Background: Programmed death ligand-1(PD-L1) functions as a negative mediator of immune response through different pathways in anti-tumor immunity. Recent studies have reported that PD-L1 plays a pivotal role in the function of regulatory T-cells (Tregs). Although increases in FOXP3+ Tregs infiltration and PD-L1 expression have been revealed in several cancers, their correlation with soft tissue sarcoma remains unknown. Methods: We included 163 cases of soft tissue sarcoma who were diagnosed and underwent extensive and radical resection at the Sun Yat-sen University Cancer Center, Guangzhou, China, from 2000-2010. PD-L1 and FOXP3 expression was evaluated by immunohistochemistry. Correlation between their expressions and associations with clinicopathological features were studied. Results: Among 163 STS samples, 19 (11.7%) exhibited PD-L1 positivity, and 41 (25.2%) cases expressed high FOXP3+ Treg infiltration. Significant correlation between PD-L1 expression and FOXP3+Treg infiltration in STS was identified (r=0.450, p<0.001). In univariate analysis, PD-L1 expression was significantly associated with high tumor grade and the age of patients, while the presence of FOXP3+ in tumor infiltrating Tregs was significantly associated with the age of patients, high tumor stage, higher tumor grade and tumor depth. Multivariate analysis revealed PD-L1 and FOXP3 as independent prognostic indicators significantly associated with OS and DFS. Conclusions: Our study revealed that PD-L1 and FOXP3+Tregs may work synergistically in promoting immune evasion of the tumors in soft tissue sarcoma. A combined strategy to block PD-L1/PD-1 with simultaneous depletion of Tregs may show promise in enhancing the therapeutic efficacy of these patients.

BackgroundInflammation can promote tumor growth, invasion, angiogenesis and even metastasis. Inflammatory markers have been identified as prognostic indicators in various malignances. This study compared the usefulness of platelet-lymphocyte ratio (PLR) with that of neutrophil-lymphocyte ratio (NLR) for predicting outcomes of patients who underwent radical resection for soft tissue sarcoma (STS).MethodsWe included 222 STS patients in this retrospective study. Kaplan-Meier curves and multivariate Cox proportional models were used to calculate overall survival (OS) and disease free survival (DFS).ResultsIn univariate analysis, elevated PLR and NLR were both significantly associated with decreased OS. In multivariate analysis, PLR (HR: 2.60; 95 % CI: 1.17–5.74, P = 0.019) but not NLR was still identified as independent predictors of outcome. Median OS was 62 and 76 months for the high PLR and low PLR groups, respectively. High PLR and NLR were both significantly associated with shorter DFS in univariate analysis, with median DFS of 18 and 57 months in the high PLR and low PLR groups. In multivariate analysis, elevated PLR (HR: 1.77; 95 % CI: 1.05–2.97, P = 0.032) was also related to decreased DFS.DiscussionOur findings provide a new and valuable clue for diagnosing and monitoring STS. Prediction of disease progression is not only determined by the use of clinical or histopathological factors including tumor grade, tumor size, and tumor site but also by host-response factors such as performance status, weight loss, and systemic inflammatory response. They also significantly affect clinical outcomes. Thus, PLR can be used to enhance clinical prognostication. Furthermore, the PLR can be assessed from peripheral blood tests that are routinely available without any other complicated expenditure, thus providing lower cost and greater convenience for the prognostication.ConclusionElevated preoperative PLR as an independent prognostic factor is superior to NLR in predicting clinical outcome in patients with STS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1654-6) contains supplementary material, which is available to authorized users.

BackgroundThe advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.MethodsWhole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.ResultsThe HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.ConclusionsThe combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

BackgroundCoagulation and nutrition play important roles in cancer progression. The aim of the present study is to evaluate the prognostic value of the preoperative fibrinogen/albumin ratio (FAR) in surgical patients with soft tissue sarcoma (STS) and to compare this value with other inflammatory biomarkers. In addition, we investigated the relationship between FAR and the clinicopathological characteristics of STS patients.MethodsWe included 310 STS patients in this retrospective study. Kaplan-Meier curves, univariate and multivariate Cox proportional models were used in the prognostic analyses.ResultsAccording to the receiver operating characteristic (ROC) analysis, the optimal FAR cut-off value was 0.0726. The FAR exhibited a greater area under the curve (AUC) value (0.680) than did the NLR and PLR. An elevated FAR (≥0.0726) was significantly associated with an old age, large tumor size, deep tumor location, high tumor grade, and advanced American Joint Committee on Cancer (AJCC) stage.Patients with an increased FAR had a shorter median survival time and a lower 5-year overall survival (OS) rate than did those with a low FAR (61.0 vs115.8 months, P < 0.001; 56.7% vs 82.4%, P < 0.001, respectively). Multivariate analysis indicated FAR (Hazard ratio (HR) 1.907, 95% confidence interval (CI) 1.161–3.132, P < 0.001) to be an independent prognostic factor for OS, as were tumor depth, grade and PLR.ConclusionsPreoperative FAR is associated with tumor progression and can be considered an independent factor for OS of resected STS patients.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4856-x) contains supplementary material, which is available to authorized users.

Background: Preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are associated with poor prognosis in soft tissue sarcoma (STS). The aim of the present study is to determine whether the combination of NLR and PLR (CNP) can better predict patient survival after resection for STS.Methods: We included 310 STS patients in this retrospective study. Preoperative CNP was calculated as follows: patients with both elevated NLR (>2.51) and PLR (>191.1) were given a score of 2; patients showing an increase in one or neither were allocated a score of 1 or 0, respectively.Results: Cut-off values of 2.51 and 191.1 were defined as elevated NLR and PLR, respectively. Elevated CNP was significantly associated with older age (P=0.034), larger tumor size (P=0.025), deeper tumor location (P=0.044), higher tumor grade (P=0.028), a more advanced stage according to the American Joint Committee on Cancer (AJCC) (P=0.005), shorter overall survival (OS) (P=0.000) and shorter disease-free survival (DFS) (P=0.000). Multivariate analysis indicated CNP but not NLR or PLR to be an independent prognostic factor for OS and DFS (P=0.000 and P=0.001, respectively).Conclusions: Preoperative CNP is associated with tumor progression and can be considered an independent marker of postoperative survival in patients with STS.

ObjectiveResearch efforts have investigated therapies targeting tyrosine kinase signaling pathways. We performed a pooled analysis to determine the frequency of severe adverse effects in patients with soft tissue sarcoma treated with pazopanib, sorafenib and sunitinib.Materials and methodsWe performed a comprehensive search of PubMed, Web of Science, Ovid, the Cochrane Library and Embase databases from the drugs’ inception to May 2017 to identify clinical trials. All-grade and severe adverse events (AEs; grade≥3) were analyzed.ResultsA total of 10 trials published between 2009 and 2016, including 843 patients, were eligible for analysis. We included 424 patients (three studies) who received pazopanib 800 mg daily, 353 patients (five studies) who received sorafenib 400 mg twice daily and 66 patients (two studies) who received sunitinib 37.5 mg daily. The incidence of AEs is different among the three VEGFR-tyrosine kinase inhibitors (TKIs). Pazopanib showed higher incidence of all-grade nausea, diarrhea and hypertension compared with sorafenib and sunitinib. However, patients in the sorafenib group experienced a significantly higher frequency of all-grade rash (26.1%), hand–foot syndrome (33.4%) and mucositis (38.5%). The difference was highly significant for sorafenib vs. pazopanib in the incidence of all-grade rash (odds ratio [OR] 1.649, 95% CI 1.086–2.505, P=0.023), hand–foot syndrome (OR 3.096, 95% CI 1.271–7.544, P=0.009) and mucositis (OR 4.562, 95% CI 2.132–9.609, P<0.001). Moreover, the frequency of grade ≥3 mucositis was significantly higher in the sunitinib group compared with the pazopanib or sorafenib group (7.6% vs. 1.3%, OR 6.448, 95% CI 1.499–27.731, P=0.013).ConclusionStatistically significant differences in certain common adverse effects, such as all-grade and severe AEs, were detected among pazopanib, sorafenib and sunitinib in the current study. Early and prompt management is critically needed to avoid unnecessary dose reductions and treatment-related discontinuations.

Purpose: Resistance to chemotherapeutic drugs in nasopharyngeal carcinoma(NPC) remains a major obstacle of clinical therapy. To address the issue, screening for natural low-toxicity products as chemosensitizers has become a promising strategy for cancer therapy. In this study, we investigated chemosensitizing effects of cardamonin (CM), a plant-derived chalcone, on cisplatin (DPP)-resistant NPC cells, and explored the molecular mechanism for its antitumor activity. Methods: The chemotherapeutic e cacy of cardamonin, cisplatin and their combination in cisplatinresistant NPC cells were analyzed using MTT assay, apoptosis assay, and cell cycle analysis. Real-time PCR, western blotting, and cell transfection analysis were performed to assess the synergistic inhibitory action of cardamonin supplemented with cisplatin on Wnt/β-catenin/ABCG2 signaling. The effect of cardamonin on ABCG2 drug e ux function was analyzed by doxorubicin accumulation assay. A CNE2/DPP nude mouse model was used to determine the combinatorial effects of cardamonin on tumor growth in vivo. Results: Cardamonin increased cisplatin-induced cytotoxicity, accompanied by induction of apoptosis and cell cycle arrest in DPP-resistant NPC cells. Moreover, cardamonin could synergized with cisplatin to downregulate β-catenin, c-Myc, and ABCG2. Speci cally, cardamonin inhibited Wnt/β-catenin/ABCG2 signaling through c-Myc-mediated transcription inactivation, thereby suppressing the expression of ABCG2 in cisplatin-resistant NPC cells. These ndings were con rmed in vivo, wherein cardamonin treatment with cisplatin resulted in reduced tumor growth in a CNE2/DPP xenograft animal model. Conclusions: Taken together, our data rstly demonstrated that cardamonin increased chemosensitivity of nasopharyngeal cancer cells to cisplatin through inactivation of Wnt/β-catenin/ABCG2 signaling, more speci cally by inhibition of β-catenin/ABCG2 signaling through c-Myc-mediated transcriptional inactivation, thereby downregulation of ABCG2 and reversal of cisplatin resistance. Thus, in addition to its chemotherapeutic potential, cardamonin may serve as a useful chemosensitizer to conventional chemotherapeutic drugs in the treatment of nasopharyngeal carcinoma.

Abstract.The relationship between TACC3, a member of the transforming acidic coiled-coil proteins (TACCs) family, and lung carcinoma remains unclear. The present study was designed to explore the prognostic and clinical significance of TACC3 in non-small cell lung cancer (NSCLC). An immunohistochemistry (IHC) assay was performed to analyze the expression of TACC3 in 195 lung cancer cases. The mRNA and protein levels of TACC3 were examined by quantitative reverse transcription-PCR or western blotting. The correlation between TACC3 expression and clinicopathological factors was analyzed by χ 2 analysis and Fisher's exact test. Kaplan-Meier analysis and the Cox proportional hazards model were used to examine the correlation of prognostic outcomes with TACC3. The results showed that the levels of TACC3 mRNA and total protein were higher in lung cancer lesions than paired non-cancerous tissues. IHC analysis revealed that TACC3 was highly expressed in 94 (48.2%) cases. The expression of TACC3 was strongly correlated with smoking status, histological classification, differentiation, cytokeratin 19 fragment levels, T stage and the clinical stage of NSCLC patients. Univariate and multivariate analyses demonstrated that TACC3 is a useful biomarker for NSCLC prognosis. The low TACC3 expression group exhibited better progression-free survival (PFS) among patients who received anti-microtubule chemotherapy. In conclusion, the results showed that a high level of TACC3 expression was correlated with advanced clinicopathological classifications, poor overall survival (OS) and poor recurrence-free survival (RFS) in NSCLC patients.Our findings indicate that TACC3 is a potential prognostic marker and therapeutic target for NSCLC.