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.
Introduction:The prognostic values of nutritional and immune-inflammatory indicators in nonmetastatic soft tissue sarcoma (STS) patients are not clear. We investigated the utility of systemic immune-inflammation index (SII) and the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) in the prediction of STS patient's prognosis. Materials and methods: Patients admitted between January 2000 and December 2016, who underwent R0 resection for STS at SYSUCC were carefully retrospectively reviewed, and 454 patients were enrolled. The laboratory data and clinical data were collected from the patient's record. ROC analysis is used to determine the optimal cutoff value. Survival curves were analysed by Kaplan-Meier method. Cox proportional hazard model was used to find out prognostic variables. Results: Increased SII and Hs-mGPS values were significantly related to larger tumour size, deep tumour location, higher tumour grade and more advanced American Joint Committee on Cancer (AJCC) stage. Patients with an elevated SII had a shorter median survival time and a lower 5-year OS rate than those with a low SII. And patients with low Hs-mGPS had longer median OS and DFS. Multivariate analysis revealed that both the SII and the Hs-mGPS were independent predictive indicators for OS. And a joint model containing both the Hsm-GPS and the SII appeared to have the strongest predictive ability. Conclusion: Our findings indicated that malnutrition and systemic inflammation are risk factors for the survival of STS patients after operation, and early recognition and intervention of malnutrition and systemic inflammation may help to improve the survival of the patients.
Objective The purpose of this retrospective study was to identify the prognostic significance of time to local recurrence (TLR) with regard to overall survival (OS) and survival after local recurrence (SAR) in patients with soft tissue sarcoma (STS) of the extremity and abdominothoracic wall. Methods We identified 477 patients who underwent R0 resection for localized STS of the extremity and abdominothoracic wall, from January 1995 to December 2016, of whom 190 patients developed local recurrence as their first recurrent event. Based on TLR, patients were divided into two groups: early local recurrence (ELR, <12 months) and late local recurrence (LLR, ≥12 months). The Kaplan–Meier method and Cox regression analysis were used to estimate the OS and SAR, and to identify factors associated with patient outcomes. Results The median follow-up time for the entire cohort was 118.4 months, and was 118.5 months for the 190 patients who developed local recurrence. Deep tumor location (HR 1.73, 95% CI 1.27–2.37, P = 0.001) and tumor grade ≥2 (G2 vs. G1: HR 1.75, 95% CI 1.21–2.53, G3 vs. G1: HR 2.57, 95% CI 1.66–3.98, P < 0.001) were associated with a higher rate of local recurrence. There were 99 patients in the ELR group and 91 in the LLR group, with a median TLR of 10.8 months for the entire cohort. Patients from the ELR group had a shorter OS and a lower 5-year OS rate than the LLR group. Univariate and multivariate analyses demonstrated TLR as an independent prognostic factor for SAR and OS, in addition to tumor grade. Also, surgical treatment and absence of metastasis after local recurrence were associated with longer SAR. Conclusions In patients with STS of the extremity and abdominothoracic wall, ELR after R0 resection indicated a worse prognosis than those with LLR, and TLR can be considered an independent prognostic factor for OS and SAR. Furthermore, local recurrence was significantly influenced by the depth and the histopathological grading of the primary tumor, and reoperation after local recurrence could improve survival, which means salvage surgery may still be the preferred treatment when there are surgical indications after recurrence.
Monodisperse carboxymethyl cellulose containing phenolic groups (CMC‐Ph) microdroplets with a radius of 100–400 μm and a coefficient of variation below 3% were produced in a coflowing microfluidic device. The CMC‐Ph solution containing horseradish peroxidase was used as the disperse phase and liquid paraffin containing H2O2 and lecithin as the continuous phase. The size of microdroplets decreased with the decreasing diameter of the inner channel and concentration of the disperse phase. When using a 0.04% CMC‐Ph solution and the device with the inner diameter of 160 μm, the size of the microdroplets can be further controlled by the flow rates of both the continuous phase and disperse phase following exponential models. The volume of the microdroplet was not inversely proportional to the flow‐rate ratio of the continuous phase to the disperse phase. There was a weak dependence of the volume on the flow of the continuous phase. The monodisperse microparticles possessed potential application for sensor, drug delivery system, cell encapsulation, catalysis, and imaging. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40663.
BackgroundUnplanned excision (UPE) of soft tissue sarcoma (STS) is often chosen in the early phase by general physicians without any radiological evaluation.PurposeThe present study aimed to evaluate the impact of UPE on the clinical outcomes of patients with STS of the trunk and extremity.Materials and MethodsPatients with STS of the trunk and extremity who underwent R0 resection between 1998 and 2016 were included and divided into the UPE and planned excision (PE) groups. Propensity score matching (PSM) was used to control the selection bias. The endpoints were disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS).ResultsIn total, 458 patients (277 males, 181 females; median age: 43 years) were included: 329 (71.8%) in the PE group and 129 (28.2%) in the UPE group. The follow-up time ranged from 7.1 to 313.78 months, with a median of 112.18 months. UPE patients were more likely to have a smaller or superficial lesion and were more frequently administered adjuvant therapy. After PSM, compared with the PE group, the UPE group had a longer LRFS (P=0.015), but there was no difference between the two groups regarding DSS and MFS. Residual disease was observed in 77.5% of the re-resected specimens in the UPE group and was a risk factor for DSS (P = 0.046) and MFS (P = 0.029) but was not associated with local recurrence (LR) (P=0.475) or LRFS (P=0.334). Moreover, we found no difference in DSS, LRFS or MFS according to the interval from UPE to definitive resection.ConclusionSTS treated with UPE had distinct characteristics. Patients who undergo UPE followed by an additional wide R0 resection have similar oncological survival compared to patients who undergo an initial PE, although the high incidence of residual tumor in the UPE group leads to an unfavorable clinical course.
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