Anlotinib in recurrent or metastatic endometrial cancer.

OBJECTIVE: For recurrent or metastatic endometrial cancer after second-line treatment, therapeutic options are limited. Anlotinib is a new multi-targeted tyrosine kinase inhibitor of tumor angiogenesis and growth. The aim of this study was to explore the efficacy and safety of anlotinib in patients with recurrent or metastatic endometrial cancer. METHODS: Patients with recurrent or metastatic endometrial cancer who received anlotinib or anlotinib plus pembrolizumab after second-line treatment between July 2017 and October 2020 were analyzed. Objective response rate, disease control rate, progression-free survival, overall survival, and safety were evaluated. RESULTS: A total of 56 patients were analyzed. The median age was 62 years (range 42-80). The median treatment of anlotinib was 5.9 cycles (range 2-21). The overall objective response rate was 42.9%, and the disease control rate was 75%. 44 (78.6%) patients received anlotinib monotherapy and 12 (21.2%) patients received anlotinib plus pembrolizumab. The objective response rate was 40.9% versus 50% (p=0.52) and the disease control rate was 72.7% versus 83.3% (p=0.59) in the monotherapy group and the combination therapy group, respectively. The median progression-free survival and overall survival from initiation of anlotinib therapy was 6 months (95% CI 4.89 to 7.11) and 13.3 months (95% CI 9.94 to 16.61), respectively. On multivariable Cox analysis, age (>60 vs ≤60 years) was an independent impact factor for both progression-free survival and overall survival, while prior lines of treatment (2 lines vs ≥3 lines) was an independent predictor of progression-free survival. The incidences of grade 3/4 adverse events were hypertension (10.7%), fatigue (7.1%), hand-foot syndrome (7.1%), proteinuria (3.6%), sore throat (3.6%), and hypothyroidism (3.6%). CONCLUSION: Anlotinib is effective and well tolerated in patients with recurrent or metastatic endometrial cancer. It may be considered a choice for patients younger than 60 years and who have had <3 lines of treatment.

[Study on Inhibitory Effect of Aqueous Extract of Taxus Chinensis var. mairei Combined Erlotnib on A549 Xenograft in Nude Mice and Its Mechanism].

OBJECTIVE: To study the effect of aqueous extract of Taxus chinensis var. mairei (AETC) combined Erlotnib on the growth of A549 xenograft in nude mice and its mechanism. METHODS: The xenograft model in nude mice was established by inoculating A549 cells subcutaneously. BALB/c nude mice bearing A549 xenograft were randomly divided into six groups, i.e., the low dose Erlotinib group (A) , the standard dose Erlotnib group (B) , the low dose Erlotinib combined AETC group (C), the standard dose Erlotnib combined AETC group (D), the AETC group (E), the control group (F), 12 in each group. Different medication was performed for 7 successive weeks after 24 h. One mL blood was withdrawn and tumor tissues taken. The tumor inhibition rate was calculated. The combined effect was analyzed by Jin's Formula [Q = Ea + b/(Ea + Eb-Ea x Eb) ]. mRNA and protein expression levels of epidermal growth factor receptor (EGFR), cyclooxygenase-2 (COX-2), and B cell lymphoma-2 (Bcl-2) in xenografts were detected using real-time RT-PCR and ELISA. RESULTS: Compared with Group F, the xenograft weight was obviously lowered in Group B-E (P < 0.05, P < 0.01). The q value was 0.92 in Group C and 0.96 in Group D, which was obtained by simple adding of the two drugs. Compared with Group F, EG- FR mRNA expression in Group D and E, COX-2 mRNA expression in Group A-E; Bcl-2 mRNA expression in Group B-D; COX-2 protein expression in Group B-E; Bcl-2 protein expression in Group C and D were obviously lowered with statistical difference (P < 0.05, P < 0.01). CONCLUSIONS: AETC combined low dose and standard dose Erlotinib had synergistic effect on tumor inhibition. Its mechanism might be associated with down-regulating mRNA and protein expression levels of COX-2 and Bcl-2.

Aqueous extract of Taxus chinensis (Pilger) Rehd inhibits lung carcinoma A549 cells through the epidermal growth factor receptor/mitogen-activated protein kinase pathway in vitro and in vivo.

OBJECTIVE: To explore the anticancer mechanism of aqueous extract of Taxus Chinensis (Pilger) Rehd (AETC). METHODS: The serum pharmacological method was used to avoid interference from administration of the crude medicinal herbs. Eight purebred New Zealand rabbits were used for preparation of serum containing various concentrations of AETC. Forty-eight Balb/c-nu mice were used for in vivo experiments. The effects of serum containing AETC on the proliferation of A549 cells and expression levels of the epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) pathway-related proteins in vitro were investigated. Additionally, the effects on the growth of A549 xenografts in nude mice, and expression levels of the EGFR/MAPK pathway-related proteins in the xenografts, were investigated. RESULTS: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay revealed that the serum containing AETC significantly decreased the viability of A549 cells in a dose-dependent manner. Western blot showed that the serum containing various concentrations of AETC strongly reduced the levels of phospho-Jun N-terminal kinase (p-JNK) and phospho-extracellular signal-regulated kinasel/2 (ERK1/2) while it increased the level of p-p38. However, no significant effects on the expression levels of JNK, ERK1/2, and p38 MAPK were found. In addition, an anticancer effect from AETC was observed in vivo in the Balb/c-nu mice bearing A549 xenografts. CONCLUSION: AETC has significant effects on the growth of A549 xenografts and on the activity of the EGFR/MAPK pathway. Therefore, AETC may be beneficial in lung carcinoma treatment.

[Study on inhibitory effect of aqueous extract of Taxus chinensis var. mairei on growth of A549 lung cancer xenografts in nude mice and its mechanism].

OBJECTIVE: To study the effect of aqueous extract of Taxus chinensis var. mairei (AETC) on the growth of A549 lung cancer xenografts in nude mice and its mechanism. METHOD: The A549 lung cancer xenograft model was established, and then randomly divided into the control group, and low, middle and high dose AETC experiment groups. After 24 hours, they were orally administered with normal saline and drugs of the same volume for seven weeks. The length and width of the xenografts were measured every three days, and the xenograft growth curve was drawn. The nude mice were sacrificed after the administration for seven weeks, and their xenografts were collected to cultivate the anti-tumor rate. Real-time PCR and Western-blot were adopted to detect mRNA and protein levels. RESULT: All of AETC experiment groups showed a significant anti-tumor effect (P < 0.05). Compared with the control group, each experimental group showed notable reduction in EGFR and Survivin mRNA in xenograft tissues (P < 0.05), with no significant change in VEGF mRNA level. The analysis on gray value ratio showed that EGFR mRNA were down-regulated (P < 0.05) in xenograft tissues in all experimental groups, but with no statistical significance in difference, and Survivin and p-EGFR were significantly down-regulated. CONCLUSION: AETC has not significant effect on angiogenesis, but may have the inhibitory effect on xenograft growth by inhibiting Survivin protein and EGFR phosphorylation.

Nanodrugs systems for therapy and diagnosis of esophageal cancer.

With the increasing incidence of esophageal cancer, its diagnosis and treatment have become one of the key issues in medical research today. However, the current diagnostic and treatment methods face many unresolved issues, such as low accuracy of early diagnosis, painful treatment process for patients, and high recurrence rate after recovery. Therefore, new methods for the diagnosis and treatment of esophageal cancer need to be further explored, and the rapid development of nanomaterials has brought new ideas for solving this problem. Nanomaterials used as drugs or drug delivery systems possess several advantages, such as high drug capacity, adjustably specific targeting capability, and stable structure, which endow nanomaterials great application potential in cancer therapy. However, even though the nanomaterials have been widely used in cancer therapy, there are still few reviews on their application in esophageal cancer, and systematical overview and analysis are deficient. Herein, we overviewed the application of nanodrug systems in therapy and diagnosis of esophageal cancer and summarized some representative case of their application in diagnosis, chemotherapy, targeted drug, radiotherapy, immunity, surgery and new therapeutic method of esophageal cancer. In addition, the nanomaterials used for therapy of esophageal cancer complications, esophageal stenosis or obstruction and oesophagitis, are also listed here. Finally, the challenge and the future of nanomaterials used in cancer therapy were discussed.

Key Targets and Molecular Mechanisms of Active Volatile Components of Rabdosia rubescens in Gastric Cancer Cells.

OBJECTIVE: To examine the effect and mechanism of volatile components of Rabdosia rubescens on gastric cancer. METHODS: Gas chromatography-mass spectrometry was used to detect and identify the volatile components of R. rubescens. The network pharmacology method was used to analyze the targets of volatile components of R. rubescens in gastric cancer and to reveal their molecular mechanisms. The effects of volatile components of R. rubescens on gastric cancer cells were verified by biological experiments. RESULTS: Thirteen volatile components of R. rubescens were selected as pharmacologically active components. The 13 active components had 83 targets in gastric cancer, and a Traditional Chinese Medicine-component-targets gastric cancer network was successfully constructed. Five core targets were obtained: TNF, IL1B, MMP9, PTGS2 and CECL8. The volatile components inhibited the proliferation of gastric cancer cells in a concentration-dependent manner and promoted the apoptosis of gastric cancer cells. The volatile components reduced the levels of TNF, IL1B, MPP9, and PTGS2 in a concentration-dependent manner. CONCLUSION: Our study demonstrates the effects of volatile components in R. rubescens on gastric cancer and provides preliminary findings on their mechanisms of action.

Apatinib combined with PD-1 antibody for third-line or later treatment of advanced gastric cancer.

Background: Both apatinib and programmed death 1 (PD-1) monoclonal antibody (mAb) monotherapy have been licensed in China for the third-line treatment of advanced gastric cancer (AGC). However, whether the combination could improve the prognosis of patients with AGC after second-line treatment has not been evaluated. Methods: We retrospectively screened 892 patients with AGC who received third-line or later treatment from June 2016 to July 2021 at the Affiliated Cancer Hospital of Zhengzhou University and second People's Hospital of Pingdingshan. 166 patients who received apatinib plus PD-1 mAb, apatinib, or PD-1 mAb were included. Based on medical records and follow-up data, we analyzed the efficacy and safety of these three treatment options. Results: Patients received apatinib plus PD-1 mAb (n=49), apatinib monotherapy (n=63), or PD-1 mAb monotherapy (n=54). Apatinib plus PD-1 mAb showed significantly longer progression-free survival (PFS) and overall surivival (OS) compared with the apatinib monotherapy (PFS: 5.5 months versus 3.0 months; p=0.002; OS: 10 months versus 7.6 months; p=0.011) or PD-1 mAb monotherapy (PFS: 5.5 months versus 2.3 months; p=0.017; OS: 10 months versus 6.5 months; p=0.004). Apatinib plus PD-1 mAb showed higher ORR and DCR than the apatinib and PD-1 mAb monotherapy (ORR: 34.7% versus 6.3% versus 9.3%; p=0.001; DCR: 75.5% versus 44.4% versus 40.7%; p=0.001). Further subgroup analysis for PFS and OS shown consistent efficacy in most subgroups with apatinib plus PD-1 mAb versus apatinib monotherapy or PD-1 mAb monotherapy. Multivariate analyses suggested that apatinib plus PD-1 mAb was significantly associated with better PFS and OS. Most of the treatment-related toxicities were mild and tolerable. Conclusion: Compared with the monotherapy of either apatinib or PD-1 mAb, apatinib plus PD-1 mAb treatment yielded longer PFS and OS, and achieved significant higher ORR and DCR.

Identification of Benign and Malignant Lung Nodules in CT Images Based on Ensemble Learning Method.

BACKGROUND AND OBJECTIVE: Under the background of urgent need for computer-aided technology to provide physicians with objective decision support, aiming at reducing the false positive rate of nodule CT detection in pulmonary nodules detection and improving the accuracy of lung nodule recognition, this paper puts forward a method based on ensemble learning to distinguish between malignant and benign pulmonary nodules. METHODS: Firstly, trained on a public data set, a multi-layer feature fusion YOLOv3 network is used to detect lung nodules. Secondly, a CNN was trained to differentiate benign from malignant pulmonary nodules. Then, based on the idea of ensemble learning, the confidence probability of the above two models and the label of the training set are taken as data features to build a Logistic regression model. Finally, two test sets (public data set and private data set) were tested, and the confidence probability output by the two models was fused into the established logistic regression model to determine benign and malignant pulmonary nodules. RESULTS: The YOLOv3 network was trained to detect chest CT images of the test set. The number of pulmonary nodules detected in the public and private test sets was 356 and 314, respectively. The accuracy, sensitivity and specificity of the two test sets were 80.97%, 81.63%, 78.75% and 79.69%, 86.59%, 72.16%, respectively. With CNN training pulmonary nodules benign and malignant discriminant model analysis of two kinds of test set, the result of accuracy, sensitivity and specificity were 90.12%, 90.66%, 89.47% and 88.57%, 85.62%, 90.87%, respectively. Fused model based on YOLOv3 network and CNN is tested on two test sets, and the result of accuracy, sensitivity and specificity were 93.82%, 94.85%, 92.59% and 92.31%, 92.68%, 91.89%, respectively. CONCLUSION: The ensemble learning model is more effective than YOLOv3 network and CNN in removing false positives, and the accuracy of the ensemble. Learning model is higher than the other two networks in identifying pulmonary nodules.

A Retrospective Observational Study of Anlotinib in Patients with Platinum-Resistant or Platinum-Refractory Epithelial Ovarian Cancer.

OBJECTIVE: Anlotinib, an oral small-molecular tyrosine kinase inhibitor (TKI) on tumor angiogenesis and growth, has a wide spectrum of inhibitory effects on targets such as vascular endothelial growth factor receptors 2/3 (VEGFR2/3), etc. The efficacy and safety of anlotinib in the treatment of platinum-resistant or platinum-refractory ovarian cancer were evaluated. PATIENTS AND METHODS: Patients with platinum-resistant or platinum-refractory ovarian cancer that treated with anlotinib in the Affiliated Cancer Hospital of Zhengzhou University from May 2018 to March 2020 were included. Medical records were reviewed in terms of objective response, survival outcomes, and safety. RESULTS: A total of 38 patients were analyzed. The median progression-free survival and the median overall survival were 7.7 months (95% CI: 6.7-8.7) and 16.5 months (95% CI: 13.3-19.7), respectively. About 17 patients received anlotinib monotherapy, and the median progression-free survival was 7.7 months (95% CI: 6.3-9.1). A total of 19 cases received anlotinib plus chemotherapy with a median progression-free survival of 8.0 months (95% CI: 4.8-11.2). A total of 2 cases received anlotinib plus anti-PD-1 antibody pembrolizumab, and 1 case had partial response, the other progressive disease. The objective response rate was 42.1% while the disease control rate was 86.8%. A total of 5 patients experienced dose reduction from 12 mg to 10 mg because of adverse effects. The most common adverse effects were hypertension (31.6%), fatigue (28.9%), anorexia (26.3%) and hand-foot syndrome (23.7%). No treatment-related deaths were recorded. CONCLUSION: Anlotinib produced moderate improvements in progression-free survival and overall survival in patients with platinum-resistant or platinum-refractory ovarian cancer. It indicates that anlotinib maybe a new treatment option for patients with platinum-resistant or platinum-refractory ovarian cancer.

Osimertinib Rechallenge With Bevacizumab vs. Chemotherapy Plus Bevacizumab in EGFR-Mutant NSCLC Patients With Osimertinib Resistance.

At present, treatment options for osimertinib resistance are very limited. Dual inhibition of the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) significantly improved the progression-free survival (PFS) of advanced EGFR-mutant non-small cell lung cancer (NSCLC). After EGFR-tyrosine kinase inhibitor (TKI) resistance, EGFR-TKI continuation combined with VEGF inhibitors still had clinical benefits. It is unclear whether the addition of bevacizumab after osimertinib progresses will prolong the duration of the osimertinib benefit. We screened 1289 patients with NSCLC and finally included 96 patients to evaluate osimertinib combined with bevacizumab (osi + bev) versus chemotherapy combined with bevacizumab (che + bev) for patients with acquired resistance to osimertinib. The overall response rate (ORR) for osi + bev and chem + bev was 15.8% (6 of 38) and 20.7% (12 of 58), respectively. The median PFS for osi + bev and che + bev was 7.0 and 4.9 months (HR 0.415 95%CI: 0.252-0.687 p = 0.001). The median OS for osi + bev and che + bev was 12.6 and 7.1 months (HR 0.430 95%CI: 0.266-0.696 p = 0.001). Multivariate analyses showed that no brain metastases and osi + bev treatment after osimertinib resistance correlated with longer PFS (p = 0.044, p = 0.001), while the median PFS of osimertinib less than 6 months (p = 0.021) had a detrimental effect on sequent treatment. Only osi + bev treatment was identified as an independent predictor of OS (p = 0.001). The most common adverse events (AEs) of grade ≥3 were hypertension (13.2%) and diarrhea (10.5%) in the osi + bevacizumab group. Neutropenia (24.1%) and thrombocytopenia (19%) were the most common grade ≥3 AEs in the che + bev group. The overall incidence of serious AEs (grade ≥3) was significantly higher in the chemotherapy plus bevacizumab group. Our study has shown the superiority of osi + bev compared to che + bev after the failure of osimertinib, making it a preferred option for patients with acquired resistance to osimertinib.

In situ decorated Au NPs on chitosan-encapsulated Fe3O4-NH2 NPs as magnetic nanocomposite: Investigation of its anti-colon carcinoma, anti-gastric cancer and anti-pancreatic cancer.

Chitosan is a linear polysaccharide and non-toxic bioactive polymer with a wide variety of applications due to its functional properties such as ease of modification, and biodegradability. In this investigation, magnetic cores (Fe3O4) were synthesized using a fabrication method involving coprecipitation of Fe2+ and Fe3+. Then the magnetic nanoparticles were encapsulated by chitosan layers. In the next step, magnetite-gold composite nanoparticles were synthesized with spherical shapes and sizes ranging from 20 to 30 nm, using sodium citrate as a natural reducing agent. The morphological and physicochemical features of the material were determined using several advanced techniques like FT-IR, ICP analysis, FESEM, EDS, XRD, TEM, XPS and VSM. In the biological part of the present study, the cell viability of Fe3O4, HAuCl4, and Fe3O4@CS/AuNPs was very low against human colorectal carcinoma cell lines i.e. Ramos.2G6.4C10, HCT-8 [HRT-18], HCT 116, and HT-29, human gastric cancer cell lines i.e. MKN45, AGS, and KATO III, and human pancreatic cancer cell lines i.e. PANC-1, AsPC-1, and MIA PaCa-2. The IC50 of Fe3O4@CS/AuNPs against Ramos.2G6.4C10, HCT-8 [HRT-18], HCT 116, HT-29, MKN45, AGS, KATO III, PANC-1, AsPC-1, and MIA PaCa-2 cell lines were 385, 429, 264, 286, 442, 498, 561, 513, 528, and 425 µg/mL, respectively. Thereby, the best cytotoxicity results of our Fe3O4@CS/AuNPs were observed in the case of the HCT 116 cell line. Seemingly, the present nanoparticles may be used for the treatment of several types of gastro-duodenal cancers especially colon, gastric, and pancreatic cancers in near future.