Prognosis Of Soft Tissue Sarcomas Research Articles

Identifying specific TLS-associated genes as potential biomarkers for predicting prognosis and evaluating the efficacy of immunotherapy in soft tissue sarcoma.

The tertiary lymphatic structure (TLS) is an important component of the tumor immune microenvironment and has important significance in patient prognosis and response to immune therapy. However, the underlying mechanism of TLS in soft tissue sarcoma remains unclear. A total of 256 RNAseq and 7 single-cell sequencing samples were collected from TCGA-SARC and GSE212527 cohorts. Based on published TLS-related gene sets, four TLS scores were established by GSVA algorithm. The immune cell infiltration was calculated via TIMER2.0 and "MCPcounter" algorithms. In addition, the univariate, LASSO, and multivariate-Cox analyses were used to select TLS-related and prognosis-significant hub genes. Single-cell sequencing dataset, clinical immunohistochemical, and cell experiments were utilized to validate the hub genes. In this study, four TLS-related scores were identified, and the total-gene TLS score more accurately reflected the infiltration level of TLS in STS. We further established two hub genes (DUSP9 and TNFSF14) prognosis markers and risk scores associated with soft tissue sarcoma prognosis and immune therapy response. Flow cytometry analysis showed that the amount of CD3, CD8, CD19, and CD11c positive immune cell infiltration in the tumor tissue dedifferentiated liposarcoma patients was significantly higher than that of liposarcoma patients. Cytological experiments showed that soft tissue sarcoma cell lines overexpressing TNFSF14 could inhibit the proliferation and migration of sarcoma cells. This study systematically explored the TLS and related genes from the perspectives of bioinformatics, clinical features and cytology experiments. The total-gene TLS score, risk score and TNFSF14 hub gene may be useful biomarkers for predicting the prognosis and immunotherapy efficacy of soft tissue sarcoma.

Targeting RCC1 to block the human soft-tissue sarcoma by disrupting nucleo-cytoplasmic trafficking of Skp2

Soft-tissue sarcomas (STS) emerges as formidable challenges in clinics due to the complex genetic heterogeneity, high rates of local recurrence and metastasis. Exploring specific targets and biomarkers would benefit the prognosis and treatment of STS. Here, we identified RCC1, a guanine-nucleotide exchange factor for Ran, as an oncogene and a potential intervention target in STS. Bioinformatics analysis indicated that RCC1 is highly expressed and correlated with poor prognosis in STS. Functional studies showed that RCC1 knockdown significantly inhibited the cell cycle transition, proliferation and migration of STS cells in vitro, and the growth of STS xenografts in mice. Mechanistically, we identified Skp2 as a downstream target of RCC1 in STS. Loss of RCC1 substantially diminished Skp2 abundance by compromising its protein stability, resulting in the upregulation of p27Kip1 and G1/S transition arrest. Specifically, RCC1 might facilitate the nucleo-cytoplasmic trafficking of Skp2 via direct interaction. As a result, the cytoplasmic retention of Skp2 would further protect it from ubiquitination and degradation. Notably, recovery of Skp2 expression largely reversed the phenotypes induced by RCC1 knockdown in STS cells. Collectively, this study unveils a novel RCC1-Skp2-p27Kip1 axis in STS oncogenesis, which holds promise for improving prognosis and treatment of this formidable malignancy.

Low NT5DC2 expression predicts favorable prognosis and suppresses soft tissue sarcoma progression via ECM-receptor interaction pathway

BackgroundSoft tissue sarcoma, a malignant tumor arising from mesenchymal tissues with poor prognosis. 5′-Nucleotidase Domain Containing 2 (NT5DC2) is a novel oncogene, and the precise involvement of NT5DC2 in soft tissue sarcoma were still undefined. Hence, our study aims to investigate NT5DC2 functions in soft tissue sarcoma progression. MethodsThe tumor immune single-cell hub 2 (TISCH2) website, The Cancer Genome Atlas (TCGA) pan-cancer or sarcoma and Gene Expression Omnibus (GEO, GSE21122) databases were applied to visualize the NT5DC2 status in the sarcoma databases. The NT5DC2 protein expression in sarcoma tissues in our hospital was detected by using immunohistochemistry (IHC) and analyzed the associations between NT5DC2 expression and clinicopathological parameters. Real-time quantitative polymerase chain reaction (RT-qPCR), colony formation, 5-ethynyl-2′-deoxyuridine (EdU) assay, wound healing, transwell, flow cytometry and xenograft model were used to elucidate the effects of NT5DC2 downregulated by lentivirus in sarcoma cell. ResultsThe TISCH2 website detection found that NT5DC2 expression is enriched in malignant cells in sarcoma single-cell database. Furthermore, the TCGA-sarcoma database indicated that NT5DC2 expression correlates with metastasis, positive margin status, prognosis, and diagnostic value. Additionally, IHC staining showed that 40 % of soft tissue sarcoma patients present high expression of NT5DC2, and NT5DC2 upregulation is closely associated with poor prognosis. Functional verification analysis further revealed that downregulating NT5DC2 expression can suppress sarcoma progression through the ECM-receptor interaction pathway. ConclusionLow expression of NT5DC2 predicts a favorable prognosis in soft tissue sarcoma, and downregulated NT5DC2 expression can suppress sarcoma cell progression through the ECM-receptor interaction pathway.

Multivisceral resection for retroperitoneal liposarcoma-is it worth it? A 20-year single-center experience.

Soft tissue sarcomas are rare malignant tumors. Liposarcoma constitutes the most frequent histological subtype of retroperitoneal sarcoma. The prognosis of soft tissue sarcomas depends on clinical and histologic characteristics. Evaluate variables that may be related to the overall and local recurrence-free survival in patients with retroperitoneal liposarcoma and discuss the need for visceral resection en-bloc for tumors. A retrospective analysis was conducted of the medical records of 60 patients seen between 1997 and 2017 who underwent surgical resection of retroperitoneal liposarcoma. The overall survival rate at 5years of follow-up was 75.22% (95% confidence interval [CI] 0.58-0.86). The probability of a local recurrence-free survival at 5years of follow-up was 26.04% (95% CI 0.11-0.44). The multivariate analysis showed that dedifferentiated or pleomorphic tumors and R2/fragmented resection were associated with a shorter time to recurrence. No other characteristics markedly influenced the overall survival (P > 0.05). Patients with dedifferentiated or pleomorphic tumors and incomplete resection were associated with higher local recurrence rates than others. This study reinforces the need for complete and en-bloc resection with organs when there is clear involvement or technical surgical difficulty to maintain the tumor integrity.

Soft tissue sarcomas of the hand and foot: characteristics of progression and main surgical approaches

Soft tissue sarcomas of the hand and foot comprise a rare subgroup of mesenchymal tumors with more favorable oncological prognosis. For this type of tumors, several options of surgical treatment exist depending on histological subtype, size and local tumor advancement. Additionally, due to significant functional load on the distal parts of the limbs, surgical techniques for treatment of these patients have specific characteristics. However, publications on progression characteristics and prognosis of soft tissue sarcomas of the hand and foot are lacking.This review describes soft tissue sarcomas of the hand and foot and analyzes surgical techniques for treatment of patients with this type of tumor.

Abstract 4804: p38 MAPK-dependent regulation of HIF-1 and expression of the hypoxia-inducible gene IGFBP-3 in leiomyosarcoma cells

Abstract Hypoxia is a common feature of tumor microenvironments and stimulates a variety of responses in a cell. Tumor hypoxia is also associated with poor prognosis in soft tissue sarcomas (STS), including leiomyosarcomas. Genes upregulated under hypoxia contribute to the adaptation of tumor cells and promote tumor progression. Using transcriptome-wide gene expression analysis, we identified IGFBP-3 as one of the most highly upregulated genes in SK-LMS-1 leiomyosarcoma cells in hypoxic conditions. IGFBP-3 has been studied in several tumor types, including STS, and is associated with their altered pathogenesis. Mechanisms responsible for the hypoxia-induced expression of IGFBP-3 in STS have not been previously well defined. Hypoxia results in the stabilization of the hypoxia-inducible transcription factor, HIF-1, and production of reactive oxygen species (ROS) in other cell types. Here, we examined HIF-1 and ROS-dependent mechanisms to determine their roles in the hypoxia-induced expression of IGFBP-3 and other genes in SK-LMS-1 cells. Our data indicate that both ROS production and HIF-1 activation are required for the enhanced IGFBP-3 mRNA expression in hypoxic SK-LMS-1 cells. We also tested the roles of the stress activated protein kinase p38 and the tumor suppressor p53 for their potential to contribute to the regulation of IGFBP-3 expression in these cells. Inhibition of p53 tumor suppressor activity only partially reduced IGFBP-3 expression. We also determined that neither hypoxia nor inhibition of p53 affected the expression of the p53 target gene, CDKN1A (p21), in these cells. In contrast, inhibition of p38 MAPK completely prevented the hypoxia-induced increase in IGFBP-3 expression. Additionally, we found that p38 MAPK inhibition reduced HIF-1 protein accumulation and activity but had no effect on its mRNA expression under hypoxic conditions. Together these results suggest that ROS-dependent activation of p38 MAPK stabilizes HIF-1 and promotes the downstream expression of IGFBP-3. In contrast, p53 appears to have a limited effect on the expression of IGFBP-3 in SK-LMS-1 cells. Our results clarify the signaling pathway involved in the response of soft tissue sarcoma cells to hypoxia and may provide new avenues for intervention in cancer progression. Citation Format: Nuha Haque, Eric Shelden. p38 MAPK-dependent regulation of HIF-1 and expression of the hypoxia-inducible gene IGFBP-3 in leiomyosarcoma cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4804.

Identification of anoikis-related molecular patterns to define tumor microenvironment and predict immunotherapy response and prognosis in soft-tissue sarcoma.

Background: Soft-tissue sarcoma (STS) is a massive threat to human health due to its high morbidity and malignancy. STS also represents more than 100 histologic and molecular subtypes, with different prognosis. There is growing evidence that anoikis play a key role in the proliferation and invasion of tumors. However, the effects of anoikis in the immune landscape and the prognosis of STS remain unclear. Methods: We analyzed the genomic and transcriptomic profiling of 34 anoikis-related genes (ARGs) in patient cohort of pan-cancer and STS from The Cancer Genome Atlas (TCGA) database. Single-cell transcriptome was used to disclose the expression patterns of ARGs in specific cell types. Gene expression was further validated by real-time PCR and our own sequencing data. We established the Anoikis cluster and Anoikis subtypes by using unsupervised consensus clustering analysis. An anoikis scoring system was further built based on the differentially expressed genes (DEGs) between Anoikis clusters. The clinical and biological characteristics of different groups were evaluated. Results: The expressions of most ARGs were significantly different between STS and normal tissues. We found some common ARGs profiles across the pan-cancers. Network of 34 ARGs demonstrated the regulatory pattern and the association with immune cell infiltration. Patients from different Anoikis clusters or Anoikis subtypes displayed distinct clinical and biological characteristics. The scoring system was efficient in prediction of prognosis and immune cell infiltration. In addition, the scoring system could be used to predict immunotherapy response. Conclusion: Overall, our study thoroughly depicted the anoikis-related molecular and biological profiling and interactions of ARGs in STS. The Anoikis score model could guide the individualized management.

M6A-related metabolism molecular classification with distinct prognosis and immunotherapy response in soft tissue sarcoma.

N6-methyladenosine (m6A) methylation, one of the most crucial RNA modifications, has been proven to play a key role that affect prognosis of soft tissue sarcoma (STS). However, m6A methylation potential role in STS metabolic processes remains unknown. We comprehensively estimated the m6A metabolic molecular subtypes and corresponding survival, immunity, genomic and stemness characteristics based on 568 STS samples and m6A related metabolic pathways. Then, to quantify the m6A metabolic subtypes, machine learning algorithms were used to develop the m6A-metabolic Scores of individual patients. Finally, two distinct m6A metabolic subtypes (Cluster A and Cluster B) among the STS patients were identified. Compared to Cluster B subtype, the Cluster A subtype was mainly characterized by better survival advantages, activated anti-tumor immune microenvironment, lower gene mutation frequency and higher anti-PD-1 immunotherapy response rates. We also found that the m6A-metabolic Scores could accurately predict the molecular subtype of STS, prognosis, the abundance of immune cell infiltration, tumor metastasis status, sensitivity to chemotherapeutics and immunotherapy response. In general, this study revealed that m6A-regulated tumor metabolism processes played a key role in terms of prognosis of STS, tumor progression, and immune microenvironment. The identification of metabolic molecular subtypes and the construction of m6A-metabolic Score will help to more effectively guide immunotherapy, metabolic therapy and chemotherapy in STS.

Identification of Prognostic lncRNA Related to the Immune Microenvironment of Soft Tissue Sarcoma.

Background Soft tissue sarcoma is a malignant tumor with high degree of malignancy and poor prognosis, originating from mesenchymal tissue. Long noncoding RNAs (lncRNAs) are involved in various biological and pathological processes in the body. They perform preprocessing, splicing, transport, degradation, and translation of mRNA to achieve posttranscriptional level regulation, resulting in the occurrence, invasion, and metastasis of tumors. Therefore, they are highly relevant with regard to early diagnoses and as prognostic indicators. Objective The objective of the present study was to identify immune microenvironment-related lncRNAs that can be used to predict soft tissue sarcomas. Methods Clinical data and follow-up data were obtained from the cBioPortal database, and RNA sequencing data used for the model structure can be accessed from The Cancer Genome Atlas (TCGA) database. LncRNAs were screened by differential expression analysis and coexpression analysis. The Cox regression model and Kaplan–Meier analysis were used to study the association between lncRNAs and soft tissue sarcoma prognosis in the immune microenvironment. Unsupervised cluster analysis was then completed to discover the impact of screening lncRNAs on disease. We constructed an mRNA-lncRNA network by Cytoscape software. Finally, qRT-PCR was used to verify the difference in the expression of the lncRNAs in normal cells and sarcoma cells. Results Unsupervised cluster analysis revealed that the 210 lncRNAs screened showed strong correlation with the tumor immune microenvironment. Two signatures containing seven and five lncRNAs related to the tumor microenvironment were constructed and used to predict overall survival (OS) and disease-free survival (DFS). The Kaplan–Meier (K-M) survival curve showed that the prognoses of patients in the high-risk and low-risk groups differed significantly, and the prognosis associated with the low-risk group was better than that associated with the high-risk group. Two nomograms with predictive capabilities were established. qRT-PCR results showed that the expression of AC108134.3 and AL031717.1 was significantly different in normal and sarcoma cells. Conclusion In summary, the experimental results showed that lncrnA associated with immune microenvironment was related to tumor, which may provide a new idea for immunotherapy of STS.

Serum lactate dehydrogenase levels predict the prognosis of patients with soft tissue sarcoma.

Several studies have reported the prognostic factors for soft tissue sarcoma. Although serum lactate dehydrogenase (LDH) levels are associated with poor prognosis in several types of cancer, their role in soft tissue sarcomas remains unclear. Therefore, the present study evaluated the association between serum LDH levels and the clinical characteristics and prognosis of soft tissue sarcoma. A total of 103 patients diagnosed with primary soft tissue sarcoma between 2003 and 2019 were retrospectively examined, and the association between serum LDH levels at the first visit and clinical characteristics were analysed. In high-grade soft tissue sarcoma, the association between survival and clinical characteristics, including stratified LDH levels, was also analysed. Serum LDH levels were stratified (>253 and ≤253 IU/l) according to the standard values used at our institution. High serum LDH levels were significantly associated with the presence of metastasis and histological grade (P<0.001 and 0.040, respectively). In both the univariate and multivariate analyses, disease-specific survival (DSS) was significantly worse in patients with high-grade soft tissue sarcoma and high serum LDH levels than in patients with normal serum LDH levels (univariate analysis: P=0.025; multivariate analysis: Hazard ratio, 4.60; 95% confidence interval, 1.16-18.2; P=0.030). In conclusion, high serum LDH levels at the first visit predicted the presence of distant metastasis, high histological grade and worse DSS in patients with high-grade soft tissue sarcoma. Therefore, in patients with high serum LDH levels at the first visit, these risks should be considered during pretreatment examinations and post-treatment follow-up.

Chemotherapy Combined With Recombinant Human Endostatin (Endostar) Significantly Improves the Progression-Free Survival of Stage IV Soft Tissue Sarcomas

PurposeOur previously study showed that recombinant human endostatin (Endostar) combined with chemotherapy had significant activity to increase the mPFS in patients with advanced sarcomas with tolerable side effects. However, the small cohort size and short follow-up time made it difficult to screen sensitive sarcoma subtypes and determine whether there is an overall survival benefit. With the largest sarcoma cohort to our knowledge, we try to confirm the efficacy and safety of chemotherapy combined with Endostar in stage IV sarcomas, with the specific purpose of finding out the sensitive sarcoma types for this combined treatment.MethodsAfter the exclusion of ineligible patients, 156 patients with stage IV bone and soft tissue sarcomas were included in this study according to the inclusion criteria.ResultsBy the end of follow-up, the ORR was 10.7% (9/84) vs 1.4% (1/72) (p=0.041), the DCR was 26.2% (22/84) vs 5.6% (4/72) (p=0.001) in the combined group and chemotherapy group, respectively. The mPFS of combined group was significantly longer than the chemotherapy group (10.42 vs 6.87 months, p=0.003). The mOS were 26.84 months and 23.56 months, without significant difference (p= 0.481). In osteogenic sarcoma, there was no statistically significant difference in the mPFS between the two groups (p=0.59), while in the soft tissue sarcoma, the mPFS in the combined group was significantly higher than that of the chemotherapy group (11.27 vs 8.05 months, p=0.004). Specifically, undifferentiated polymorphic sarcoma (UPS) was the possible sarcoma subtypes that benefited from the combined therapy. For the 38 UPS patients (28 patients in the combined group and 10 patients in the chemotherapy group), the mPFS in the combined group was up to 14.88 months, while it was only 7.1 months in the chemotherapy group, with a significant difference (p=0.006). The most common adverse events in the combined group were myelosuppression, gastrointestinal reactions and abnormal liver function, without significant difference in two groups.ConclusionChemotherapy plus Endostar could prolong mPFS and improve ORR and DCR in patients with stage IV soft tissue sarcoma, suggesting that the combined therapy could improve the patient prognosis in soft tissue sarcomas, especially the UPS patients.

Ribonucleotide reductase subunit M2 is a potential prognostic marker and therapeutic target for soft tissue sarcoma.

Soft tissue sarcomas (STSs) are highly aggressive malignant tumors that exhibit poor therapeutic outcomes. Hence, we aimed to track down a potential gene that can be used as a prognostic marker and therapeutic target for this malignancy. We integrated omics analysis of clinical data and in vitro studies and identified Ribonucleotide reductase subunit M2 (RRM2) as a potential oncogene associated with STS prognosis. We found RRM2 is highly expressed in STS cell lines and tissues. STS patients with increased RRM2 levels showed worse overall survival, disease-free survival, progression-free survival, and disease-specific survival. Further, overexpression of RRM2 in HT1080 cells induces proliferation, migration, invasion, and colony formation, whereas its silencing arrest the cell cycle at G0/G1 phase and induces apoptosis. Taken together, we established RRM2 to be positively associated with oncogenesis and prognosis of STS and therefore could be a promising prognostic marker and therapeutic target.

Establishment of A Nomogram for Predicting the Prognosis of Soft Tissue Sarcoma Based on Seven Glycolysis-Related Gene Risk Score.

Background: Soft tissue sarcoma (STS) is a group of tumors with a low incidence and a complex type. Therefore, it is an arduous task to accurately diagnose and treat them. Glycolysis-related genes are closely related to tumor progression and metastasis. Hence, our study is dedicated to the development of risk characteristics and nomograms based on glycolysis-related genes to assess the survival possibility of patients with STS. Methods: All data sets used in our research include gene expression data and clinical medical characteristics in the Genomic Data Commons Data Portal (National Cancer Institute) Soft Tissue Sarcoma (TCGA SARC) and GEO database, gene sequence data of corresponding non-diseased human tissues in the Genotype Tissue Expression (GTEx).Next, transcriptome data in TCGA SARC was analyzed as the training set to construct a glycolysis-related gene risk signature and nomogram, which were confirmed in external test set. Results: We identified and verified the 7 glycolysis-related gene signature that is highly correlated with the overall survival (OS) of STS patients, which performed excellently in the evaluation of the size of AUC, and calibration curve. As well as, the results of the analysis of univariate and multivariate Cox regression demonstrated that this 7 glycolysis-related gene characteristic acts independently as an influence predictor for STS patients. Therefore, a prognostic-related nomogram combing 7 gene signature with clinical influencing features was constructed to predict OS of patients with STS in the training set that demonstrated strong predictive values for survival. Conclusion: These results demonstrate that both glycolysis-related gene risk signature and nomogram were efficient prognostic indicators for patients with STS. These findings may contribute to make individualize clinical decisions on prognosis and treatment.

Radiomics Analysis of Fat-Saturated T2-Weighted MRI Sequences for the Prediction of Prognosis in Soft Tissue Sarcoma of the Extremities and Trunk Treated With Neoadjuvant Radiotherapy.

PurposeTo create a prognostic prediction radiomics model for soft tissue sarcoma (STS) of the extremities and trunk treated with neoadjuvant radiotherapy.MethodsThis study included 62 patients with STS of the extremities and trunk who underwent magnetic resonance imaging (MRI) before neoadjuvant radiotherapy. After tumour segmentation and preprocessing, 851 radiomics features were extracted. The radiomics score was constructed according to the least absolute shrinkage and selection operator (LASSO) method. Survival analysis (disease-free survival; DFS) was performed using the log-rank test and Cox’s proportional hazards regression model. The nomogram model was established based on the log-rank test and Cox regression model. Harrell’s concordance index (C-index), calibration curve and receiver operating characteristic (ROC) curve analysis were used to evaluate the prognostic factors. The clinical utility of the model was assessed by decision curve analysis (DCA).ResultsThe univariate survival analysis showed that tumour location (p = 0.032), clinical stage (p = 0.022), tumour size (p = 0.005) and the radiomics score were correlated with DFS (p < 0.05). The multivariate analysis showed that tumour location, tumour size, and the radiomics score were independent prognostic factors for DFS (p < 0.05). The combined clinical-radiomics model based on the multivariate analysis showed the best predictive ability for DFS (C-index: 0.781; Area Under Curve: 0.791). DCA revealed that the use of the radiomics score-based nomogram was associated with better benefit gains relative to the prediction of 2-year DFS events than other models in the threshold probability range between 0.12 and 0.38.ConclusionThe radiomics score from pretreatment MRI is an independent prognostic factor for DFS in patients with STS of the extremities and trunk. The radiomics score-based nomogram could improve prognostic stratification ability and thus contribute to individualized therapy for STS patients.

Prognostic value of pretreatment anemia in patients with soft tissue sarcoma: A meta-analysis.

Background:Anemia is one of the most common manifestations in patients with cancer. Recently, multiple studies have shown a positive correlation between pretreatment anemia and tumor prognosis. Yet, the relationship between pretreatment anemia and the prognosis of soft tissue sarcomas (STS) is unclear.Methods:We searched the PubMed and EMBASE databases to identify relevant studies. Eligible studies were included according to the inclusion criteria to assess the relationship between pretreatment anemia and the prognosis of patients with STS. Prognostic significance was determined by studying hazard ratios (HR) and 95% confidence intervals (CIs).Results:A total of 12 studies are included. If there is significant heterogeneity, a random-effects model is used. Pooled data indicated that pretreatment anemia is related to poor overall survival (HR = 2.13; 95%CI = 1.52–2.98), disease-specific survival (HR = 1.53; 95%CI = 1.20–1.96), and disease-free survival (HR = 1.55; 95%CI = 1.10–2.17). The results of the subgroup analysis also support this conclusion.Conclusion:Our results suggest that pretreatment anemia may be a prognostic biomarker for STS.

Expression of IL4R\u03b1 and IL13R\u03b11 are associated with poor prognosis of soft-tissue sarcoma of the extremities, superficial trunk, and retroperitoneum

BackgroundIL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited.MethodsThis study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test.ResultsIn human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001).ConclusionsThis study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.

Cancer Testis Antigens and Immunotherapy: Expression of PRAME Is Associated with Prognosis in Soft Tissue Sarcoma.

(1) Background: PRAME, NY-ESO-1, and SSX2 are cancer testis antigens (CTAs), which are expressed in testicular germ cells with re-expression in numerous cancer types. Their ability to elicit humoral and cellular immune responses have rendered them promising targets for cancer immunotherapy, but they have never been studied in a large and well-characterised cohort of soft tissue sarcomas (STS). (2) Methods: On a protein level, we examined PRAME, NY-ESO-1, and SSX2 expression in tumour tissues of 249 high-risk STS using immunohistochemistry. We correlated expression levels with clinicopathological parameters including tumour-infiltrating lymphocyte (TIL) counts, grading, and long-term survival. (3) Results: Expression of PRAME, NY-ESO-1, and SSX2 was observed in 25 (10%), 19 (8%), and 11 (4%) of 249 specimens with distinct patterns for histo-subtypes. Expression of PRAME was associated with shorter patient survival (p = 0.005) and higher grade (G2 vs. G3, p = 0.001), while NY-ESO-1 expression was correlated with more favourable survival (p = 0.037) and lower grade (G2 vs. G3, p = 0.029). Both PRAME and NY-ESO-1 expression were more frequent in STS with low TIL counts. In multivariate analysis, high PRAME and low SSX2 expression levels as well as metastatic disease and non-radical resections were independent predictors of shorter overall survival. (4) Conclusions: CTAs PRAME, NY-ESO-1, and SSX2 show distinct expression patterns in different STS subtypes. These results demonstrate their prognostic relevance and may guide future immunotherapeutic approaches in STS.

High cumulative doxorubicin dose for advanced soft tissue sarcoma

BackgroundThe recommended cumulative doxorubicin dose in soft tissue sarcoma (STS) treatment was based on cardiotoxicity data from retrospective studies of breast cancer patients. However, the treatment and prognosis of STS and breast cancer are quite different, and reference to breast cancer data alone may not reflect the efficacy of doxorubicin treatment in STS. This study, thus, aimed to review and analyze clinical data of STS patients treated with a high cumulative doxorubicin dose, to provide a reference for treatment selection and clinical trial design.MethodsWe retrospectively collected and analyzed clinical data of patients with advanced STS who received doxorubicin-based chemotherapy from January 2016 to January 2020. The patients were divided into a standard-dose group (who received ≤6 cycles of doxorubicin after the initial diagnosis) and an over-dose group (who were re-administered doxorubicin [doxorubicin-rechallenge] after receiving 6 cycles of doxorubicin therapy discontinuously). Patient characteristics, cumulative doxorubicin dose, objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), cardiotoxicity incidence, and treatment effectiveness were evaluated in both groups.ResultsA total of 170 patients with advanced STS were recruited (146 in the standard-dose group and 24 in the over-dose group). The average cumulative doxorubicin dose was 364.04 ± 63.81 mg/m2 in the standard-dose group and 714.38 ± 210.09 mg/m2 in the over-dose group. The ORR, DCR, and median PFS were 15.07, 58.9%, and 6 (95% confidence interval [CI]: 5.8–6.5) months in the standard-dose group and 16.67, 66.67%, and 4 (95%CI: 2.0–5.8) months in the over-dose group, respectively. Symptomatic heart failure occurred in five patients (3.42%) of the standard-dose group and in one patient (4.17%) of the over-dose group. In these patients with cardiotoxicity, doxorubicin was discontinued, and all of them died of uncontrolled tumor growth. No drug-related deaths occurred.ConclusionsThe continuation of or rechallenge with doxorubicin beyond the recommended cumulative dose could be a promising therapeutic option in the treatment of chemotherapy-sensitive advanced sarcomas. Further evaluation is necessary in prospective trials.

Soluble programmed death-ligand 1 rather than PD-L1 on tumor cells effectively predicts metastasis and prognosis in soft tissue sarcomas

The soluble form of PD-L1 (sPD-L1) is related to a poor prognosis in various cancers. Comparisons of sPD-L1 and PD-L1 expressed on tumor cells in soft tissue tumor patients have not been reported. The purpose of this study was to analyze serum sPD-L1 and PD-L1 levels in soft tissue tumor patients. A total of 135 patients with primary soft tissue tumors were enrolled in this study. The sPD-L1 level was quantitatively measured by enzyme immunoassay, and PD-L1 expression on high grade sarcoma cells was analyzed immunohistologically. There were no significant differences in sPD-L1 levels between benign (48) and soft tissue sarcoma (STS) patients (87). In STS, the high sPD-L1 (>44.26 pg/mL) group had significantly lower metastasis-free survival (MS) and lower overall survival (OS) than the low sPD-L1 group (≤44.26 pg/mL) at 5 years using the log-rank test. On multivariate Cox proportional hazard analysis, the high sPD-L1 group had significant differences in MS and OS compared to the low sPD-L1 group. Between positive and negative immunostaining groups, recurrence-free survival (RS), MS, and OS were not significantly different. No correlation was found between immunostaining and sPD-L1 with the Kappa coefficient. The sPD-L1 concentration could predict future metastasis and prognosis in STS patients. High sPD-L1 in STS patients may be a target for treatment with checkpoint inhibitors.

Defining Which Patients Are at High Risk for Recurrence of Soft Tissue Sarcoma.

Several studies have investigated the prognosis of soft tissue sarcomas and the influence of a variety of factors, such as size, histology subtype, malignancy grade, site, margins, on overall survival, recurrence-free survival, incidence of local and distant spreading. The impact of genomic and expression profiling on long-term outcomes of patients with sarcomas has been also evaluated in order to fill the knowledge gap of this heterogeneous disease. Nomograms represent a prognostic tool that extends the standard staging systems on an individualized basis, taking into account tumor- and patient-related factors. They are used to assist the health provider and the patients in the decision-making process, for patient counseling, treatment decision-making, follow-up scheduling, and clinical trial eligibility determination. None of the available nomograms include molecular characterization of sarcomas. In the future, omics signatures might be incorporated into prognostic nomograms possibly improving their performance. In the present review, we focus on the complexity of prognostic and predictive factors for extremity and trunk wall as well as for retroperitoneal soft tissue sarcomas, while exploring the available prognostic models.