Characteristics and Prognostic Analysis of 55 Patients With Pulmonary Sarcomatoid Carcinoma.

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.

Apatinib enhances the anti-tumor effect of paclitaxel via the PI3K/p65/Bcl-xl pathway in triple-negative breast cancer.

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<0.05). In vivo, apatinib and PTX could inhibit tumor size and weight of model mice, and the combined agents had a more significant effect. CONCLUSIONS: Apatinib could enhance the anti-tumor effect of PTX on TNBC cells through the PI3K/p65/Bcl-xl molecular pathway, and apatinib combined with PTX might be a promising option for TNBC treatment.

The Synergistic Effects of Pyrotinib Combined With Adriamycin on HER2-Positive Breast Cancer.

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.

A Systematic Review and Meta-Analysis of Immune-Related Adverse Events of Anti-PD-1 Drugs in Randomized Controlled Trials.

OBJECTIVE: We aimed to evaluate immune-related adverse events occurring in clinical trials of anti-programmed cell death 1 (PD-1) drugs, compared with control treatments, including chemotherapy, targeted drugs, or placebo. Further we compared the occurrence of immune -related events in patients treated with different anti-PD-1 drugs. DATA SOURCES: Randomized controlled trial (RCT) data were sourced from PubMed, Embase, and the Cochrane Central Register of Controlled Trials combined with https://clinicaltrials.gov. METHODS: Randomized controlled trial of anti-PD-1 drugs compared with control treatments published between January 1, 1970 and March 1,2019, were searched and data on trial patient characteristics, and adverse events extracted, reviewed, and subjected to meta-analysis. RESULTS: Eighteen Randomized controlled trials were included in our study. The Randomized controlled trials compared nivolumab (n = 12), pembrolizumab (n = 6), with chemotherapy (n = 13), targeted drugs (n = 2), or placebo (n = 3). Compared with the control group, the risk of any immune-related adverse events in patients treated with anti-PD-1 drugs was increased (RR, 2.65; 95% confidence interval, 1.84-3.83; P < 0.00001). Of the immune-related adverse events, the risk rates of pneumonitis (risk ratio, 2.10; 95% CI, 0.85-5.18), colitis (2.96;1.62-5.38), hypophysitis(4.79;1.54-14.89), hypothyroidism(7.87;5.36-11.57), hyperthyroidism (7.03;4.35-11.34), rash (1.58;0.98-2.54), pruritus (2.28; 1.38-3.76), and hepatitis (9.31;2.18-39.85) were increased by anti-PD-1 drugs. Further, the risk of immune-related adverse events was similar for patients treated with pembrolizumab and nivolumab (P = 0.14). CONCLUSIONS: In addition to previously reported organ-specific immune-related adverse events, we found that the risk of hyperthyroidism was also increased, in anit-PD-1-treated patients, relative to control treatments. The risk of total immune-related adverse events, was similar for pembrolizumab and nivolumab.

The anti-B7-H4 checkpoint synergizes trastuzumab treatment to promote phagocytosis and eradicate breast cancer.

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.

Dual HER2 Blockade in Neoadjuvant Treatment of HER2+ Breast Cancer: A Meta-Analysis and Review.

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.

GASC1-Adapted Neoadjuvant Chemotherapy for Resectable Esophageal Squamous Cell Carcinoma: A Prospective Clinical Biomarker Trial.

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.

Circulating microRNAs as novel potential diagnostic biomarkers for ovarian cancer: a systematic review and updated meta-analysis.

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.

Cell-free DNA in blood and urine as a diagnostic tool for bladder cancer: a meta-analysis.

OBJECTIVE: To assess the diagnostic performance of cell-free DNA assays in the detection of bladder cancer. PATIENTS AND METHODS: The quality of the studies included in this meta-analysis was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Statistical analyses were performed using the software RevMan 5.3 and Stata 14.0. We assessed the pooled sensitivity and specificity, positive/negative likelihood ratios (PLRs/NLRs), diagnostic odds ratios (DORs), and corresponding 95% confidence intervals (95% CIs). Summary receiver operating characteristic curve (ROC curve) and area under the curve (AUC) were used to summarize the overall test performance. Heterogeneity and publication bias were also examined. RESULTS: Eleven studies included 802 bladder cancer patients and 668 controls met the eligibility criteria. The overall diagnostic accuracy was measured as follows: sensitivity 0.71 (95% CI = 0.64-0.77), specificity 0.78 (95% CI = 0.70-0.85), PLR 3.3 (95% CI = 2.4-54.5), NLR 0.37 (95% CI = 0.30-0.46), DOR 9 (95% CI = 6-14), and AUC 0.80 (95% CI = 0.77-0.83). Subgroup analysis suggested that ethnicity significantly accounted for the heterogeneity of specificity. The Deeks' funnel plot asymmetry test (P = 0.97) suggested no potential publication bias. CONCLUSIONS: Cell-free DNA has a high diagnostic value in bladder cancer.

A highly integrated precision nanomedicine strategy to target esophageal squamous cell cancer molecularly and physically.

The prognosis of esophageal squamous cell carcinoma is poor. We hereby presented a highly integrated and clinically relevant precision nanomedicine strategy to target ESCC molecularly and physically for significant improvement of the treatment efficacy. We firstly identified PI3K overexpression in patient samples and its relation to poor patient survival. With our highly versatile tumor-targeted drug delivery platform (DCM), we were able to load a potent but toxic docetaxel (DTX) and a PI3K inhibitor (AZD8186) with favorable physical properties. The combination of the DTX-DCM and AZD8186-DCM showed a highly efficacious and synergistic anti-tumor effect and decreased hematotoxicity. A pro-apoptotic protein, Bax was significantly upregulated in ESCC cells treated with combination therapy compared to that with monotherapy. This study utilized a highly integrated precision nano-medicine strategy that combines the identification of cancer molecular target from human patients, precision drug delivery and effective combination therapy for the development of better ESCC treatment.

Nanoformulated paclitaxel and AZD9291 synergistically eradicate non-small-cell lung cancers in vivo.

AIM: This study aims to develop new nanoformulations of EGFR T790M targeted inhibitor AZD9291 and paclitaxel (PTX) for combination therapy of lung cancer. MATERIALS & METHODS: We prepared and characterized PTX- and AZD9291-loaded disulfide cross-linking micelles (DCMs), and evaluate their combination effect and toxicity in vitro and in lung cancer-bearing mice. RESULTS: Drug-loaded DCMs were relatively small in size, and possessed glutathione-responsive drug release. The combination of PTX-DCMs and AZD92921-DCMs exhibited strong synergistic effects in both cell line and in vivo without additional toxicity. Molecular studies demonstrated the synergistic modification in both IKB-α/NF-κB/Bcl-2 and EGFR/Akt pathways. CONCLUSION: The combination of DCM-loaded AZD9291 and PTX could potentially offer more effective and less toxicity treatment options for lung cancer patients.

A versatile nanoplatform for synergistic combination therapy to treat human esophageal cancer.

One of the major goals of precision oncology is to promote combination therapy to improve efficacy and reduce side effects of anti-cancer drugs based on their molecular mechanisms. In this study, we aimed to develop and validate new nanoformulations of docetaxel (DTX) and bortezomib (BTZ) for targeted combination therapy to treat human esophageal cancer. By leveraging our versatile disulfide cross-linked micelles (DCMs) platform, we developed nanoformulations of DTX and BTZ (named DTX-DCMs and BTZ-DCMs). Their physical properties were characterized; their anti-cancer efficacies and mechanisms of action were investigated in a human esophageal cancer cell line in vitro. Furthermore, the in vitro anti-tumor activities of combination therapies (concurrent drug treatment, sequential drug treatment, and treatment using different ratios of the drugs) were examined in comparison with the single drug treatment and free drug strategies. These drug-loaded nanoparticles were spherical in shape and relatively small in size of approximately 20-22 nm. The entrapment efficiencies of DTX and BTZ into nanoparticles were 82.4% and 84.1%, respectively. The drug release rates of DTX-DCMs and BTZ-DCMs were sustained, and greatly increased in the presence of GSH. These nanodrugs were effectively internalized by KYSE30 esophageal cancer cells, and dose-dependently induced cell apoptosis. We further revealed a strong synergistic effect between DTX-DCMs and BTZ-DCMs against KYSE30 esophageal cancer cells. Sequential combination therapy with DTX-DCMs followed by BTZ-DCMs exhibited the best anti-tumor efficacy in vitro. This study demonstrates that DTX and BTZ could be successfully nanoformulated into disulfide cross-linked micelles. The nanoformulations of DTX and BTZ demonstrate an immense potential for synergistic combination therapy to treat human esophageal cancer.

The effect of consolidation chemotherapy after concurrent chemoradiotherapy on the survival of patients with locally advanced non-small cell lung cancer: a meta-analysis.

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.