Immune modulation in malignant pleural effusion: from microenvironment to therapeutic implications.

Immune microenvironment and immunotherapy have become the focus and frontier of tumor research, and the immune checkpoint inhibitors has provided novel strategies for tumor treatment. Malignant pleural effusion (MPE) is a common end-stage manifestation of lung cancer, malignant pleural mesothelioma and other thoracic malignancies, which is invasive and often accompanied by poor prognosis, affecting the quality of life of affected patients. Currently, clinical therapy for MPE is limited to pleural puncture, pleural fixation, catheter drainage, and other palliative therapies. Immunization is a new direction for rehabilitation and treatment of MPE. The effusion caused by cancer cells establishes its own immune microenvironment during its formation. Immune cells, cytokines, signal pathways of microenvironment affect the MPE progress and prognosis of patients. The interaction between them have been proved. The relevant studies were obtained through a systematic search of PubMed database according to keywords search method. Then through screening and sorting and reading full-text, 300 literatures were screened out. Exclude irrelevant and poor quality articles, 238 literatures were cited in the references. In this study, the mechanism of immune microenvironment affecting malignant pleural effusion was discussed from the perspectives of adaptive immune cells, innate immune cells, cytokines and molecular targets. Meanwhile, this study focused on the clinical value of microenvironmental components in the immunotherapy and prognosis of malignant pleural effusion.

Exosomes in the lung cancer microenvironment: biological functions and potential use as clinical biomarkers.

Lung cancer is one of the most common malignant tumours worldwide. however, emerging immunotherapy and targeted therapies continue to show limited efficacy. In the search for new targets for lung cancer treatment, exosomes have become a major focus of research. Exosomes play an important role in the tumour microenvironment (TME) of lung cancer and affect invasion, metastasis, and treatment responses. This review describes our current understanding of the release of exosomes derived from different cells in the TME, the effects of exosomes on T/Tregs, myeloid-derived suppressor cells, tumour-associated macrophages, dendritic cells, and natural killer cells, and the role of exosomes in the endothelial-mesenchymal transition, angiogenesis, and cancer-associated fibroblasts. In particular, this review focuses on the potential clinical applications of exosomes in the lung cancer microenvironment and their prognostic and diagnostic value.

Regulation of T cells by myeloid-derived suppressor cells: emerging immunosuppressor in lung cancer.

Myeloid-derived suppressor cells (MDSCs), major components maintaining the immune suppressive microenvironment in lung cancer, are relevant to the invasion, metastasis, and poor prognosis of lung cancer, through the regulation of epithelial-mesenchymal transition, remodeling of the immune microenvironment, and regulation of angiogenesis. MDSCs regulate T-cell immune functions by maintaining a strong immunosuppressive microenvironment and promoting tumor invasion. This raises the question of whether reversing the immunosuppressive effect of MDSCs on T cells can improve lung cancer treatment. To understand this further, this review explores the interactions and specific mechanisms of different MDSCs subsets, including regulatory T cells, T helper cells, CD8 + T cells, natural killer T cells, and exhausted T cells, as part of the lung cancer immune microenvironment. Second, it focuses on the guiding significance confirmed via clinical liquid biopsy and tissue biopsy that different MDSC subsets improve the prognosis of lung cancer. Finally, we conclude that targeting MDSCs through action targets or signaling pathways can help regulate T-cell immune functions and suppress T-cell exhaustion. In addition, immune checkpoint inhibitors targeting MDSCs may serve as a new approach for enhancing the efficiency of immunotherapy and targeted therapy for lung cancer in the future, providing better comprehensive options for lung cancer treatment.

Retrospective Clinical Study on Integrated Chinese and Western Medicine in Treatment of Limited-Stage Small Cell Lung Cancer.

OBJECTIVE: To investigate the efficacy of integrated Chinese and Western medicine extending the progression-free survival (PFS) and overall survival (OS) of limited-stage small cell lung cancer (LS-SCLC) patients after the first-line chemoradiotherapy. METHODS: The data of 67 LS-SCLC patients who received combined treatment of CM and Western medicine (WM) between January 2013 and May 2020 at the outpatient clinic of Guang'anmen Hospital were retrospectively analyzed. Thirty-six LS-SCLC patients who received only WM treatment was used as the WM control group. The medical data of the two groups were statistically analyzed. Survival analysis was performed using the product-limit method (Kaplan-Meier analysis). The median OS and PFS were calculated, and survival curves were compared by the Log rank test. The cumulative survival rates at 1, 2, and 5 years were estimated by the life table analysis. Stratified survival analysis was performed between patients with different CM administration time. RESULTS: The median PFS in the CM and WM combination treatment group and the WM group were 19 months (95% CI: 12.357-25.643) vs. 9 months (95% CI: 5.957-12.043), HR=0.43 (95% CI: 0.27-0.69, P<0.001), respectively. The median OS in the CM and WM combination group and the WM group were 34 months (95% CI could not be calculated) vs. 18.63 months (95% CI: 16.425-20.835), HR=0.40 (95% CI: 0.24-0.66, P<0.001), respectively. Similar results were obtained in the further stratified analysis of whether the duration of CM administration exceeded 18 and 24 months (P<0.001). CONCLUSION: The combination treatment of CM and WM with continuing oral administration of CM treatment after the first-line chemoradiotherapy for LS-SCLC patients produced better prognosis, lower risks of progression, and longer survival than the WM treatment alone. (Registration No. ChiCTR2200056616).

Breast cancer prognosis and P-cadherin expression: systematic review and study-level meta-analysis.

OBJECTIVE: P-cadherin can act both as a tumour suppressor and an oncogene. The clinical prognostic value of P-cadherin overexpression in breast cancer (BC) remains unclear. We conducted a study-level meta-analysis to determine whether P-cadherin expression can help predict prognosis in BC. METHODS: A systematic literature search was performed to review eligible studies and clarify the relationship between P-cadherin overexpression and overall survival (OS), disease-free survival (DFS), pathological features, molecular subtypes and molecular phenotypes in BC. RESULTS: Thirty-one studies including 12 332 patients were included. P-cadherin overexpression was correlated with significantly worse OS (HR=1.77, p<0.00001) and DFS (HR=1.96, p<0.00001) than P-cadherin-negative. P-cadherin overexpression could lead to high histological grade (OR=3.33, p<0.00001) and lymph node metastasis (OR=1.62, p<0.00001). Moreover, P-cadherin overexpression was associated with low odds of the luminal A subtype and high odds of the human epidermal growth factor receptor-2 (HER2)-positive and triple-negative subtypes. P-cadherin expression led to low expression of oestrogen and progesterone receptor (OR=0.37 and OR=0.36, respectively, both p<0.00001) and high expression of HER2 (OR=2.31, p<0.00001), Ki-67 (OR=2.79, p<0.00001), epidermal growth factor receptor (OR=5.85, p<0.00001) and cytokeratin 5/6 (OR=6.79, p<0.00001). CONCLUSIONS: P-cadherin was found to be associated with invasiveness and metastasis. P-cadherin expression can probably be a useful biomarker for predicting poor survival and may act as an independent prognostic predictor.

Ultra-Performance Liquid Chromatography/Mass Spectrometry-Based Metabolomics for Discovering Potential Biomarkers and Metabolic Pathways of Colorectal Cancer in Mouse Model (ApcMin/+) and Revealing the Effect of Honokiol.

Endogenous metabolites are a class of molecules playing diverse and significant roles in many metabolic pathways for disease. Honokiol (HNK), an active poly-phenolic compound, has shown potent anticancer activities. However, the detailed crucial mechanism regulated by HNK in colorectal cancer remains unclear. In the present study, we investigated the therapeutic effects and the underlying molecular mechanisms of HNK on colorectal cancer in a mouse model (ApcMin/+) by analyzing the urine metabolic profile based on metabolomics, which is a powerful tool for characterizing metabolic disturbances. We found that potential urine biomarkers were involved in the metabolism of compounds such as purines, tyrosines, tryptophans, etc. Moreover, we showed that a total of 27 metabolites were the most contribution biomarkers for intestinal tumors, and we found that the citrate cycle (TCA cycle) was regulated by HNK. In addition, it was suggested that the efficacy of HNK was achieved by affecting the multi-pathway system via influencing relevant metabolic pathways and regulating metabolic function. Our work also showed that high-throughput metabolomics can characterize the regulation of metabolic disorders as a therapeutic strategy to prevent colorectal cancer.

Efficacy and Safety of Astragalus-Containing Traditional Chinese Medicine Combined With Platinum-Based Chemotherapy in Advanced Gastric Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Astragalus-containing traditional Chinese medicine (TCM) is widely used as adjunctive treatment to platinum-based chemotherapy (PBC) in patients with advanced gastric cancer (AGC) in China. However, evidence regarding its efficacy remains limited. This study aimed to evaluate the efficacy and safety of Astragalus-containing TCM combined with PBC in AGC treatment. METHODS: We searched for literature (up to July 19, 2020) in eight electronic databases. The included studies were reviewed by two researchers. The main outcomes were the objective response rate (ORR), disease control rate (DCR), survival rate, quality of life (QOL), adverse drug reactions (ADRs), and peripheral blood lymphocyte levels. The effect estimate of interest was the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). Trial sequential analysis (TSA) was used to detect the robustness of the primary outcome and to calculate the required information size (RIS). Certainty of the evidence was assessed using the GRADE profiler. RESULTS: Results based on available literature showed that, compared with patients treated with PBC alone, those treated with Astragalus-containing TCM had a better ORR (RR: 1.24, 95% CI: 1.15-1.34, P < 0.00001), DCR (RR: 1.10, 95% CI: 1.06-1.14, P < 0.00001), 1-year survival rate (RR: 1.41, 95% CI: 1.09-1.82, P = 0.009), 2-year survival rate (RR: 3.13, 95% CI: 1.80-5.46, P < 0.0001), and QOL (RR: 2.03, 95% CI: 1.70-2.43, P < 0.00001 and MD: 12.39, 95% CI: 5.48-19.30, P = 0.0004); higher proportions of CD3+ T cells and CD3+ CD4+ T cells; higher ratio of CD4+/CD8+ T cells; nature killer cells; and lower incidence of ADRs. Subgroup analysis showed that both oral and injection administration of Astragalus-containing TCM increased tumor response. Whether treatment duration was ≥8 weeks or <8 weeks, Astragalus-containing TCM could increase tumor response in AGC patients. Furthermore, Astragalus-containing TCM combined with oxaliplatin-based chemotherapy could increase the ORR and DCR; when with cisplatin, it could only increase the ORR. CONCLUSION: Current low to moderate evidence revealed that Astragalus-containing TCM combined with PBC had better efficacy and less side effects in the treatment of AGC; however, more high-quality randomized studies are warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, identifier CRD42020203486.

Chinese medicine Xiaoshui decoction inhibits malignant pleural effusion in mice and mediates tumor-associated macrophage polarization by activating autophagy.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoshui decoction (XSD) is a traditional Chinese medicine compound prescription that has been shown to reinforce the spleen and remove the fluid retention, while being widely used in the treatment of malignant pleural effusion (MPE). We previously reported that XSD alleviates symptoms and improves the quality of life in patients with MPE; however, the mechanism employed by XSD on MPE has not yet been elucidated. AIM OF THE STUDY: To investigate the role and mechanism of XSD in inhibiting the development of MPE, and in regulating macrophage polarization in vitro and in vivo. MATERIALS AND METHODS: A murine MPE model was used to study the effect of XSD on MPE. Mice with MPE were randomly allocated to a control group and XSD-low-dose (1.144 g/mL), XSD-middle-dose (2.288 g/mL), XSD-high-dose (4.576 g/mL), or cisplatin groups. RAW264.7 cells were induced to form tumor-associated macrophages (TAMs) as well as M1 and M2 macrophages using different conditioned media in vitro. RESULTS: XSD effectively inhibited MPE formation, reduced pleural permeability and angiogenesis, and prolonged mice survival. Particularly, XSD treatment induced the polarization of TAMs to the M1 phenotype in MPE. Moreover, in-vitro XSD remarkably promoted the expansion of M1 macrophages and reduced M2 macrophages by enhancing autophagy. CONCLUSIONS: XSD inhibits MPE development and regulates macrophage polarization by activating autophagy, indicating that XSD may serve as a novel option for integrative MPE therapies.

Chinese herbal medicine for small cell lung cancer patients: A protocol for a systematic review and meta-analysis.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive disease. Chemotherapy is the standard treatment for SCLC, but the resistance and the adverse effects of Chemotherapy still remains a major problem. Although Chinese herbal medicine (traditional Chinese medicine) is wildly applied for patients with SCLC in China, the evidence of traditional Chinese medicine in the treatment for SCLC is limited. METHOD: We conducted a systematic search of PubMed, EMBASE, the Chinese National Knowledge Infrastructure, the VIP Information Database, and the Wanfang Database for relevant studies. Only randomized controlled trials were included. Two investigators independently reviewed the included studies and extracted relevant data. The effect estimate of interest was the relative risk or mean difference with 95% confidence intervals. ETHICS AND DISSEMINATION: Ethical approval is not required, as this study is based on the review of published research. This review will be published in a peer-reviewed journal and disseminated both electronically and in print. INPLASY REGISTRATION NUMBER: INPLASY2020110055.

Prognostic significance of E-cadherin expression in prostatic carcinoma: A protocol for systematic review and meta-analysis.

BACKGROUND: Increasing studies were performed to explore the prognostic value of E-cadherin in prostatic carcinoma, however, with inconsistent results. Hence, this systematic review is aimed to evaluate the prognostic role of E-cadherin in patients with prostatic carcinoma (PCa). METHODS: A comprehensive literature search in all available databases will be conducted to identify eligible studies. We will employ hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the correlations between E-cadherin expression and overall survival (OS), disease-free survival (DFS), relapse-free survival (RFS), progression-free survival (PFS) and clinicopathological features. Meta-analysis will be performed using Review Manager (Revman) 5.3.5 software (Cochrane Community, London, United Kingdom) and STATA 14 software (version 14.0; Stata Corp, College Station, TX). RESULTS: This study will provide a high-quality synthesis of current evidence of the correlations between snail expression and OS, DFS/RFS, PFS and clinicopathological features. CONCLUSION: The study will provide updated evidence to assess whether the expression of E-cadherin is in association with poor prognosis in patients with PCa. ETHICS AND DISSEMINATION: It is not necessary for ethical approval because individuals cannot be identified. The protocol will be disseminated in a peer-reviewed journal or presented at a relevant conference. PROSPERO REGISTRATION NUMBER: This systematic review protocol has been registered in the PROSPERO network (No. CRD42019128353).

Efficacy and safety of TCM combined with chemotherapy for SCLC: a systematic review and meta-analysis.

BACKGROUND: Chemotherapy is the standard treatment for small cell lung cancer (SCLC), but chemotherapy resistance and adverse reactions remain major problems. Although Traditional Chinese Medicine (TCM) is wildly applied for patients with SCLC in China, the evidence of TCM in the treatment for SCLC is limited. PURPOSE: To evaluate the efficacy and safety of TCM combined with chemotherapy for patients with SCLC. METHOD: We conducted a systematic search of PubMed, EMBASE, the Chinese National Knowledge Infrastructure, the VIP Information Database, and the Wanfang Database for randomized-controlled trials (RCTs) that are relevant. The included studies were reviewed by two investigators, with relevant data extracted independently. The effect estimate of interest was the relative risk (RR) or mean difference with 95% confidence intervals (95% CIs). RESULTS: 22 RCTs involving 1887 patients were included in this study. Compared with patients treated with chemotherapy© alone, those with Chinese herbal medicine and chemotherapy (TCM-C) had better therapeutic effects (RR = 1.295, 95% CI 1.205-1.391, P < 0.001), KPS scores (RR = 1.310, 95% CI 1.210-1.418, P < 0.001), 1-year survival rate (RR = 1.282, 95% CI 1.129-1.456, P < 0.001), 3-year survival rate (RR = 2.109, 95% CI 1.514-2.939, P < 0.001), and 5-year survival rate (RR = 2.373, 95% CI 1.227-4.587, P = 0.01). The incidence of gastrointestinal reaction (RR of = 0.786, 95% CI 0.709-0.870, P < 0.000) and bone marrow depression (RR = 0.837, 95% CI 0.726-0.965, P = 0.014) in TCM-C group were lower than that in the C group. CONCLUSION: The systematic review indicated that TCM combined with chemotherapy may improve therapeutic effect, quality of life, and prolong survival time. More large-scale and higher quality RCTs are warranted to support our findings. PROSPERO REGISTRATION NUMBER: CRD42016038016.

Taxane-based chemotherapy and risk of breast cancer-related lymphedema: Protocol for a systematic review and meta-analysis.

BACKGROUND: Many studies were performed to explore the correlation between taxane-based chemotherapy and the risk of breast cancer-related lymphedema (BCRL), however, with inconsistent results. Hence, the purpose of this study is to evaluate whether taxane-based chemotherapy is a risk factor for BCRL. METHODS: A comprehensive systematic search of clinical trials published in the PubMed, Embase and the Cochrane Library databases will be conducted to identify eligible studies up to the date of December 31, 2018. We will employ risk ratios with 95% confidence intervals (95% CIs) to estimate the correlations between taxane-based chemotherapy and BCRL. Meta-analysis will be performed using Stata SE version 12.0 software. RESULTS: The results of this systematic review and meta-analysis will provide a high-quality synthesis of existing evidence of the correlations between taxane-based chemotherapy and the risk of BCRL. CONCLUSION: The protocol will provide updated evidence for the use of taxane-based chemotherapy in postoperative breast cancer patients. ETHICS AND DISSEMINATION: It is not necessary for ethical approval because it is based on published studies. The protocol will be disseminated in a peer-reviewed journal or presented at a topic-related conference. TRIAL REGISTRATION: This systematic review protocol has been registered with a number of CRD42019123989.

TCM therapies combined with chemotherapy for preventing recurrence and metastasis in postoperative II to IIIA NSCLC: A protocol for a systematic review and meta-analysis.

BACKGROUND: Traditional Chinese Medicine (TCM) therapies have been combined with chemotherapy for preventing Recurrence and metastasis in postoperative II to IIIA non-small-cell lung cancer (NSCLC) and the associated better disease-free survival (DFS), but its effects remain elusive. The purpose of this review is to assess the efficacy of TCM therapies as a treatment for postoperative II to IIIA NSCLC. METHODS AND ANALYSIS: Seventh databases will be searched for relevant studies from inception to the present date. We will include randomized controlled trials assessing TCM therapies combined with chemotherapy for preventing Recurrence and metastasis in postoperative II to IIIA NSCLC. The methodological qualities, including the risk of bias, will be evaluated using the Cochrane risk of bias assessment tool, while confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. ETHICS AND DISSEMINATION: Ethical approval is not required, as this study is based on the review of published research. This review will be published in a peer-reviewed journal and disseminated both electronically and in print. PROSPERO REGISTRATION NUMBER: The protocol for this systematic review has been registered on PROSPERO under the number CRD42019116594.

Study on the treatment of pancreatic cancer with integrated traditional Chinese and Western medicine: A study protocol of a multicenter prospective cohort study.

INTRODUCTION: Pancreatic cancer is one of the most lethal malignancies worldwide. Most patients are diagnosed at an advanced stage, which leads to a poor prognosis and a low survival rate. At present, treatment options for pancreatic cancer are limited, so it is vital to explore new treatments and strategies. Traditional Chinese medicine (TCM) is an important method for cancer prevention and treatment in China. We will conduct a multicenter, prospective cohort study to evaluate the survival and quality of life of patients with advanced pancreatic cancer treated with integrated traditional Chinese and Western medicine, further refine the core pathogenesis of TCM for pancreatic cancer, form a core prescription, and provide clinical data support for the clinical plan of integrated treatment of pancreatic cancer using Chinese and Western medicine; this will aid in the development of the best comprehensive treatment plan for patients. METHODS AND ANALYSIS: This study will recruit patients with stage 3 to 4 pancreatic cancer in 12 medical units from April 2019 to June 2020. Patients will be divided into a Western medicine treatment group and an integrated traditional Chinese and Western medicine treatment group, with a total of 148 patients. Overall survival is the main efficacy index, while the secondary efficacy indexes are progression-free survival, tumor markers, TCM symptom grading scale, quality of life assessment, Eastern Cooperative Oncology Group (ECOG) score, and imaging assessment. A follow-up will be performed every 6 weeks ±1 week. The end point is the death of the patient or the end of the study (October 31, 2021). Statistical analysis will be performed using Statistical Packages of Social Sciences software (SPSS). ETHICS AND DISSEMINATION: This work was supported by Beijing Municipal Science and Technology Commission and approved by the ethics committee of Guang'anmen Hospital, China Academy of Chinese Medical Sciences (Approval No. 2019-016-KY). All patients will sign a written informed consent prior to data collection. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial. TRIAL REGISTRATION: The trial was registered with the Chinese Clinical Trials Registry (ChiCTR1900022632, pre-registration).