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.

Bioinformatics analyses of infiltrating immune cell participation on pancreatic ductal adenocarcinoma progression and in vivo experiment of the therapeutic effect of Shuangshen granules.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuangshen granules (SSG), a nationally patented Chinese medicinal formula, including Panax quinquefolium L., Panax notoginseng (Burkill) F. H. Chen, and Cordyceps sinensis (Berk.) Sacc., has demonstrated remarkable therapeutic effects on pancreatic cancer in clinical treatment for nearly 10 years. Previous pharmacological researches have found that its main components, including ginsenosides and cordycepin have anticancer or preventive effects on pancreatic ductal adenocarcinoma (PDAC), which may be associated with immune metabolism. However, the underlying pharmacological mechanism of SSG in the truncation effect of PDAC progression is still unclear. AIM OF THE STUDY: To comprehensively understand the infiltrating immune cells during the different stages of the PDAC development chain and search for immune-related biomarkers that could potentially serve as drug targets through bioinformatic analysis. Meanwhile, the truncation effect of SSG on PDAC progression was also investigated. MATERIALS AND METHODS: The gene expression profiles at different PDAC developmental stages, including normal pancreas, pancreatic intraepithelial neoplasia (PanIN), and PDAC, were retrieved from the GEO database. The GEO2R tool was used to identify differentially expressed genes among the three groups. Functional enrichment analysis was performed with the GSEA software and Metascape platform. The CIBERSORT algorithm evaluated immune cell infiltration in the three groups, and immune-related biomarkers were identified. Correlation analysis was employed to examine the association between immune cells and the biomarkers. One of these biomarkers was selected for immunohistochemistry validation in human samples. Lastly, the effectiveness of SSG against PDAC progression and the influence on the selected biomarker were validated in vivo. The underlying pharmacological mechanisms were also explored. RESULTS: One dataset was obtained, where the functional enrichment of DEGs primarily involved immune effector processes and cytokine production of immune cells. The differential immune cells reflected during the progression from PanIN to PDAC were B memory cells, monocytes, M2 macrophages, and activated dendritic cells. The upregulation of ACTA2 was closely associated with M2 macrophage regulation. The immunohistochemistry on human samples validated significant differences in ACTA2 expression levels as the PDAC progressed. Moreover, animal experiments revealed that the national patented drug SSG ameliorated the pathological changes, decreased the expression of ACTA2 and its functional protein α-smooth muscle actin during PDAC progression. The underlying pharmacological mechanism was related to the regulation of macrophage polarization and downregulation of TGF-ß/Smad signaling pathway. CONCLUSIONS: The immunosuppressive environment changes during the PDAC progression. ACTA2 is a potential immuned-target for drug prevention of PDAC, while SSG could be a promising drug candidate.

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.

A nomogram for predicting severe myelosuppression in small cell lung cancer patients following the first-line chemotherapy.

This study aimed at establishing and validating a nomogram to predict the probability of severe myelosuppression in small cell lung cancer (SCLC) patients following the first-line chemotherapy. A total of 179 SCLC cases were screened as the training group and another 124 patients were used for the validation group. Predictors were determined by the smallest Akaike's information criterion (AIC) in multivariate logistic regression analysis, leading to a new nomogram. The nomogram was validated in both training and validation groups and the predicting value was evaluated by area under the receiver operating characteristics (ROC) curve (AUC), calibration curve, and decision curve analysis (DCA). Age and tumor staging were extracted as predictors to establish a nomogram, which displayed the AUC values as 0.725 and 0.727 in the training and validation groups, respectively. This nomogram exhibited acceptable calibration curves in the two groups and its prediction added more net benefits than the treat-all scheme and treat-none scheme if the range of threshold probability in the DCA was between 15 and 60% in the training and validation groups. Therefore, the nomogram objectively and accurately predict the occurrence of severe myelosuppression in SCLC patients following the first-line chemotherapy.

Guidelines for the Diagnosis and Treatment of Primary Liver Cancer (2022 Edition).

Background: Primary liver cancer, of which around 75-85% is hepatocellular carcinoma in China, is the fourth most common malignancy and the second leading cause of tumor-related death, thereby posing a significant threat to the life and health of the Chinese people. Summary: Since the publication of Guidelines for Diagnosis and Treatment of Primary Liver Cancer in China in June 2017, which were updated by the National Health Commission in December 2019, additional high-quality evidence has emerged from researchers worldwide regarding the diagnosis, staging, and treatment of liver cancer, that requires the guidelines to be updated again. The new edition (2022 Edition) was written by more than 100 experts in the field of liver cancer in China, which not only reflects the real-world situation in China but also may reshape the nationwide diagnosis and treatment of liver cancer. Key Messages: The new guideline aims to encourage the implementation of evidence-based practice and improve the national average 5-year survival rate for patients with liver cancer, as proposed in the "Health China 2030 Blueprint."

Ginseng-containing traditional medicine preparations in combination with fluoropyrimidine-based chemotherapy for advanced gastric cancer: A systematic review and meta-analysis.

BACKGROUND: Ginseng-containing traditional medicine preparations (G-TMPs) in combination with fluoropyrimidine-based chemotherapy (FBC) are well-known treatments for advanced gastric cancer (AGC), with a superior efficacy to FBC alone. However, evidence regarding their efficacy remains limited. The purpose of this meta-analysis is to evaluate the efficacy and safety of G-TMPs in combination with FBC for the treatment of AGC. METHODS: Eight electronic databases were searched for randomized controlled trials (RCTs) using G-TMPs with FBC for the treatment of AGC. The primary outcome included the tumor response, while the secondary outcomes included the quality of life (QoL), proportions of peripheral blood lymphocytes, adverse drug reactions (ADRs), and levels of cancer biomarkers. The quality of evidence for each outcome was assessed using GRADE profilers. RESULTS: A total of 1,960 participants were involved in the 26 RCTs included. Patients treated with FBC plus G-TMPs had better objective response (risk ratio [RR] = 1.23, 95% confidence interval [CI]: 1.13 to 1.35, p < 0.00001) and disease control (RR = 1.13, 95% CI: 1.08 to 1.19, p < 0.00001) rates than those treated with FBC alone. Additionally, the combination group had a better QoL, higher proportions of CD3+ T cells, CD4+ T cells, and natural killer cells, as well as a higher CD4+/CD8+ T-cell ratio. Furthermore, lower levels of CA19-9, CA72-4, and CEA were confirmed in the combination treatment group. In addition, G-TMPs reduced the incidence of ADRs during chemotherapy. CONCLUSION: In combination with FBC, G-TMPs can potentially enhance efficacy, reduce ADRs, and improve prognosis for patients with AGC. However, high-quality randomized studies remain warranted. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Number: CRD42021264938.

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).

Platycodin D induces apoptosis through JNK1/AP-1/PUMA pathway in non-small cell lung cancer cells: A new mechanism for an old compound.

Platycodin D, a triterpenoid monomer, has been shown to possess an anti-tumor effect on various types of cancer. Although Platycodin D has been reported to suppress tumorigenesis, the detailed underlying mechanism remains elusive. Platycodin D treatment significantly reduced the cell viability, decreased the number of colonies, impaired the mitochondrial function, and induced apoptosis in non-small cell lung cancer (NSCLC) cells. To understand the mechanism by which platycodin D induces apoptosis, the expression levels of apoptosis-related proteins were examined, and we found that the expression of PUMA (p53 upregulated modulator of apoptosis) was upregulated upon platycodin D treatment. Knockdown of PUMA resulted in attenuation of platycodin D-induced apoptosis, indicating that PUMA up-regulation is essential for platycodin D to induce apoptosis. The induction of PUMA expression by platycodin D treatment was through activation of AP-1 since mutation of AP-1 binding site in the PUMA promoter abolished the PUMA promoter activity. In addition, the chromatin immunoprecipitation further demonstrated that platycodin D promoted AP-1 binding to PUMA promoter. Moreover, knockdown of JNK1, but not JNK2, significantly abolished the phosphorylation of c-Jun at Ser63 (a component of AP-1), decreased the platycodin D-induced expression of PUMA and cleaved caspase 3, indicating that platycodin D inhibits JNK1/AP-1 signaling pathway. Furthermore, immunohistochemical staining studies showed that tumors from the mice treated with platycodin D activated JNK by translocation of JNK into nuclei, increased phosphorylation of JNK and c-Jun at Ser63 in nuclei, and boosted the PUMA expression. Taken together, our in vitro and in vivo data revealed a novel mechanism by which platycodin D up-regulates PUMA to induce apoptosis through JNK1/AP-1 axis in NSCLC.

Immortal Time Bias-Corrected Effectiveness of Traditional Chinese Medicine in Non-Small Cell Lung Cancer (C-EVID): A Prospective Cohort Study.

Background: Relatively little is known about the effect of traditional Chinese medicine (TCM) on prognosis of non-small cell lung cancer (NSCLC). Methods: In this nationwide, multicenter, prospective, cohort study, eligible patients aged 18-75 years with radical resection, and histologically confirmed stage II-IIIA NSCLC were enrolled. All patients received 4 cycles of standard adjuvant chemotherapy. Patients who received Chinese herbal decoction and (or) oral Chinese patent medicine for a cumulative period of not less than 6 months were defined as TCM group, otherwise they were considered as control group. The primary endpoint was DFS calculated using the Kaplan-Meier method. A time-dependent Cox proportional hazards model was used to correct immortal time bias. The secondary endpoints included DFS in patients of different characteristics, and safety analyses. This study was registered with the Chinese Clinical Trial Registry (ChiCTR1800015776). Results: A total of 507 patients were included (230 patients in the TCM group; 277 patients in the control group). The median follow-up was 32.1 months. 101 (44%) in the TCM group and 186 (67%) in the control group had disease relapse. The median DFS was not reached in the TCM group and was 19.4 months (95% CI, 14.2 to 24.6) in the control group. The adjusted time-dependent HR was 0.61 (95% CI, 0.47 to 0.78), equalling to a 39% reduction in the risk of disease recurrence with TCM. the number needed to treat to prevent one patient from relapsing was 4.29 (95% CI, 3.15 to 6.73) at 5 years. Similar results were observed in most of subgroups. Patients had a significant improvement in white blood cell decrease, nausea, decreased appetite, diarrhea, pain, and fatigue in the TCM group. Conclusion: TCM may improves DFS and has a better tolerability profile in patients with stage II-IIIA NSCLC receiving standard chemotherapy after complete resection compared with those receiving standard chemotherapy alone. Further studies are warranted.

Clinical Efficacy and Safety of Traditional Medicine Preparations Combined With Chemotherapy for Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Background: Traditional medicine preparations (TMPs) combined with chemotherapy is widely used for patients with advanced pancreatic cancer (APC); however, its efficacy and safety are still unclear. The purpose of this meta-analysis was to evaluate the clinical efficacy and safety of TMPs combined with chemotherapy for the treatment of APC. Methods: A systematic search of eight electronic databases for randomized controlled trials (RCTs) was conducted from inception to October 15, 2021. Tumor response was identified as primary outcome, whereas quality of life (QoL), cancer biomarkers, and adverse drug reactions (ADRs) were identified as secondary outcomes. Quality of the evidence for each outcome was evaluated by GRADE profiler. Results: In total, 31 RCTs involving 1,989 individuals were included. This meta-analysis showed that TMPs combined with chemotherapy significantly improved the objective response rate (ORR) (RR=1.64, 95% CI [1.43 to 1.88], p <0.00001), disease control rate (DCR) (RR=1.29, 95% CI [1.21 to 1.38], p <0.00001), and QoL (continuous data: SMD=0.81, 95% CI [0.44 to 1.18], p <0.0001, dichotomous data: RR=1.44, 95% CI [1.22 to 1.70], p<0.0001), compared to those with chemotherapy alone. In addition, the combined treatment group also had lower levels of CA19-9 (SMD=-0.46, 95% CI [-0.90 to -0.02], p=0.04) and CEA (SMD=-0.55, 95% CI [-0.93 to -0.17], p=0.004). Moreover, TMPs reduced the ADRs during chemotherapy. Conclusion: This systematic review suggests that TMPs combined with chemotherapy might be a potential option to enhance therapeutic effects and reduce ADRs during the treatment of APC. However, more high-quality randomized controlled trials with more participants are needed. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=209825, identifier PROSPERO Number: CRD42021264938.

UGT1A1 Allele Test Not Only Minimizes the Toxicity But Also Maximizes the Therapeutic Effect of Irinotecan in the Treatment of Colorectal Cancer: A Narrative Review.

Background: Irinotecan is a first-line agent in the systematic treatment of colorectal cancer (CRC). Adjusting the dose of irinotecan according to the uridine diphosphate glucuronosyltransferase (UGT) 1A1 genotype reflects the principle of individualized and precision medicine, and may improve the chemotherapy response and survival of CRC. Methods: To summarize the feasibility, efficacy and safety of high dose irinotecan in CRC patients with UGT1A1 wild-type or heterozygous alleles, PubMed, EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials online databases were searched from the date of creation to October 22, 2021. Results: A total of 1,186 related literatures were searched, and 14 studies were included for review according to the inclusion criteria. The results indicated that the maximum tolerated dose of irinotecan in CRC patients with UGT1A1 wild-type or heterozygous variant was significantly higher than the conventional recommended dose. Chemotherapy based on high dose irinotecan improved the clinical efficacy in mCRC patients with UGT1A1*28 wild-type and heterozygous variant, and the toxicity was tolerated, as reflected in most studies. Conclusions: We are optimistic about the application of high dose irinotecan for mCRC patients with UGT1A1*28 wild-type or heterozygous variant, which will provide a relatively clear direction for future research and certain norms for clinical practice.

Wnt Signaling Pathways: A Role in Pain Processing.

The wingless-related integration site (Wnt) signaling pathway plays an essential role in embryonic development and nervous system regulation. It is critically involved in multiple types of neuropathic pain (NP), such as HIV-related NP, cancer pain, diabetic neuralgia, multiple sclerosis-related NP, endometriosis pain, and other painful diseases. Wnt signaling is also implicated in the pain induced by sciatic nerve compression injury and selective spinal nerve ligation. Thus, the Wnt signaling pathway may be a potential therapeutic target for NP.

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.

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.

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.

The nonreceptor protein tyrosine kinase Src participates in every step of cancer-induced bone pain.

Cancer-induced bone pain (CIBP) is a refractory form of pain that has a high incidence in advanced tumors. Src protein tyrosine kinase is mainly composed of six domains, with two states of automatic inhibition and activation. The modular domain allows Src to conveniently regulate by and communicate with a variety of proteins, directly or indirectly participate in each step of the CIBP process. Src is beneficial to the growth and proliferation of tumor cells, and it can promote the metastases of primary tumors to bone. In the microenvironment of bone metastasis, it mainly mediates bone resorption, activates related peripheral receptors to participate in the formation of pain signals, and may promote the generation of pathological sensory nerve fibers. In the process of pain signal transmission, it mainly mediates NMDAR and central glial cells to regulate pain signal intensity and central sensitization, but it is not limited to these two aspects. Both basic experimentation and clinical research have shown encouraging potential, providing new ideas and inspiration for the prevention and treatment of CIBP.

Shuangshen granules attenuate lung metastasis by modulating bone marrow differentiation through mTOR signalling inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine Shuangshen granules (SSG) have been used to treat lung cancer patients with Qi deficiency and blood stasis for decades. According to clinical experience, SSG indeed improve the quality of life and prolong the survival time of patients with lung cancer after surgery. Each of the components herbs was proved to be effective in anti-cancer therapy. Both the American ginseng and notoginseng belong to genus Panax of the family Araliaceae. Preclinical and clinical studies demonstrated that ginsenosides of them have anti- or preventive activities to various tumors, including cancers of gastric, breast, liver, lung, ovarian, colon, melanoma and leukemia. PDS, such as ginsenoside Rb1, and PTS, such as ginsenoside Rg1 are the main anticancer compositions. Cordyceps sinensis had also been found effective in inhibiting tumour growth and metastasis, especially on tumour associated immune cells, such as macrophages. However, limited information is available regarding potential mechanisms of SSG. Myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, which is closely associated with poor clinical outcomes in cancer patients, may be the target of SSG, which regulate immune function. AIM OF THE STUDY: The present study aimed to explore whether SSG attenuate the differentiation of bone marrow cells (BMCs) into MDSCs by blocking the mTOR signalling, leading to the suppression of lung metastasis. MATERIALS AND METHODS: First, we observed the differentiation of BMCs into MDSCs in vitro and in vivo. BMCs were cultured alone or co-cultured with Lewis lung carcinoma (LLC) cell supernatant in vitro. The effects of different concentrations of SSG, or LLC cell supernatant as a control, on BMC differentiation were detected by flow cytometry and western blotting. Male C57BL/6J mice were subcutaneously implanted with LLC cells, and SSG were administered by gavage twice daily before and after implantation for 7 or 14 days, respectively. The tumour weight, proportion of MDSCs, presence of CD11b+Ly6C+Ly6G- and CD11b+Ly6C+Ly6G+ cells in the bone marrow, blood, and lungs, as well as the expression levels of differentiation-related proteins in the bone marrow and lungs were evaluated. RESULTS: SSG attenuated the differentiation of BMCs into MDSCs, and reduced the fraction of CD11b+Ly6C+Ly6G+ cells by inhibiting the mTOR/S6K1/Myc signalling pathway. In vivo, SSG attenuated differentiation-associated protein markers and reduced the fractions of MDSCs and CD11b+Ly6C+Ly6G+ cells in the bone marrow, blood, and lungs. In addition, SSG administration reduced the tumour weight and inhibited lung metastasis. CONCLUSIONS: SSG may reduce lung metastasis by attenuating BMC differentiation into CD11b+Ly6C+Ly6G+ cells by inhibiting mTOR signalling in vitro and in vivo.

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.

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.