate the genome sequence. The sequence type (ST) and antimicrobial resistance genes were then identified. The core genome multilocus sequence typing (cgMLST) analysis with other closely related L. monocytogenes stored in the NCBI GenBank database was performed using BacWGSTdb 2.0. Results: The complete genome sequence of L. monocytogenes ST1 is made up of 20 contigs totaling 2,914,725 bp, with 2886 protein-coding sequences and a GC content of 37.9%. Fosfomycin [fosX], Lincosamide antibiotic [lin] and peptide antibiotic [mprF] were discovered as antimicrobial resistance genes. In silico serogroup typing prediction revealed that L. monocytogenes ST1 belonged to serotype IVb. The closest relative of L. monocytogenes ST1, obtained from Poland in 2015, differs by only 15 cgMLST alleles. Conclusion: We identified a L. monocytogenes ST1 strain from blood sample of a woman with third trimester stillbirth in China. These discoveries would aid in our understanding of the genomic characteristics, mechanisms of antimicrobial resistance, and epidemiological features of this pathogen.

The Efficacy and Safety of Anlotinib in Extensive-Stage Small Cell Lung Cancer: A Multicenter Real-World Study.

Purpose: Anlotinib, an antiangiogenic multi-target tyrosine kinase inhibitor (TKI), has shown favorable anticancer efficacy and acceptable safety in treating extensive-stage small cell lung cancer (ES-SCLC) in some clinical studies. This research aimed to explore the real-world efficacy and safety of anlotinib in ES-SCLC. Methods: Pathologically confirmed ES-SCLC patients receiving anlotinib were enrolled for this retrospective study. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions. Results: In total, 202 patients were included in this study. The median PFS of all patients was 4.8 months [95% confidence interval (CI): 3.9-5.7], and the median OS was 7.6 months (95% CI 6.5-8.7). Respectively, the overall ORR and DCR were 30.2% and 87.1%. The univariate and multivariate Cox regression analyses revealed that patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1, plus chemotherapy or immunotherapy, plus radiotherapy, and post-medication hypertension might have longer PFS and OS. The PFS and OS were significantly prolonged in combination group than that in monotherapy group [PFS 6.0 vs 3.6 months, hazards ratio (HR)=0.49, 95% CI 0.34-0.70, P < 0.001; OS 9.2 vs 4.8 months, HR = 0.48, 95% CI 0.32-0.72, P < 0.001]. The main treatment-related adverse reactions were generally tolerated. The incidence of adverse reactions in combination group was higher than that in monotherapy group (75.0% vs 52.6%, P = 0.001). The most common adverse reaction was hypertension, followed by hand-foot syndrome and fatigue, regardless of monotherapy or combination group. Conclusion: Anlotinib is effective and well tolerated in patients with ES-SCLC in the real-world. The clinical efficacy of anlotinib combined with chemotherapy or immunotherapy is better than that of monotherapy. Further investigations are needed for prospective studies with larger sample size.