Jinfukang inhibits lung cancer metastasis by upregulating CX3CL1 to recruit NK cells to kill CTCs.

ETHNOPHARMACOLOGICAL RELEVANCE: Circulating tumor cells (CTCs) play an important role in tumor metastasis and may be a target for metastasis prevention. The traditional Chinese medicine Jinfukang functions to improve immunity, prevent metastasis, and prolong lung cancer patient survival periods. Yet, whether Jinfukang prevents metastasis by regulating immune cells to clearance CTCs is still unknown. AIM OF THE STUDY: To explore the anti-metastasis mechanism of Jinfukang from the perspective of regulating NK cells to clear CTCs. MATERIALS AND METHODS: CTC-TJH-01 cell was treated with Jinfukang. Cytokine chip was used to detect cytokines in cell culture supernatant. Lymphocyte recruitment assay was detected by Transwell and flow cytometry. Protein expression was analysis by Western blot. LDH kit was used to detect cytotoxicity. NOD-SCID mice used for tail vein injection to study lung metastasis. RESULTS: Jinfukang could promote the expression and secretion of the chemokine CX3CL1 by CTCs. In addition, Jinfukang could promote the recruitment of natural killer (NK) cells by CTCs and significantly increase the cytotoxic effect of NK cells on CTCs. Moreover, Jinfukang could upregulate the expression of FasL and promote the secretion of TNF-α by NK cells and that NK cells could induce the apoptosis of CTCs through the Fas/FasL signaling pathway. Finally, we confirmed that Jinfukang could promote NK cells to kill CTCs and then inhibit lung cancer metastasis in vivo. The above effects of Jinfukang could be partially reversed by an anti-CX3CL1 mAb. CONCLUSIONS: These results suggest that Jinfukang may prevent lung cancer metastasis by enhancing the clearance of CTCs in the peripheral blood by NK cells, providing evidence for the anti-metastasis effect of Jinfukang.

Risk factors and their diagnostic values for ocular metastases in invasive ductal carcinoma.

Invasive ductal carcinoma (IDC) is a major type of breast cancer. Ocular metastasis (OM) in IDC is rarely seen, but patients with OM often have a poor prognosis. Furthermore, OM is difficult to detect in the early stages by common imaging examinations. In the present study, we tried to figure out the risk factors of OM in IDC and evaluate their diagnostic values for early detection. There were 1192 IDC patients who were divided into two groups according to ocular metastasis involved in this study. Clinical parameters of those patients were used to detect differences. The binary logistic regression test was then used to determine the risk factors of OM in IDC. Furthermore, ROC curves of both single and combined risk factors were established to examine their diagnostic values. The incidence of axillary lymph node metastases was significantly higher in the OM group (p = 0.002). Higher carbohydrate antigen 153 (CA153), lower apolipoprotein A1 (ApoA1), and hemoglobin (Hb) were risk factors for OM in IDC (p < 0.001, p < 0.001, p = 0.038, respectively). In the single risk factor ROC analysis, cutoff values of CA153, ApoA1, and Hb were 43.3 u/mL (CI: 0.966-0.984, p < 0.001), 1.11 g/L (CI: 0.923-0.951, p < 0.001), and 112 g/L (CI: 0.815-0.857, p < 0.001), respectively. Among the ROC curves of combined risk factors, CA153+ApoA1+Hb had the best accuracy, with the sensitivity and specificity of 89.47% and 99.32%, respectively (CI: 0.964-0.983, p < 0.001). CA153, ApoA1, and Hb are risk factors for OM in IDC. In clinical practice, the three parameters could be used as predictive factors for the early detection of OM.

Proteomics analysis of tumor exosomes reveals vital pathways of Jinfukang inhibiting circulating tumor cells metastasis in lung cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinfukang has long been used for the clinical treatment of lung cancer. Previous studies have shown that Jinfukang can induce the apoptosis of circulating tumor cells by intervening ROS-mediated DNA damage pathway. However, whether Jinfukang can inhibit the metastasis of circulating tumor cells and its mechanism are still unclear. AIM OF THE STUDY: To further investigate the mechanism of Jinfukang in anti-metastasis of lung cancer from the perspective of intervention of tumor exosomes. MATERIALS AND METHODS: The invadopodia formation was determined with immunofluorescence. Invasion and migration were detected using the Transwell assay. Ultracentrifugation was used to isolate exosomes. Exosomes were characterized by electron microscopy, nanoparticle tracking analysis and immunoblotting, and the protein profile was evaluated by proteomic analysis. The molecular functions, biological processes and signaling pathway enrichment analysis were performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Key differentially expressed proteins were verified by Western blot. RESULTS: Jinfukang can inhibit the expression of MMP14, cortactin, Tks5 and the formation of invadopodia of CTC-TJH-01 cells. Furthermore, Jinfukang can significantly inhibit the invasion and migration of CTC-TJH-01 cells. The diameter of exosomes extracted from the CTC-TJH-01 cells treated by Jinfukang was 30-100 nm, and the exosomal markers CD63, CD81 and TSG101 were expressed. We identified 680 deferentially expressed proteins. Gene oncology analysis indicated that exosomes were mostly derived from plasma membrane and mainly involved in protein localization and intracellular signaling. The ingenuity pathway analysis showed that the EGF pathway was significantly inhibited, whereas the GP6 signaling pathway was significantly activated. We also confirmed that Jinfukang inhibited the expression of EGF pathway-related proteins in CTC-TJH-01 cells. Besides, when EGF was used to activate EGF signaling pathway, the inhibition of Jinfukang on CTC cell metastasis was reversed. CONCLUSION: Jinfukang inhibits the metastasis of CTC-TJH-01 cells through the EGF pathway.

Traditional Chinese Medicine Treatment as Adjuvant Therapy in Completely Resected Stage IB-IIIA Non-Small-Cell Lung Cancer: Study Protocol for a Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial.

Adjuvant chemotherapy (AC) has been proven to yield an approximately 5% improvement in 5-year survival for patients with early-stage non-small-cell lung cancer. With such small gains in survival, the optimal treatment regimen remains to be established. Traditional Chinese medicine (TCM) treatment in combination with AC is frequently used in China. The efficacy and safety of this integrated approach should be scientifically evaluated. We present the rationale and study design of the Combined Adjuvant Chemotherapy and Traditional Chinese Medicine (ACTCM) trial (ChiCTR-IPR-16009062). The ACTCM trial, a prospective multicenter double-blind randomized placebo-controlled study, will recruit 312 patients overall from 5 clinical research centers in China. Within 6 weeks of the thoracic surgery, eligible participants with stages IB-IIIA non-small-cell lung cancer will be randomly assigned in a 1:1 ratio to either the treatment or control group. Patients in the treatment group will receive AC combined with TCM herbal treatment for 4 cycles, then TCM herbal plus injection treatment for 4 cycles. Patients in the control group will receive AC combined with TCM placebo for 4 cycles and then TCM placebo for 4 cycles. Treatment will be discontinued if disease progression or unacceptable toxicity occurs. The primary end point is 2-year disease-free survival. Secondary end points include disease-free survival and quality of life. Other end points are TCM symptoms, performance status, and safety of the regimens. Recruitment started in October 2016 and is ongoing.

Apolipoprotein A1 and B as risk factors for development of intraocular metastasis in patients with breast cancer.

Objective: Breast cancer is the most common primary lesion resulting in intraocular metastasis (IOM). In this study, we investigated the differences between breast cancer patients with and without IOM, and clarified the risk factors for IOM in patients with breast cancer. Methods: A total of 2,381 patients with breast cancer were included in this study from January 2005 to December 2017. The chi-square test and Student's t-test were applied to evaluate differences between the IOM and non-IOM (NIOM) groups. Risk factors were calculated using binary logistic regression analysis. Receiver operating curve (ROC) analysis was used to assess the diagnostic value of IOM in patients with breast cancer. Results: The IOM incidence in patients with breast cancer was 1.35%. No significant differences were detected in age, gender, menopausal status, or histopathology between the IOM and NIOM groups. The IOM group had more axillary lymph node metastases, lower ApoA1 and higher ApoB, compared with the NIOM group. Binary logistic regression indicated that ApoA1 and ApoB were risk factors for IOM in breast cancer patients (P-values<0.001 and P-values=0.005, respectively). ROC curve analysis revealed area under the curve values for ApoA1 and ApoB of 0.871 and 0.633, using cutoff values of 1.165 and 0.835 g/L, respectively. The sensitivity and specificity values for ApoA1 were 0.813 and 0.849, respectively, while those for ApoB were 0.813 and 0.481. Conclusion: Our data indicate that ApoA1 and ApoB are risk factors for IOM in patients with breast cancer and that ApoA1 is more reliable than ApoB at distinguishing IOM from NIOM in patients with breast cancer.

Traditional Chinese Medicine treatment as maintenance therapy in advanced non-small-cell lung cancer: A randomized controlled trial.

OBJECTIVES: Maintenance therapy for patients with advanced non-small-cell lung cancer (NSCLC) is an increasingly hot topic in the field of clinical NSCLC research. This study aimed to evaluate the effects of Traditional Chinese Medicine (TCM) treatment as maintenance therapy on time to progression (TTP), quality of life (QOL), overall survival (OS) and 1-year survival rate in patients with advanced NSCLC. METHODS: This study was conducted as a randomized, controlled, open-label trial. 64 non-progressive patients who responded to initial therapy were randomized 1:1 to the TCM arm (treated with herbal injection (Cinobufacini, 20ml/d, d1-d10), herbal decoction (d1-d21) and Chinese acupoint application (d1-d21), n=32) or to the chemotherapy arm (treated with pemetrexed (non-squamous NSCLC, 500mg/m(2), d1), docetaxel (75mg/m(2), d1) or gemcitabine (1250mg/m(2), d1 and d8), n=32). Each therapy cycle was 21 days. They were repeated until disease progression, unacceptable toxicity, or until the patients requested therapy discontinuation. The primary end point was TTP; the secondary end points were QOL, OS and 1-year survival rate. "Intention-to-treat" analysis included all randomized participants. RESULTS: TCM treatment prolonged median TTP for 0.7 months compared with chemotherapy, but it was not statistically significant (3.0 months vs. 2.3 months, P=0.114). Median OS time for TCM treatment did not offer a significant advantage over for chemotherapy (21.5 months vs. 18.8 months, P=0.601). 1-year survival rate of TCM treatment significantly improved than that of chemotherapy (78.1% vs. 53.1%, P=0.035). TCM treatment can significantly improve QOL when compared to chemotherapy as assessed by EORTC QLQ-C30 and EORTC QLQ-LC13 QOL instruments. CONCLUSIONS: TCM maintenance treatment had similar effects on TTP and OS compared with maintenance chemotherapy, but it improved patients' QOL and had higher 1-year survival rate. TCM Maintenance treatment is a promising option for advanced NSCLC patients without progression following first-line chemotherapy.

Traditional Chinese medicine herbal treatment may have a relevant impact on the prognosis of patients with stage IV adenocarcinoma of the lung treated with platinum-based chemotherapy or combined targeted therapy and chemotherapy.

BACKGROUND: Targeted therapy (TT), chemotherapy, and traditional Chinese medicine herbal treatment (TCM) can improve the prognosis of advanced pulmonary adenocarcinoma patients. Their independent prognostic value is unknown. OBJECTIVE: To study whether TCM improves survival in stage IV pulmonary adenocarcinoma patients with platinum-based chemotherapy (PBT), or combined PBT and second-line TT. METHODS: Retrospective analysis of 133 fully ambulant clinical outpatients treated with PBT alone or PBT with/without second-line TT, with/without TCM. Univariate (Kaplan-Meier) and multivariable (Cox model) survival analysis were performed, using disease-specific mortality as an endpoint. RESULTS: Gender (P = .002), TT (P < .0001), and TCM (P < .0001) had univariate prognostic value but not age, radiotherapy, or TCM syndrome differentiation (P > .10). TCM herbal treatment (P < .0001) and TT (P = .03) had multivariable independent prognostic value. TCM-treated patients (n = 103, PBT+TT+TCM+ = 62; PBT+TT-TCM+ =41) had 88% 1-year overall survival rate with median survival time (MST) of 27 months, contrasting 27% 1-year overall survival and MST of 5.0 months for non-TCM-treated (n = 30) patients. Patients with chemotherapy/TT/TCM (PBT+TT+TCM+, n = 62), TCM without TT (PBT+TT-TCM+, n = 41), or chemotherapy only (PBT+TT-TCM-, n = 30), had 1-year survival rates of 94%, 78%, and 27% respectively; for these 3 groups, respectively, MST was not reached (MST of 30.9 months), 22.6, and 5.0 months (P < .0001). CONCLUSIONS: TCM herbal treatment may improve survival of stage IV pulmonary adenocarcinoma patients treated with chemotherapy without or with second-line TT. This warrants formal phase 1 and 2 trials and ultimately properly designed prospective clinical validation trials with adequate methodology developed for data collection.

[Regulatory effect of jianpi wenshen recipe in combining with chemotherapy on the blood level of estradiol in patients with lung cancer].

OBJECTIVE: To observe the regulatory effect of Jianpi Wenshen Recipe (JPWS), a Chinese herbal preparation for strengthening Pi and warming Shen, combined with chemotherapy on the level of estradiol (E2) in patients with mid-late non-small cell lung cancer (NSCLC), and to analyse the relationship between the changes of estradiol and tumor size. METHODS: Fifty-one NSCLC patients were randomized into three groups: 16 cases in the JPWS group treated with JPWS alone, 18 cases in the test group treated with combined therapy of JPWS plus chemotherapy, and 17 cases in the chemotherapy group treated with chemotherapy alone, all were treated for 2 months. The changes of blood E2 level and tumor size before and after treatment were compared. RESULTS: The disease control rate in the JPWS group and combined therapy group was 53.85% (7/13) and 80.00% (8/10), respectively, both were higher than that in the chemotherapy group (44.40%, 4/9), but the difference showed statistical insignificance (P > 0.05). E2 level was significantly lowered after treatment in the former two groups (all P < 0.05), and the change was in accordance with that of tumor size in 26 out of 31 patients (P < 0.01). CONCLUSION: JPWS combined with chemthherapy can stabilize the tumor size and down-regulate E2 levelo, with the change of E2 correlated with that of tumor size in patients. Hence, decreasing E2 is one of the mechanisms for JPWS in treating lung cancer.

[Clinical effect of yiqi yangyin jiedu decoction in treating patients with advanced non-small cell lung cancer].

OBJECTIVE: To observe the clinical therapeutic effect and mechanism of Yiqi Yangyin Jiedu Decoction (YYJD, a Chinese herbal recipe for strengthening qi, nourishing yin and removing toxic substance, consisting of milkvetch root 30 g, glehnia root 30 g, asparagus root 15 g, lilyturf root 15 g, grossy privet fruit 12 g, spikemoss herb 30 g, Chinese sage herb 30 g, manyleaf paris rhizome 30 g, etc. ) in treating patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Sixty patients with advanced lung cancer of qi-yin deficiency syndrome were randomized into three groups: the TCM group (A) treated with YYJD, the chemotherapy group (B) treated by chemotherapy with NP or GP protocol, and the combined treated group (C) treated with YYJD and chemotherapy in combination. The efficacy was evaluated after two cycles of treatment. RESULTS: The total effective rate for alleviating qi-yin deficiency syndrome in group A was 80%, significantly higher than that in Group C and B (35% and 20%, P <0.01) respectively. The KPS increasing and stabilizing rate in Group A and C was 90% and 85% respectively, significantly higher than that in Group B (75%), and difference between A and B was significant (P <0.05). In Group C after treatment, CD(3)+ showed a rising trend (P = 0.05), different to that in Group A and B (P <0.05 and P <0.01); CD(4)+ significantly increased (P <0.05) and CD(4)+/CD(8)+ ratio showed increasing trend (P = 0.06), while in Group B both were decreased significantly, showed significantly difference (P < 0.05). CD(8)+ CD(28)+ significantly increased after treatment in Group A and C (P <0.01 and P <0.05), but showed decreasing trend (P = 0.06) in Group B, significant difference was shown between B and C (P <0.05). CONCLUSION: YYJD can ameliorate the qi-yin deficiency syndrome evidently in advance lung cancer patients; improve their quality of life, the mechanism might be by way of enhancing T-lymphocyte activity and killer T-cell function, to elevate the T-cell mediated immunity in a round way.

[Effects of Yifei Kangliu Oral Liquid on cell cycle and protein-nucleic acid synthesis of experimental lung cancer].

OBJECTIVE: To explore the effect of the traditional Chinese medicine Yifei Kangliu (YFKL) Oral Liquid on the proliferation, cell cycle and protein-nucleic acid synthesis of murine Lewis lung cancer cell and human lung adenocarcinoma cell line SPC-A-1. METHODS: The inhibiting rates of tumor growth were calculated by weighing the weight of tumor inoculated in vivo, combined by counting cancer cells in vitro. The ratio of the cell cycle and exponents of DNA, RNA, and protein were measured by flow cytometry (FCM). RESULTS: The inhibiting rate of tumor growth in the treated group with YFKL Oral Liquid was 30.38% (P<0.05). The proportion of cells in S phase of the treated groups with YFKL Oral Liquid was lower than that of the control group. In the group with most significant result, 72% of the cells were stagnated in G0/G1 phase. The inhibiting rates of DNA, RNA and protein in murine Lewis lung cancer were 7.4%, 23.73% and 23.31% respectively. In SPC-A-1 cell line, the inhibiting rates were 9.3%, 10.1% and 14.7% respectively, demonstrating amplified effects on lower levels. CONCLUSION: YFKL Oral Liquid significantly inhibited the proliferation of murine Lewis lung cancer cell and human lung adenocarcinoma cell line SPC-A-1 by blocking the cancer cells entering the proliferative phase resulted from its inhibition of DNA.