Anlotinib in patients with relapsed or refractory thymic epithelial tumors: a study of 50 cases.

The optimal pharmaceutical regimen for advanced thymic epithelial tumors (TETs) remains controversial when first-line chemotherapy fails. This retrospective study aims to evaluate the efficacy and safety of anlotinib treatment for patients with relapsed and refractory TETs. Patients with progressive disease after failure of platinum-based chemotherapy were enrolled in this study. Anlotinib was orally taken once a day at an initial dose of 12 mg (10 mg when body weight <60 kg). The cycle was repeated every 3 weeks (2 weeks of treatment followed by 1-week rest). Objective response rate (ORR) and progression-free survival (PFS) were recorded as primary endpoints. There were 50 patients enrolled in this study from October 2018 to June 2021 at a median age of 50 (range 23-79) years old. Patients with thymoma and thymic carcinoma were 33 (66%) and 17 (34%), respectively. The ORR in thymoma and thymic carcinoma patients were 33% (11/33) and 41% (7/17), respectively. The median PFS (mPFS) was 7 (95% CI, 5.9-10.2) months in thymoma patients and 6 (95% CI, 4.6-9.3) months in the thymic carcinoma group. Eleven patients experienced dose reduction due to toxicities, among whom, eight patients discontinued treatment even after dose reduction. Six patients with thymoma showed myasthenia gravis deterioration during treatment, and two of them died of myasthenia gravis crisis. Anlotinib is active in patients with advanced TETs refractory to routine chemotherapy. Prescription of anlotinib to patients with myasthenia gravis should be made cautiously.

[A study on quality of Paridis Rhizoma and consideration on standards of Paridis Rhizoma in Chinese Pharmacopoeia].

Thin layer chromatography, high performance liquid chromatography and multivariate statistical analysis were integrated in current study to provide a basis for the quality evaluation and the standard improvement of Paridis Rhizoma(Chinese name: Chong-lou). The results demonstrated that the primary saponins in the two authorized sources of Paridis Rhizoma were polyphyllinsⅠ, Ⅱ and Ⅶ, while the rhizome of Trillium tschonoskii an adulterant of Paridis Rhizoma was rich of polyphyllin Ⅵ. Therefore, the apparent content of polyphyllin Ⅵ plays a determinant role towards the source authentication of raw materials and decoction slices of Paridis Rhizoma, whose adulterants frequently occur in the market. Moreover, the contents of polyphyllin Ⅵ in the two authorized sources could meet the requirements of Chinese Pharmacopoeia. Therefore, we suggested that polyphyllin Ⅵ should not be omitted from the quality standard of Paridis Rhizoma in the Chinese Pharmacopoeia, and on the other side, polyphyllinsⅠ, Ⅱ and Ⅶ should be the eligible quality indicators. The study aims to sound information and evidences for the quality evaluation of Paridis Rhizoma, and also to provide a theoretical basis for the standard revision of Paridis Rhizoma in the future Chinese Pharmacopoeia.

[Comparative study on quality of decoction pieces of Saposhnikovia divaricata with different growth patterns and years and thinking of standard of decoction pieces of S. divaricata in Chinese Pharmacopoeia].

This study aims to compare the internal chemical composition and appearance indifferent growth patterns and years of Saposhnikovia divaricata decoction pieces,which was applied to explore the effect of growth patterns and years on its quality. The appearance characteristic data of 55 batches of different growth patterns and years of S. divaricata were collected using PANTONE color card.High performance liquid chromatography( HPLC) was used to determine the contents of prim-O-glucosyl-cinmifugin,cimifugin,4-O-ß-D-glucosyl-5-O-methylvisamminol and sec-O-glucosylhamaudol. The content of alcohol soluble extract and water-soluble extract were determined by hot-dip method. The content of volatile oil was determined by steam distillation. The correlation between growth patterns and years and the contents of 4 chromones,extracts and volatile oil were analyzed by modern statistical methods. Also,the method of comprehensively evaluating the quality of Chinese herbal pieces was developed by combining the growth patterns and years,appearance and chemical indexes. MTT assay was used to evaluate the effects on the survival rate of RAW264. 7 cells at four different concentrations of chromones and LPS was used to stimulate well-growing RAW264. 7 cells to establish an inflammatory model. The contents of NO and TNF-α in cell supernatant were detected by NO test kit and ELISA method. The contents of alcohol soluble extracts and water-soluble extracts in different growth patterns and years are: wild productsperennial cultivation>annual cultivation; the contents of four chromones are: wild products>perennial cultivation and annual cultivation. There was no significant difference between the sum of the two indexes in the Pharmacopoeia of perennial cultivation and wild products. 4 chromones showed no toxicity to RAW264. 7 cells at 5 mg·L-1. The release of NO and TNF-α was inhibited by 4 chromones and the anti-inflammatory effect of cimifugin was the best. In summary,there are obvious differences in appearance characteristics,internal quality and effects between different growth patterns and years. It showed that the wild products were superior to the perennial cultivation and the perennial cultivation was superior to the annual cultivation. In order to alleviate the shortage of wild S. divaricata resources,it is suggested that the Chinese Pharmacopoeia standard should increase the character of decoction pieces of perennial cultivation,and properly raise the limit requirement of the sum of the two indexes in the Chinese Pharmacopoeia to ensure the clinical demands and effect.

Comparative Studies on Chemical Contents and Effect in Kidney-Yang Deficiency Rats of Salt-Processed Product and Wine-Processed Product of Cuscutae Semen.

Cuscutae Semen mainly includes salt-processed product (SPP) and wine-processed product (WPP), which are most commonly used in traditional Chinese medicine. However, the differences between SPP and WPP have not been reported. In this paper, comparative studies between SPP and WPP on chemical contents and effect in kidney-yang deficiency rats have been investigated. UPLC-MS/MS was used to study the differences in chemical components. Kidney-yang deficiency was induced by hydrocortisone in rats. Rats were orally administrated with different doses of Jinkui Shenqi Pills, SPP, and WPP for 28 days. The average organ coefficients, renal function indexes, sex hormone levels, and testicular morphology were detected. As a result, the contents of flavonoids and chlorogenic acids were higher in SPP than in WPP, which may be caused by different processing methods. The improvement on reproduction of SPP was reflected in organ coefficients, renal function indexes, and biochemical properties of seminal plasma; furthermore, WPP was in sex hormone levels and morphology of testis. As a conclusion, these results indicated that both SPP and WPP can improve the reproductive function of kidney-yang deficiency rats with different mechanisms, which may be due to the differences in chemical contents between WPP and SPP as well as different processing methods. It is the first time that the differences between SPP and WPP have been studied in reproductive function in rats with kidney-yang deficiency.

Identifying EGFR mutations in lung adenocarcinoma by noninvasive imaging using radiomics features and random forest modeling.

OBJECTIVES: The tyrosine kinase inhibitor (TKI)-sensitive mutations of the epidermal growth factor receptor (EGFR) gene is essential in the treatment of lung adenocarcinoma. To overcome the difficulty of EGFR gene test in situations where surgery and biopsy samples are too risky to obtain, we tried a noninvasive imaging method using radiomics features and random forest models. METHODS: Five hundred three lung adenocarcinoma patients who received surgery-based treatment were included in this study. The diagnosis and EGFR gene test were based on resections. TKI-sensitive mutations were found in 60.8% of the patients. CT scans before any invasive operation were gathered and analyzed to extract quantitative radiomics features and build random forest classifiers to identify EGFR mutants from wild types. Clinical features (sex and smoking history) were added to the image-based model. The model was trained on a set of 345 patients and validated on an independent test group (n = 158) using the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. RESULTS: The performance of the random forest model with 94 radiomics features reached an AUC of 0.802. Its AUC was further improved to 0.828 by adding sex and smoking history. The sensitivity and specificity are 60.6% and 85.1% at the best diagnostic decision point. CONCLUSION: Our results showed that radiomics could not only reflect the genetic differences among tumors but also have diagnostic value and the potential to be a diagnostic tool. KEY POINTS: • Radiomics provides a potential noninvasive method for the prediction of EGFR mutation status. • In situations where surgeries and biopsy are not available, CT image-based radiomics models could help to make treatment decisions. • The accuracy, sensitivity, and specificity still need to be improved before the image-based EGFR identifier could be used in clinics.

Identifying epidermal growth factor receptor mutation status in patients with lung adenocarcinoma by three-dimensional convolutional neural networks.

OBJECTIVE:: Genetic phenotype plays a central role in making treatment decisions of lung adenocarcinoma, especially the tyrosine-kinase-inhibitors-sensitive mutations of the epidermal growth factor receptor (EGFR) gene. We constructed three-dimensional convolutional neural networks (CNN) to analyze underlying patterns in CT images that could indicate that EGFR gene mutation status but are invisible to human eyes. METHODS:: From 2012 to 2015, 503 Chinese patients with lung adenocarcinoma that had underwent surgery were included. Pathological types and EGFR mutation status were tested from surgical resections. EGFR mutations (exon 19 deletion or exon 21 L858R) were found in 215/345 (62.3%) and 91/158 (57.6%) patients in the training and independent validation set, respectively. CT images were taken before any invasive operation. The patients were randomly chosen to train the CNNs or validate the CNNs' performance. The performance was quantified using area under receiver operating characteristic curve (AUC), sensitivity, specificity, and accuracy. RESULTS:: The CNNs showed an AUC of 0.776 (range: 0.702-0.849, p< 0.0001) in the independent validation set and a fusion model of CNNs and clinical features (sex and smoking history) showed an AUC of 0.838 (range: 0.778-0.899, p< 0.0001), accuracy of 77.2%, sensitivity of 75.8% and specificity of 79.1% at the best diagnostic decision point. CONCLUSION:: The CNN exhibits potential ability to identify EGFR mutation status in patients with lung adenocarcinoma which might help make clinical decisions. ADVANCES IN KNOWLEDGE:: The CNN showed some diagnostic power and its performance could be further improved by increasing the training set, optimizing the network structure and training strategy. Medical image based CNN has the potential to reflect spatial heterogeneity.

Detection of epithelial growth factor receptor (EGFR) mutations on CT images of patients with lung adenocarcinoma using radiomics and/or multi-level residual convolutionary neural networks.

BACKGROUND: We aim to analyze the ability to detect epithelial growth factor receptor (EGFR) mutations on chest CT images of patients with lung adenocarcinoma using radiomics and/or multi-level residual convolutionary neural networks (MCNNs). METHODS: We retrospectively collected 1,010 consecutive patients in Shanghai Chest Hospital from 2013 to 2017, among which 510 patients were EGFR-mutated and 500 patients were wild-type. The patients were randomly divided into a training set (810 patients) and a validation set (200 patients) according to a balanced distribution of clinical features. The CT images and the corresponding EGFR status measured by Amplification Refractory Mutation System (ARMS) method of the patients in the training set were utilized to construct both a radiomics-based model (MRadiomics) and MCNNs-based model (MMCNNs). The MRadiomics and MMCNNs were combined to build the ModelRadiomics+MCNNs (MRadiomics+MCNNs). Clinical data of gender and smoking history constructed the clinical features-based model (MClinical). MClinical was then added into MRadiomics, MMCNNs, and MRadiomics+MCNNs to establish the ModelRadiomics+Clinical (MRadiomics+Clinical), the ModelMCNNs+Clinical (MMCNNs+Clinical) and the ModelRadiomics+MCNNs+Clinical (MRadiomics+MCNNs+Clinical). All the seven models were tested in the validation set to ascertain whether they were competent to detect EGFR mutations. The detection efficiency of each model was also compared in terms of area under the curve (AUC), sensitivity and specificity. RESULTS: The AUC of the MRadiomics, MMCNNs and MRadiomics+MCNNs to predict EGFR mutations was 0.740, 0.810 and 0.811 respectively. The performance of MMCNNs was better than that of MRadiomics (P=0.0225). The addition of clinical features did not improve the AUC of the MRadiomics (P=0.623), the MMCNNs (P=0.114) and the MRadiomics+MCNNs (P=0.058). The MRadiomics+MCNNs+Clinical demonstrated the highest AUC value of 0.834. The MMCNNs did not demonstrate any inferiority when compared with the MRadiomics+MCNNs (P=0.742) and the MRadiomics+MCNNs+Clinical (P=0.056). CONCLUSIONS: Both of the MRadiomics and the MCNNs could predict EGFR mutations on CT images of patients with lung adenocarcinoma. The MMCNNs outperformed the MRadiomics in the detection of EGFR mutations. The combination of these two models, even added with clinical features, is not significantly more efficient than MMCNNs alone.