PARP1 promotes EGFR-TKI drug-resistance via PI3K/AKT pathway in non-small-cell lung cancer.

PURPOSE: Tyrosine kinase inhibitor (TKI) resistance is the main type of drug resistance in lung cancer patients with epidermal growth factor receptor (EGFR) mutations, but its underlying mechanism remains unclear. The purpose of this work was to investigate the mechanism by which PARP1 regulates EGFR-TKI resistance to identify potential targets for combating drug resistance. METHODS: The GEO databases, TCGA databases, western blot and qPCR studies were used to investigate the expression of PARP1 in lung cancer cells and tissues and its correlation with the prognosis of lung cancer. The expression of PARP1 in lung cancer TKI resistant cell PC9-ER and TKI sensitive cell PC9 was analyzed by qPCR and western blot. After knocking down of PARP1, CCK-8 assays, colony formation, flow cytometry were used to investigate its impact on erlotinib sensitivity, cell survival, cell cycle, and apoptosis. RNA-seq was used to investigate the mechanism by which PARP1 participates in EGFR-TKI resistance, and the results were validated in vitro and in vivo studies. RESULTS: PARP1 was highly expressed in both lung cancer tissues and cells. Subsequently, increased PARP1 expression was observed in PC9-ER compared with its parental cell line. Knockdown of PARP1 increased erlotinib sensitivity, promoted cell apoptosis, and suppressed cell growth. RNA-seq and previous studies have shown that the PI3K/AKT/mTOR/P70S6K pathway is involved in PARP1-mediated TKI resistance, and these results were confirmed by Western blot in vitro and in vivo. CONCLUSION: PARP1 may serve as a potential therapeutic target for reversing EGFR-TKI resistance in NSCLC via the PI3K/AKT/mTOR/P70S6K pathway.

NEAR-INFRARED DYE IR-780 ALLEVIATES HEMATOPOIETIC SYSTEM DAMAGE BY PROMOTING HEMATOPOIETIC STEM CELLS INTO QUIESCENCE.

ABSTRACT: Potential radiation exposure is a general concern, but there still lacks radioprotective countermeasures. Here, we found a small molecular near-infrared dye IR-780, which promoted hematopoietic stem cells (HSCs) into quiescence to resist stress. When mice were treated with IR-780 before stress, increased HSC quiescence and better hematopoietic recovery were observed in mice in stress conditions. However, when given after radiation, IR-780 did not show obvious benefit. Transplantation assay and colony-forming assay were carried out to determine self-renewal ability and repopulation capacity of HSCs. Furthermore, IR-780 pretreatment reduced the generation of reactive oxygen species (ROS) and DNA damage in HSCs after radiation. In homeostasis, the percentage of Lineage - , Sca-1 + , and c-Kit + cells and long-term HSCs (LT-HSCs) were improved, and more HSCs were in G0 state after administration of IR-780. Further investigations showed that IR-780 selectively accumulated in mitochondria membrane potential high LT-HSCs (MMP-high LT-HSCs). Finally, IR-780 promoted human CD34 + HSC reconstruction ability in NOD-Prkdc scid Il2rg null mice after transplantation and improved repopulation capacity in vitro culture. Our research showed that IR-780 selectively entered MMP-high LT-HSCs and promoted them into dormancy, thus reducing hematopoietic injury and improving regeneration capacity. This novel approach might hold promise as a potential countermeasure for radiation injury.

Implication of PD­L1 polymorphisms rs2297136 on clinical outcomes of patients with advanced NSCLC who received PD­1 blockades: A retrospective exploratory study.

Clinically, programmed death-1 (PD-1) blockades have demonstrated promising therapeutic outcomes for patients with advanced non-small cell lung cancer (NSCLC). The present study aimed to examine the impact of programmed death-ligand 1 (PD-L1) polymorphism on clinical outcomes of patients with advanced NSCLC who were treated with PD-1 blockades therapy. The present study was designed as a retrospective analysis, where a consecutive screening of 89 patients with advanced NSCLC who received PD-1 blockades monotherapy were screened. Biological specimens were collected to determine the presence of polymorphism and PD-L1 mRNA expression through genotyping. The analysis focused on examining the relationship between the genotype status of PD-L1 polymorphism and clinical outcomes. Among the 89 patients with advanced NSCLC, the use of PD-1 blockades monotherapy resulted in objective response rate (ORR) of 22.5%, a median progression-free survival (PFS) of 3.4 months [95% Confidence Interval (CI): 1.80-5.00) and a median overall survival (OS) of 11.3 months (95% CI: 7.93-14.67). The analysis of polymorphism indicated that only rs2297136 had clinical significance. Among the 89 patients with NSCLC, the prevalence of rs2297136 was as follows: A total of 58 cases (65.2%) had the AA genotype, 28 cases (31.5%) had the AG genotype and 3 cases (3.4%) had the GG genotype. This resulted in a minor allele frequency of 0.19, which was in consistent with Hardy-Weinberg Equilibrium (P=0.865). The correlation analysis between genotype status of rs2297136 and clinical outcomes indicated that patients with the AA genotype had an ORR of 19.0%, while those with the AG/GG genotype had an ORR of 29.0% (P=0.278). Additionally, the median PFS for the AA genotype was 2.95 months, compared with 5.30 months for the AG/GG genotype (P=0.038). Accordingly, median OS of the AA and AG/GG genotypes was 8.8 and 18.4 months, respectively (P=0.011). The mRNA expression of PD-L1 was significantly higher in patients with AG/GG genotype compared with those with AA genotype (P<0.001). In clinical practice, PD-1 blockades demonstrated promising effectiveness in treating patients with advanced NSCLC. The presence of the rs2297136 variant in PD-L1 gene could potentially be used as a biomarker to predict the clinical outcomes of PD-1 blockades.

Identification and validation of basic fibroblast growth factor as a prognostic biomarker for the response of lung adenocarcinoma patients to bevacizumab treatment.

Basic fibroblast growth factor (bFGF) stimulates angiogenesis, influencing the proliferation, migration, and survival of tumour cells, which have pivotal roles in tumour progression. This study investigated the prognostic significance of bFGF expression in lung adenocarcinoma treated with bevacizumab. The expression levels of bFGF were assessed in bevacizumab-treated patients with lung adenocarcinoma using immunohistochemistry. Propensity score matching (PSM) analysis was performed to evaluate prognostic potential. bFGF expression was also investigated in another independent cohort of patients with lung adenocarcinoma treated with routinechemotherapy. We also compared the PSM value of bFGF expression levels independently and in combination with epidermal growth factor receptor and vascularendothelial growth factor expression levels. A high bFGF expression level was found to be an independent prognostic factor for disease-free survival in patients receiving bevacizumab-based chemotherapy. Similar results were not observed in patients who underwent routinechemotherapy. In conclusion, the bFGF expression level may be a clinically feasible prognostic marker and bFGF is a potential therapeutic target for patients with lung adenocarcinoma receiving routinechemotherapy.

Inhibition of CARM1 suppresses proliferation of multiple myeloma cells through activation of p53 signaling pathway.

BACKGROUND: Multiple myeloma (MM) is a malignant proliferative disease of plasma cells, the incidence of which is increasing every year and remains incurable. The enzyme co-activator-associated arginine methyltransferase 1 (CARM1) is highly expressed in a variety of cancers, such as Hodgkin's lymphoma and acute myeloid leukemia, and CARM1 is closely associated with tumor cell proliferation. However, the role of CARM1 in MM has not been elucidated. METHODS AND RESULTS: In this study, we found that CARM1 is overexpressed in MM and closely associated with poor prognosis in MM. CCK-8 and colony formation assays showed that the proliferation of MM cell lines was downregulated when CARM1 expression was knockdown by specific shRNA. Knockdown of CARM1 reduced the proportion of MM cell lines in the S phase and increased the proportion in G0/G1 phase. RNA-seq analysis of the CARM1-KD cell line revealed that it was closely associated with apoptosis and activated the p53 pathway. CCK-8 and apoptosis results showed that CARM1 knockdown made MM cells more sensitive to standard-of-care drugs. CONCLUSION: This study provides an experimental basis for elucidating the pathogenesis of multiple myeloma and searching for potential therapeutic targets.

A novel report of Cys1298Gly mutation in exon 24 of NOTCH3 gene in a Chinese family with CADASIL.

OBJECTIVES: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is the most common monogenic hereditary small cerebral vessel disease, which is caused by mutation of the neurogenic locus notch homolog protein 3 gene (NOTCH3). The exon 24 encodes EGF-like repeats, variants on this exon are rare. Here, we report a novel heterozygous variant c.3892 T >G (p. Cys1298Gly) on exon 24 of NOTCH3 gene in a 57-year-old Chinese woman. MATERIALS AND METHODS: We present a patient with clinical manifestations, laboratory examination and imaging reveal suspicion of CADASIL. The family and genetic test and pathological examination were performed. RESULTS: Magnetic resonance imaging revealed diffuse leukoencephalopathy with hyperintense signals in the bilateral temporal poles, periventricular white matter, centrum semiovale, basal ganglia, frontal and parietal cortex and subcortical areas bilaterally. Molecular Genetic testing identified a heterozygous variant c.3892 T >G (p. Cys1298Gly) on exon 24 of NOTCH3 gene. Her brother and his son were confirmed as subclinical carriers of the variant. The skin biopsy was negative, but the pathologic role of this mutation is predicted by using the DynaMut database and results showed the stability of the NOTCH gene is decreased. CONCLUSIONS: To the best of our knowledge, this is the second case of exon 24 mutations reported from China and the variant of c.3892 T >G (p. Cys1298Gly) on exon 24 of NOTCH3 has not been reported so far. Our report broadens the mutation spectrum of the NOTCH3 gene in CADASIL.

Recent advances and challenges in primary central nervous system lymphoma: a narrative review.

Background and Objective: Primary central nervous system lymphoma (PCNSL) is a rare and highly invasive non-Hodgkin lymphoma that is challenging to diagnose and treat. It is typically confined to the brain, spinal cord, and eyes. The diagnosis of PCNSL lacks specificity, and the misdiagnosis and missed diagnosis rates of PCNSL are high. Traditional treatments for PCNSL, such as surgery, whole-brain radiation therapy, high-dose methotrexate-based chemotherapy, and rituximab (RTX), have been associated with higher initial remission rates. However, the duration of any remission is short, the recurrence rate is high, and treatment-related neurotoxicity is strong, which are challenges for medical researchers. This review provides an overview of and perspectives on the diagnosis, treatment, and evaluation of patients with PCNSL. Methods: The PubMed database was searched to retrieve articles published from January 1, 1991, to June 2, 2022 using the following Medical Subject Headings (MeSH) terms: "Primary central nervous system lymphoma" and "clinical trial". The American Society of Clinical Oncology and the National Comprehensive Cancer Network guidelines were also reviewed to obtain additional information. The search was limited to articles published in English, German, and French. In total, 126 articles were deemed eligible for inclusion in this study. Key Content and Findings: In terms of the diagnosis of PCNSL, a combination of flow cytometry and cytology has been shown to improve the diagnostic accuracy of PCNSL. Additionally, interleukin 10 and chemokine C-X-C motif ligand 13 are promising biomarkers. In terms of the treatment of PCNSL, programmed death-1 (PD-1) blockage and chimeric antigen receptor T cell (CAR-T) therapy treatments have shown prospective efficacy, but more clinical trials need to be conducted to gather further evidence. We also reviewed and summarized prospective clinical trials on PCNSL. Conclusions: PCNSL is a rare and highly aggressive lymphoma. The treatment of PCNSL has progressed significantly, and while the survival of patients has improved, relapse and low long-term survival remain huge challenges. Continuous in-depth research is being conducted on new drug therapies and combination therapies for PCNSL. A combination of targeted drugs (e.g., ibrutinib, lenalidomide, and PD-1 monoclonal antibody) and traditional therapy represents the main research direction for future PCNSL treatments. CAR-T has also shown great potential in the treatment of PCNSL. With the development of these new diagnostic and therapeutic methods and further research into the molecular biology of PCNSL, patients with PCNSL should achieve a better prognosis.

Cold atmospheric plasma alleviates radiation-induced skin injury by suppressing inflammation and promoting repair.

Currently, there is no effective treatment for chronic skin radiation injury, which burdens patients significantly. Previous studies have shown that cold atmospheric plasma has an apparent therapeutic effect on acute and chronic skin injuries in clinical. However, whether CAP is effective for radiation-induced skin injury has not been reported. We created 35Gy X-ray radiation exposure within 3 * 3 cm2 region of the left leg of rats and applied CAP to the wound bed. Wound healing, cell proliferation and apoptosis were examined in vivo or vitro. CAP alleviated radiation-induced skin injury by enhancing proliferation and migration and cellular antioxidant stress and promoting DNA damage repair through regulated nuclear translocation of NRF2. In addition, CAP inhibited the proinflammatory factors' expression of IL-1ß, TNF-α and temporarily increased the pro repair factor's expression of IL-6 in irradiated tissues. At the same time, CAP also changed the polarity of macrophages to a repair-promoting phenotype. Our finding suggested that CAP ameliorated radiation-induced skin injury by activating NRF2 and ameliorating the inflammatory response. Our work provided a preliminary theoretical foundation for the clinical administration of CAP in high-dose irradiated skin injury.

Wuzi Yanzong Pill protects neural tube defects by activating PI3K/Akt signaling pathway.

Neural tube defects (NTDs) are severe congenital malformations that can lead to lifelong disability. Wuzi Yanzong Pill (WYP) is an herbal formula of traditional Chinese medicine (TCM) that has been shown to have a protective effect against NTDs in a rodent model induced by all-trans retinoic acid (atRA), but the mechanism remains unclear. In this study, the neuroprotective effect and mechanism of WYP on NTDs were investigated in vivo using an atRA-induced mouse model and in vitro using cell injury model induced by atRA in Chinese hamster ovary (CHO) cells and Chinese hamster dihydrofolate reductase-deficient (CHO/dhFr) cells. Our findings suggest that WYP has an excellent preventive effect on atRA-induced NTDs in mouse embryos, which may be related to the activation of the PI3K/Akt signaling pathway, improved embryonic antioxidant capacity, and anti-apoptotic effects, and this effect is not dependent on folic acid (FA). Our results demonstrated that WYP significantly reduced the incidence of NTDs induced by atRA; increased the activity of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and content of glutathione (GSH); decreased the apoptosis of neural tube cells; up-regulated the expression of phosphatidylinositol 3 kinase (PI3K), phospho protein kinase B (p-Akt), nuclear factor erythroid-2 related factor (Nrf2), and b-cell lymphoma-2 (Bcl-2); and down-regulated the expression of bcl-2-associated X protein (Bax). Our in vitro studies suggested that the preventive effect of WYP on atRA-treated NTDs was independent of FA, which might be attributed to the herbal ingredients of WYP. The results suggest that WYP had an excellent prevention effect on atRA-induced NTDs mouse embryos, which may be independent of FA but related to the activation of the PI3K/Akt signaling pathway and improvement of embryonic antioxidant capacity and anti-apoptosis.

Targeting positive cofactor 4 induces autophagic cell death in MYC-expressing diffuse large B-cell lymphoma.

MYC-expressing diffuse large B-cell lymphoma (DLBCL) is one of the refractory lymphomas. Currently, the pathogenesis of MYC-expressing DLBCL is still unclear, and there is a lack of effective therapy. We characterized positive cofactor 4 (PC4) as an upstream regulator of c-Myc, and PC4 is overexpressed in DLBCL and is closely related to clinical staging, prognosis, and c-Myc expression. Furthermore, our in vivo and in vitro studies revealed that PC4 knockdown can induce autophagic cell death and enhance the therapeutic effect of doxorubicin in MYC-expressing DLBCL. Inhibition of c-Myc-mediated aerobic glycolysis and activation of the AMPK/mTOR signaling pathway are responsible for the autophagic cell death induced by PC4 knockdown in MYC-expressing DLBCL. Using dual-luciferase reporter assay and electrophoretic mobility shift assay assays, we also found that PC4 exerts its oncogenic functions by directly binding to c-Myc promoters. To sum up, our study provides novel insights into the functions and mechanisms of PC4 in MYC-expressing DLBCL and suggests that PC4 may be a promising therapeutic target for MYC-expressing DLBCL.

Erratum: [Corrigendum] Expression of porcine protegrin­1 in Pichia pastoris and its anticancer activity in vitro.

[This corrects the article DOI: 10.3892/etm.2015.2202.].

Genomic profiling identifies distinct genetic subtypes in extra-nodal natural killer/T-cell lymphoma.

Extra-nodal NK/T-cell lymphoma, nasal type (ENKTCL) is a highly aggressive Epstein-Barr virus associated lymphoma, typically presenting in the nasal and paranasal areas. We assembled a large series of ENKTCL (n = 209) for comprehensive genomic analysis and correlative clinical study. The International Lymphoma Prognostic Index (IPI), site of disease, stage, lymphadenopathy, and hepatomegaly were associated with overall survival. Genetic analysis revealed frequent oncogenic activation of the JAK/STAT3 pathway and alterations in tumor suppressor genes (TSGs) and genes associated with epigenomic regulation. Integrated genomic analysis including recurrent mutations and genomic copy number alterations using consensus clustering identified seven distinct genetic clusters that were associated with different clinical outcomes, thus constituting previously unrecognized risk groups. The genetic profiles of ENTKCLs from Asian and Hispanic ethnic groups showed striking similarity, indicating shared pathogenetic mechanism and tumor evolution. Interestingly, we discovered a novel functional cooperation between activating STAT3 mutations and loss of the TSG, PRDM1, in promoting NK-cell growth and survival. This study provides a genetic roadmap for further analysis and facilitates investigation of actionable therapeutic opportunities in this aggressive lymphoma.

Positive Cofactor 4 as a Potential Radiation Biodosimeter for Early Assessment.

During a major radiation event, a large number of people need to be rapidly assessed for radiation damage to ensure effective medical treatment and efficient use of medical resources. However, current techniques cannot meet the requirement of rapid detection of large quantities of samples in an emergency. It is essential to develop rapid and accurate radiation biodosimeters in peripheral blood. Here, we identified radiation sensitive genes in mice by RNA sequencing and evaluated their utility as radiation biodosimeters in human cell lines. Mice were subjected to gamma-irradiation with different doses (0-8 Gy, .85 Gy/min), and the tail venous blood was analyzed by RNA sequencing. We have identified 5 genes with significantly differential expression after radiation exposure. We found that positive cofactor 4(PC4) had well correlation with radiation dose in human lymphoblastoid cell line after irradiation. The relative expression of PC4 gene showed a good linear correlation with the radiation dose after 1-5 Gy irradiation (.85 Gy/min). PC4 gene can be rapidly recruited to the DNA damage sites faster than γ-H2AX after radiation in immunofluorescence detection. In conclusion, PC4 may be represented as new radiation biological dosimeter for early assessment.

Clinical outcomes and safety of osimertinib plus anlotinib for patients with previously treated EGFR T790M-positive NSCLC: A retrospective study.

WHAT IS KNOWN AND OBJECTIVE: Although osimertinib achieved convincing efficacy for patients with EGFR T790M-positive non-small-cell lung cancer (NSCLC) as second-line treatment in the AURA3 clinical trials, patients developed drug resistance ultimately. Therefore, the present study was to investigate the clinical outcome and safety of osimertinib plus anlotinib for patients with previously treated EGFR T790M-positive NSCLC. METHODS: Designed as a retrospective study, this study consecutively included a total of 33 patients with advanced NSCLC who possessed a EGFR T790M-positive mutation and progressed after the first-line therapy. Eligible patients were treated with osimertinib plus anlotinib. Baseline characteristics of the patients were collected during hospitalization. Efficacy of the combination regimen was assessed with the change of target lesion using imaging evidence according to RECIST 1.1 criteria, and all the patients were followed up regularly. Adverse reactions were collected and documented during the treatment. Univariate analysis according to baseline characteristic subgroups was performed using log-rank test, and multivariate analysis was carried out by Cox regression analysis. RESULTS AND DISCUSSION: The best overall response of the patients during osimertinib and anlotinib combination indicated that complete response was found in one patient, partial response was observed in 26 patients, stable disease was noted in 5 patients and progressive disease was reported in one patient. Therefore, objective response rate (ORR) of the combination regimen was 81.8% (95%CI: 64.5%-93.0%), and disease control rate (DCR) was 97.0% (95%CI: 84.2%-99.9%). Furthermore, the median progression-free survival (PFS) of the 33 patients with NSCLC was 15.5 months (95%CI: 6.19-24.81). In addition, the median overall survival (OS) of the 33 patients with NSCLC was 23.8 months (95% CI: 17.67-29.93). Safety profile suggested that the most common adverse reactions of the patients with NSCLC who received anlotinib plus osimertinib were hypertension (63.6%), fatigue (57.6%), diarrhoea (48.5%%), dermal toxicity (39.4%) and proteinuria (33.3%). Interestingly, multivariate Cox regression analysis for PFS demonstrated that ECOG performance status was an independent factor to predict the PFS of the combination regimen. WHAT IS NEW AND CONCLUSION: Osimertinib plus anlotinib regimen preliminarily exhibited encouraging clinical outcomes and acceptable safety profile for patients with previously treated EGFR T790M-positive NSCLC numerically. This conclusion should be validated in prospective clinical trials.

Notch1 Protects against Ischemic-Reperfusion Injury by Suppressing PTEN-Pink1-Mediated Mitochondrial Dysfunction and Mitophagy.

BACKGROUND: Myocardial ischemia/reperfusion injury is associated with adverse cardiovascular outcomes after acute myocardial infarction. However, the molecular mechanism of ischemia/reperfusion injury remains unclear. Mitochondria dysfunction is a participant in and regulator of myocardial ischemia-reperfusion injury. However, the molecular mechanisms involved in this process are not yet fully understood. We previously reported that Notch1 can reduce mitochondrial lysis, reduce myocardial infarct size, and inhibit ventricular remodeling. Herein, we explore the role of the downstream target Notch1 in mitochondrial regulation. METHODS: This study constructs an ischemic/reperfusion injury rat model and a hypoxia/reoxygenation cell model. The expression of PTEN is detected by real-time PCR, Western blot, and immunofluorescence staining. Cell viability is analyzed with CCK-8. Apoptosis level is detected via the TUNEL assay, and mitochondrial fission/fusion is analyzed with MitoTracker Green staining. Cardiac troponin I (cTnI), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and CK levels of creatine kinase-MB (CK) are measured with ELISA kits. RESULTS: We found that PETN-Pink1-Parkin signaling is inhibited by Notch1 I/R in injured neonatal cardiomyocytes and hearts, i.e., via the inhibition of mitochondrial dysfunction and fragmentation. With the recure of PTEN or Pink1, the protective effect of Notch1 was largely diminished. CONCLUSION: These results suggest that N1ICD acts protectively against ischemic reperfusion injury by suppressing PTEN-Pink1-mediated mitochondrial dysfunction and fragmentation.

Early Death and Survival of Patients With Acute Promyelocytic Leukemia in ATRA Plus Arsenic Era: A Population-Based Study.

Most randomized trials for acute promyelocytic leukemia (APL) have investigated highly selected patients under idealized conditions, and the findings need to be validated in the real world. We conducted a population-based study of all APL patients in Zhejiang Province, China, with a total population of 82 million people, to assess the generalization of all-trans retinoic acid (ATRA) and arsenic as front-line treatment. The outcomes of APL patients were also analyzed. Between January 2015 and December 2019, 1,233 eligible patients were included in the final analysis. The rate of ATRA and arsenic as front-line treatment increased steadily from 66.2% in 2015 to 83.3% in 2019, with no difference among the size of the center (≥5 or <5 patients per year, p = 0.12) or age (≥60 or <60 years, p = 0.35). The early death (ED) rate, defined as death within 30 days after diagnosis, was 8.2%, and the 3-year overall survival (OS) was 87.9% in the whole patient population. Age (≥60 years) and white blood cell count (>10 × 109/L) were independent risk factors for ED and OS in the multivariate analysis. This population-based study showed that ATRA and arsenic as front-line treatment are widely used under real-world conditions and yield a low ED rate and a high survival rate, which mimic the results from clinical trials, thereby supporting the wider application of APL guidelines in the future.

Efficacy and Safety of Anlotinib Monotherapy as Third-Line Therapy for Elderly Patients with Non-Small Cell Lung Cancer: A Real-World Exploratory Study.

PURPOSE: The present study was to investigate the real-world efficacy and safety of anlotinib monotherapy as third-line therapy for elderly patients with advanced non-small cell lung cancer (NSCLC). METHODS: A total of 83 elderly patients (>65 years) with NSCLC who were progressed at least two lines of previous systemic therapy were recruited retrospectively. Patients were treated with anlotinib monotherapy (12 mg or 10 mg). Efficacy of anlotinib was assessed and all the patients were followed up regularly. Adverse reactions were collected during anlotinib administration. Univariate analysis was performed using Log rank test and multivariate analysis was adjusted by Cox regression analysis. Additionally, prognostic analysis according to common adverse reactions was implemented to identify the potential clinical significance. RESULTS: The best overall response of the 83 elderly patients during anlotinib monotherapy indicated that partial response (PR) was observed in six patients, stable disease (SD) was noted in 59 patients, and progressive disease (PD) was reported in 18 patients. Consequently, the objective response rate (ORR) was 7.2% (95% CI=2.7-15.1%) and the disease control rate (DCR) was 78.3% (95% CI=67.9-86.6%). The median progression-free survival (PFS) of the 83 elderly patients with NSCLC was 4.2 months (95% CI=3.51-4.89). Furthermore, the median overall survival (OS) of the 83 patients was 9.6 months (95% CI=6.65-12.55). The safety profile suggested that the relatively common adverse reactions of the elderly patients with ES-SCLC receiving anlotinib therapy were hypertension (49.4%), fatigue (45.8%), and hand-foot syndrome (39.8%). Interestingly, association analysis exhibited that the median PFS of patients with hypertension and non-hypertension was 4.5 and 3.0 months, respectively (χ 2=6.306, P=0.012). CONCLUSION: Anlotinib monotherapy demonstrated a satisfactory efficacy and tolerable safety profile in third-line settings for elderly patients with advanced NSCLC. Patients who experienced a hypertension adverse reaction induced by anlotinib therapy might confer superior PFS. The conclusion should be validated in prospective clinical trials subsequently.