Molecular predictors of response to chemotherapy and survival have not been put into clinical practice in high-risk soft tissue sarcomas (HR-STS) by now. The expression of TOP2A and SIRT1 has implications for the mechanism of action of doxorubicin, which is the backbone of chemotherapy in HR-STS. Pre-treatment samples of 167 patients with HR-STS were collected. Protein expression levels of TOP2A and SIRT1 were evaluated with tissue microarrays and immunohistochemistry and correlated with clinicopathological parameters, including overall survival (OS). The expression of TOP2A and SIRT1 was seen in 47% and 60% of patients with HR-STS, respectively. TOP2A expression was associated with higher tumor grading and shorter 5-year OS. The expression of SIRT1 was correlated with a better 5- and 10-year OS. The combination of high SIRT1 and low TOP2A (“Top survivors”) significantly predicted a better OS compared to other biomarker combinations. A multivariate analysis confirmed the expression of SIRT1 and the “Top survivor” biomarker combination as independent predictive factors of OS. This is the first study to associate SIRT1 overexpression with a statistically significant prolongation of OS in HR-STS. Both individual markers and their combination can be used as predictive indicators for HR-STS patients scheduled for neoadjuvant anthracycline-based chemotherapy.

Local ablative therapies (LAT) are increasingly used in patients with metastatic soft tissue sarcoma (STS), yet evidence-based standards are lacking. This study aimed to assess the impact of LAT on survival of metastatic STS patients and to identify prognostic factors. In this retrospective multicenter study, 246 STS patients with metastatic disease who underwent LAT on tumor board recommendation between 2017 and 2021 were analyzed. A mixed effects model was applied to evaluate multiple survival events per patient. Median overall survival (OS) after first metastasis was 5.4 years with 1-, 2- and 5-year survival rates of 93.7, 81.7, and 53.1 %, respectively. A treatment-free interval ≥12 months and treatment of liver metastases were positively correlated with progression-free survival (PFS) after LAT (HR = 0.61, p = 0.00032 and HR = 0.52, p = 0.0081, respectively). A treatment-free interval ≥12 months and treatment of metastatic lesions in a single organ site other than lung and liver were positive prognostic factors for OS after first LAT (HR = 0.50, p = 0.028 and HR = 0.40, p = 0.026, respectively) while rare histotypes and LAT other than surgery and radiotherapy were negatively associated with OS after first LAT (HR = 2.56, p = 0.020 and HR = 3.87, p = 0.025). Additional systemic therapy was independently associated with a PFS benefit in patients ≤60 years with ≥4 metastatic lesions (for max. diameter of treated lesions ≤2 cm: HR = 0.32, p = 0.02 and >2 cm: HR = 0.20, p = 0.0011, respectively). This multicenter study conducted at six German university hospitals underlines the value of LAT in metastatic STS. The exceptionally high survival rates are likely to be associated with patient selection and treatment in specialized sarcoma centers.

(1) Background: The expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), an immune checkpoint receptor on T cells, has been associated with dismal outcomes and advanced tumor stages in various solid tumors. The blockade of TIM-3 is currently under examination in several clinical trials. This study examines TIM-3 expression in high-risk soft tissue sarcomas (HR-STS). (2) Methods: Tumor cell expression of TIM-3 on protein level was analyzed in pre-treatment biopsies of patients with HR-STS. TIM-3 expression was correlated with clinicopathological parameters including tumor-infiltrating lymphocyte (TIL) counts, programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PDL-1) expression in patients with HR-STS. Survival dependent on the expression of TIM-3 was analyzed. (3) Results: TIM-3 expression was observed in 101 (56%) out of 179 pre-treatment biopsies of patients with HR-STS. TIM-3 expression was significantly more often observed in undifferentiated pleomorphic sarcomas (UPS) compared to other histological subtypes (p < 0.001), high TIL counts (p < 0.001), and high PD-1 (p < 0.001) and PD-L1 expression (p < 0.001). TIM-3 expression did not have a prognostic impact on survival in patients with HR-STS. (4) Conclusions: This is the first study to demonstrate a significant tumor cell expression of TIM-3 in specific subsets of patients with HR-STS. TIM-3 qualifies as a potential immunotherapeutic target in HR-STS.

Background: The current understanding of the prognostic value of routine pre-treatment laboratory parameters in patients with high-risk soft tissue sarcoma (HR-STS) is limited. We sought to analyze several inflammatory biomarkers in a large cohort of HR-STS patients undergoing neoadjuvant therapy followed by curative surgical resection. Methods: 123 patients with locally advanced high-risk undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), and synovial sarcoma (SS) who underwent preoperative chemotherapy and regional hyperthermia (RHT) between 2014 and 2022 were retrospectively evaluated. The association of several pre-treatment laboratory parameters with radiologic treatment response, event-free survival (EFS), and overall survival (OS), were analyzed. Results: Low pre-treatment hemoglobin (HR 2.51, p = 0.018; HR 2.78, p = 0.030) and lactate dehydrogenase (LDH, HR 0.29, p = 0.0044; HR 0.23, p = 0.010) were significantly associated with EFS and OS in the multivariable analysis. Systemic inflammatory indices such as the neutrophil-to-lymphocyte ratio (NLR) did not have a significant impact on survival. Low C-reactive protein (CRP) and high albumin values were associated with poor radiologic response according to RECIST (p = 0.021 and p = 0.010, respectively). Conclusion: Pre-treatment LDH and hemoglobin are strong independent predictors of survival in HR-STS patients. Systemic inflammatory indices based on circulating immune cells may not serve as reliable prognostic factors for HR-STS patients undergoing curative-intent treatment. Higher pre-treatment albumin levels and lower CRP values may reflect a reduced inflammatory status and could be associated with a poorer radiologic response to preoperative treatment.

Background: The prognostic and predictive value of obesity and sarcopenia remains poorly defined in patients with high-risk soft tissue sarcoma (HR-STS). We sought to correlate clinical outcomes with CT-based body composition parameters in patients with HR-STS undergoing a multimodal preoperative therapy. The impact of radiologic and histopathologic response to preoperative treatment was correlated with individual fat and muscle distribution. Methods: Patients with locally advanced non-abdominal HR-STS and treatment with preoperative chemotherapy + regional hyperthermia (RHT) +/- radiotherapy (RT) followed by surgery between 2015 and 2022 were retrospectively evaluated. Body composition parameters measured on baseline CT scans were correlated with clinical outcomes including event-free survival (EFS) and overall survival (OS) as well as radiologic and histopathologic treatment response. Results: A total of 85 patients were included. Body composition parameters showed no significant correlation with radiologic or histopathologic treatment response. High total fat indices such as the total fat index (TFI, HR 3.56, p = 0.005) and high total fat to muscle ratio (FMR, HR 3.22, p = 0.020) were strongly associated with poor OS. Parameters for sarcopenia including skeletal muscle index (SMI) were not significantly linked to survival outcomes. Conclusion: High fat indices and a high FMR are strong predictors of poor OS in patients with HR-STS. Larger studies are warranted to further clarify the prognostic impact of sarcopenia and the predictive value of body composition parameters on preoperative treatment response.

Background: Dacarbazine is currently considered the better combination partner for doxorubicin compared to ifosfamide for the treatment of leiomyosarcoma (LMS). Regional hyperthermia (RHT) combined with neoadjuvant chemotherapy has been shown to improve survival in patients with locally advanced high‐risk STS. We sought to evaluate the role of doxorubicin and dacarbazine (AD) versus doxorubicin and ifosfamide (AI) in combination with RHT in patients with LMS.Methods: Patients with locally advanced high‐grade LMS, including limited metastases, eligible for RHT and first‐line treatment with either AI + RHT or AD + RHT between 2014 and 2022 were retrospectively evaluated. Endpoints were progression‐free survival (PFS) and overall survival (OS). Patients were matched using propensity scores, which were estimated with a logistic regression model accounting for tumor site, presence of metastasis, surgery, and radiotherapy.Results: A total of 105 patients were included in this study, of which 101 were included in the propensity score‐matched cohort. In the matched cohort, treatment with AD + RHT was associated with a significantly improved PFS (HR 0.32, 95% CI 0.13–0.74, p = 0.0081). Multivariable analysis revealed several significant predictors of PFS, including treatment with AD + RHT (HR 0.42, 95% CI 0.19–0.92, p = 0.031).Conclusion: Treatment with AD + RHT showed improved PFS and better treatment tolerability compared to AI + RHT. Our results support the use of AD instead of AI for the treatment of patients with LMS in combination with RHT.