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Trastuzumab is a humanized mAb used to treat HER2-overexpressing breast cancer; however its mechanisms remain to be fully elucidated. Previous studies suggest a role for immunity in mediating trastuzumab-specific antitumor effects. This study evaluated the role(s) of trastuzumab and other antibodies on macrophage activation and Ab-dependent cell-mediated phagocytosis (ADCP) of HER2+ breast cancer cells in vitro and in vivo. We employed orthotopic implantation of HER2+ murine breast cancer (BC) cells in immunocompetent mouse models, a human HER2+ BC xenograft in an immune humanized mouse model, and human PDXs involving adoptive transfer of autologous macrophages to simulate an endogenous mammary tumor-immune microenvironment. Our study demonstrated that trastuzumab greatly and consistently increased macrophage frequency and tumor-cell phagocytosis, and that concurrent knockdown of B7-H4 by a neutralizing antibody increased immune cell infiltration and promoted an antitumor phenotype. Furthermore, neoadjuvant trastuzumab therapy significantly upregulated B7-H4 in the cancer-infiltrating macrophages of HER2+ BC patients, which predicted poor trastuzumab response. We suggest that strategies to specifically enhance ADCP activity might be critical to overcoming resistance to HER2 mAb therapies by inhibiting tumor growth and potentially enhance antigen presentation. Furthermore, these results advance the understanding of macrophage plasticity by uncovering a dual role for ADCP in macrophages involving elimination of tumors by engulfing cancer cells while causing a concomitant undesired effect by upregulating immunosuppressive checkpoints.

Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive subtype of non-small-cell lung cancer (NSCLC). Here, we present information on the clinicopathologic characteristics and clinical outcomes of this type of cancer. Clinicopathologic data from 55 patients treated at a single cancer center from January 2011 to December 2018 were retrospectively analyzed. The patients were mostly male (76.4%), with a median age of 66 years and a history of smoking (54.5%). Most had symptoms, and about 60% presented with locally advanced or metastatic disease at diagnosis. Of the 55 cases, 21 were diagnosed by surgical resection. Pleomorphic cancer was the most common subtype (58.1%). With a median follow-up period of 13.2 months, the average survival time of the patients was 16.1 months, and the median survival time was 12 months. The overall survival rates for 1, 2, and 3 years were 52.7%, 18.2%, and 9.1%, respectively. Univariate analysis showed that prognosis of the patients was influenced by tumor size, T stage, metastatic status, and surgery (p < 0.05). Multivariate analysis showed that T stage (p = 0.034) was an independent prognostic factor. There are few reports on the natural history of PSC, and its clinicopathological characteristics remain unclear. Herein, a retrospective review 55 individuals with PSC found that T stage was an independent predictor of survival. Surgical resection was associated with better prognosis.

Pyrotinib (PYR) is a pan-HER kinase inhibitor that inhibits signaling via the RAS/RAF/MEK/MAPK and PI3K/AKT pathways. In this study, we aimed to investigate the antitumor efficacy of pyrotinib combined with adriamycin (ADM) and explore its mechanisms on HER2+ breast cancer. We investigated the effects of PYR and ADM on breast cancer in vitro and in vivo. MTT assay, Wound-healing, and transwell invasion assays were used to determine the effects of PYR, ADM or PYR combined with ADM on cell proliferation, migration, and invasion of SK-BR-3 and AU565 cells in vitro. Cell apoptosis and cycle were detected through flow cytometry. In vivo, xenograft models were established to test the effect of PYR, ADM, or the combined therapy on the nude mice. Western blotting was performed to assess the expression of Akt, p-Akt, p-65, p-p65, and FOXC1. The results indicated that PYR and ADM significantly inhibited the proliferation, migration, and invasion of SK-BR-3 and AU565 cells, and the inhibitory rate of the combination group was higher than each monotherapy group. PYR induced G1 phase cell-cycle arrest, while ADM induced G2 phase arrest, while the combination group induced G2 phase arrest. The combined treatment showed synergistic anticancer activities. Moreover, PYR significantly downregulated the expression of p-Akt, p-p65, and FOXC1. In clinical settings, PYR also exerts satisfactory efficacy against breast cancer. These findings suggest that the combination of PYR and ADM shows synergistic effects both in vitro and in vivo. PYR suppresses the proliferation, migration, and invasion of breast cancers through down-regulation of the Akt/p65/FOXC1 pathway.

Object Ovarian cancer is the primary cause of cancer-associated deaths among gynaecological malignancies. Increasing evidence suggests that microRNAs may be potential biomarkers for the diagnosis and prognosis of cancer. In this study, we conducted a systematic review and meta-analysis to summarize the global research and to evaluate the overall diagnostic accuracy of miRNAs in detecting ovarian cancer. Methods A systematic literature search was conducted for relevant studies through July 20, 2017, in English databases (CENTRAL, MEDLINE, and EMBASE), the Grey reference database and Chinese databases. Statistical analysis was conducted using OpenMetaAnalyst, STATA 14.0 and RevMan 5.3. Pooled sensitivity, specificity, and other parameters were used to assess the overall miRNA assay performance using a bivariate random-effects model (BRM). Meta-regression and subgroup analyses were performed to dissect the heterogeneity. Sensitivity analysis was performed to assess the robustness of our analysis, and the publication bias of the selected studies was assessed using Deeks’ funnel plot asymmetry test. Results Thirteen articles described 33 studies, including 1081 patients with ovarian cancer and 518 controls. The pooled results were as follows: sensitivity, 0.89 (95% CI: 0.84–0.93); specificity, 0.64 (95% CI: 0.56–0.72); positive likelihood ratio, 2.18 (95% CI: 1.89–2.51); negative likelihood ratio, 0.15 (95% CI: 0.11–0.22); and diagnostic odds ratio (DOR), 13.21 (95% CI: 9.00–19.38). We conducted subgroup analyses based on ethnicity, research design, and miRNA profiling and found that multiple miRNA panels were more accurate in detecting ovarian cancer, with a combined DOR of 30.06 (95% CI: 8.58–105.37). Conclusion Per the meta-analysis, circulating miRNAs may be novel and non-invasive biomarkers for detecting ovarian cancer, particularly multiple miRNA panels, which have potential diagnostic value as screening tools in clinical practice. Electronic supplementary material The online version of this article (10.1186/s13048-019-0482-8) contains supplementary material, which is available to authorized users.

275 Background: To determine Quality-of-Life (QoL) improvement by Megestrol Acetate (MA) in local advanced esophageal squamous cell carcinoma (ESCC) with definitive concurrent chemoradiotherapy (DCRT). Secondary aims were to examine the safety and the impact of MA on the efficacy of DCRT. Methods: Patients (with previously untreated T1bN+M0 or T2-4aN0-2M0 ESCC) were randomly assigned at a one-to-one ratio to receive MA or placebo (blind). All received 5-FU based chemotherapy with concurrent radiotherapy (50Gy/25F). QoL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) questionnaires at pretreatment and 3, 6, 16 weeks of DCRT. The good status (GS) rate of appetite loss (AL), nausea and vomiting (NV), weight (WT) and performance status (PS) were chosen as predefined primary end points. GS defined as the score were ≤ 0 for AL or NV and ≥ 0 for WE or PS when the designed time points compared with last one. Secondary end points were the comprehensive QoL (remaining items of QLQ-C30 changes analysis at 16th week), myelosuppression (MS), and deep vein thrombosis (DVT). The exploratory end points were the objective response rate (ORR), 1-year overall survival (OS) and progression-free survival (PFS). Results: 84 completed the follow-up and were analyzed from which 120 patients randomly assigned. The GS rates of AL (3th week: P = 0.011; 6th week: P < 0.001; 16th week: P = 0.001), NV (6th week: P = 0.001) and PS (6th week: P = 0.01) were higher in MA than Placebo. There were no statistical differences between MA and Placebo on WT. At 16th week, the change degree analysis shown the fatigue was worse in MA than Placebo ( p = 0.031). There were no differences on MS, DVT, ORR, OS and PFS between two arms. Nevertheless the rate of DVT was slightly higher in MA than Placebo (12.5% vs. 2.8%, P = 0.113). Conclusions: MA is helpful for ESCC patients receiving DCRT as well as the risk of DVT needed be careful.

Background:To investigate the pathologic complete response (pCR) rates of dual human epidermal growth factor receptor 2 (HER2) blockade in a neoadjuvant setting for HER2+ breast cancer.Methods:We searched randomized clinical trials (RCTs) using dual HER2 blockade in a neoadjuvant setting for HER2+ breast cancer in PubMed, the Cochrane Library, Embase and ClinicalTrials.gov up to July 5, 2020, and all included studies were assessed according to the Cochrane Collaboration tool for assessing the risk of bias of RCTs, and the statistical analyses were performed using STATA 14.0 software.Results:A total of 9 RCTs involving 2758 patients were included. Meta-analysis indicated that the pCR rates of lapatinib/pertuzumab/neratinib plus trastuzumab versus trastuzumab [relative risk (RR) = 1.31; 95% confidence interval (CI): 1.21-1.43; p < 0.001)] and lapatinib plus trastuzumab versus lapatinib (RR = 1.39; 95%CI: 1.25-1.53; p < 0.001) showed a significant statistical difference between dual HER2-blockade treatment and single-agent treatment in a neoadjuvant setting for HER2+ breast cancer. Additionally, there was no statistically significant difference in disease-free survival (HR = 0.72; 95% CI: 0.47-1.09; p = 0.123), incidence of serious adverse events (SAEs) (RR = 1.04; 95%CI: 0.81-1.33; p = 0.778) and cardiotoxicity(RR = 1.30; 95%CI: 0.81-2.08; p = 0.280), and the pCR rate was unaffected by hormone receptor status.Conclusions:The pCR rate of neoadjuvant dual-target therapy for HER2+ breast cancer was significantly higher than that of single-target therapy. Furthermore, the results indicated that the safety of dual-target therapy is similar to that of single-target therapy.

Neoadjuvant chemotherapy (NCT) is a standard care for esophageal squamous cell carcinoma (ESCC), but the efficacy is unsatisfactory. Cancer stem cells (CSCs) play key roles in chemotherapy resistance. Gene amplified in squamous cell carcinoma 1 (GASC1) is a neoteric gene in stemness maintaining of ESCC. We aimed to reveal whether GASC1 could be a predictive biomarker for NCT in ESCC. ESCC patients (T2-4N0-2M0) were evaluated for GASC1 expression using immunohistochemical staining and classified as GASC1-low group (GLG) and GASC1-high group (GHG). NCT was delivered in two cycles and then the surgery was completed. Primary endpoints were tumor regression grade (TRG) and objective response rate (ORR); secondary endpoints were radical surgical resection (R0) rate and three-year overall survival (OS). 60 patients were eligible with evaluable outcomes: 24 in GHG and 36 in GLG. Between GHG and GLG, TRG1, TRG2, TRG3, and TRG4 were 0 : 16.7%, 20.8% : 41.7%, 58.3% : 36.1%, and 20.8% : 5.6%, respectively (P=0.006); ORR and R0 rate were 33.3% : 69.4% (P=0.006) and 75% : 94.4% (P=0.046), respectively; the median OS was 20 : 32 (months) (P=0.0356). No significant difference in the three-year OS was observed between GHG and GLG: 29.2% : 41.7% (P=0.24). Furthermore, the GASC1 expression level was associated with poor OS independent of other factors by univariate and multivariate analyses. Therefore, GASC1 might be a potential biomarker to predict NCT efficacy for ESCC.

BACKGROUND: Apatinib is a new generation of small molecule tyrosine kinase inhibitor, which can highly selectively inhibit phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2). This study aimed to investigate the synergistic effects of apatinib and paclitaxel (PTX) on triple-negative breast cancer (TNBC) in vivo and in vitro, and to explore the molecular mechanism of the PI3K/p65/Bcl-xl pathway. METHODS: In vitro, 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) method, flow cytometry (FCM), wound healing assay, and transwell matrix assay were conducted to measure the effects of apatinib and PTX on cell viability, apoptosis, migration, and invasion in TNBC cell line MDA-MB-468. Western blot (WB) was conducted to detect protein expression levels of PI3K, p65, and Bcl-xl after the application of apatinib and PTX. In vivo, MDA-MB-468 tumor-bearing nude mice were treated with apatinib and PTX, and tumor growth was observed. RESULTS: In vitro, apatinib and PTX could synergistically suppress the cell viability, the combined group had the most obvious effect. Apatinib and PTX could promote apoptosis and suppress migration and invasion of TNBC cells. Apatinib could reduce the expression of p-PI3K, p65, and Bcl-xl proteins (P

Whether consolidation chemotherapy (CCT) after chemoradiotherapy (CRT) helps in the treatment of locally advanced non-small cell lung cancer (LA-NSCLC) is controversial. The aim of this meta-analysis was to evaluate the impact of CCT on overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and toxicities in patients with inoperable LA-NSCLC. PubMed, Embase, The Cochrane Library, WanFang, VIP, and CNKI were searched to identify any relevant publications. After screening the literature and completing quality assessment and data extraction, the meta-analysis was performed using RevMan5.3 software. Ultimately, 5 eligible studies with a total of 1036 patients were selected for the present meta-analysis. The results of the analysis indicated that treatment of LA-NSCLC patients with CRT followed by CCT improved OS (pooled HR 0.85; 95% CI 0.73-0.99; P = 0.03), but did not improve PFS (pooled HR 0.78; 95% CI 0.60-1.02; P = 0.07) and ORR (P = 0.26). Although it could increase the risk of grade ≥3 infection (P = 0.04), it may not increase the risk of grade ≥3 radiation pneumonitis (P = 0.09) during the CCT period. CCT after concurrent CRT may provide additional benefits in the treatment of LA-NSCLC. Although this therapeutic strategy did not prolong PFS, further assessment is warranted.