Retroperitoneal well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are rare tumors presenting as bulky abdominal tumors requiring multidisciplinary management in high-volume centers. Surgery is the mainstay of treatment through complete en bloc resection with the goal of achieving macroscopically complete resection, with a single specimen encompassing the tumor and involved contiguous organs. Preoperative radiation therapy is not standard of care and the role of preoperative chemotherapy is under investigation. If the tumor is not resectable or metastatic, the preferred treatment is doxorubicin-based chemotherapy in the case of DDLPS, whereas WDLPS are generally thought of as chemo-resistant.

Undifferentiated pleomorphic sarcoma (UPS)/malignant fibrous histiocytoma (MFH) is the second most common soft-tissue sarcoma. The standard treatment options for UPS/MFH include tumor excision with appropriate surgical margins, radiation therapy, and chemotherapy. Preferable clinical outcomes can be expected in patients with resectable disease, whereas the clinical outcomes in patients with metastatic disease are unsatisfactory despite multidisciplinary treatment. Although patients with metastatic diseases require chemotherapy, the response rate to conventional chemotherapy has been reported to be only 27-33% in previous reports. Systemic treatment is required to eliminate metastatic disease and improve clinical outcomes in patients with UPS/MFH. Recent clinical studies have investigated the optimal period of conventional chemotherapy and the efficacy of various combinations of anticancer agents. Furthermore, molecular targeted drugs and immune checkpoint inhibitors have shown superior outcomes compared to standard treatments for various types of malignancies. Therefore, these anticancer agents are considered as new treatment options for patients with UPS/MFH. Recent clinical trials have demonstrated the safety and efficacy of these agents in patients with soft-tissue sarcomas, including UPS/MFH. In particular, a high response rate to immune checkpoint inhibitors combined with doxorubicin has been reported in recent clinical trials; however, combination therapy needs to be assessed in a large number of patients with UPS/MFH. In this review article, recent clinical studies on the systemic treatment of UPS/MFH are discussed.

Neoadjuvant immunotherapy (NIT) with checkpoint blockade has been increasingly studied for soft tissue sarcomas, however, survival outcomes data are limited, and dedifferentiated liposarcoma (DDLPS) histology remains underrepresented in recent trial cohorts. We assessed the impact of NIT with or without radiation therapy (RT) on overall survival (OS) for resectable DDLPS.

The National Cancer Database (NCDB) was used to identify patients diagnosed with nonmetastatic DDLPS who received NIT and underwent surgical resection between 2016 and 2022. Primary outcome was 5-year OS.

A total of 3414 patients with DDLPS met the inclusion criteria and NIT was administered to 31 (1%) patients. Factors associated with receipt of NIT were receipt of neoadjuvant RT (NRT, odds ratio [OR]: 5.75, p < 0.001) and male sex (OR: 3.33, p = 0.036). NIT was associated with a hazard ratio (HR) for mortality of 0.89 (p = 0.786). No difference was found in 5-year OS in the overall cohort (NIT 72% vs. 61% no NIT, p = 0.320) or in the propensity-matched cohort (68% vs. 65%, p = 0.848). Subanalysis between NIT with NRT versus NRT-only also did not find any significant difference in 5-year OS (88% vs. 59%, p = 0.331).

In this retrospective NCDB analysis of patients with resectable DDLPS, administration of NIT did not significantly affect OS.

Liquid-liquid phase separation (LLPS) is a significant reversible and dynamic process in organisms. Cells form droplets that are distinct from membrane-bound cell organelles by phase separation to keep biochemical processes in order. Nevertheless, the pathological state of LLPS contributes to the progression of a variety of tumor-related pathogenic issues. Sarcoma is one kind of highly malignant tumor characterized by aggressive metastatic potential and resistance to conventional therapeutic agents. Despite the significant clinical relevance, research on phase separation in sarcomas currently faces several major challenges. These include the limited availability of sarcoma samples, insufficient attention from the research community, and the complex genetic heterogeneity of sarcomas. Recently, emerging evidence have elaborated the specific effects and pathways of phase separation on different sarcoma subtypes, including the effect of sarcoma fusion proteins and other physicochemical factors on phase separation. This review aims to summarize the multiple roles of phase separation in sarcoma and novel molecular inhibitors that target phase separation. These insights will broaden the understanding of the mechanisms concerning sarcoma and offer new perspectives for future therapeutic strategies.

To evaluate the preliminary efficacy and safety of the combination of pexidartinib, an inhibitor of colony-stimulating factor-1 receptor (CSF1R), and sirolimus, a mammalian target of rapamycin inhibitor, to target infiltrating M2 macrophages in malignant peripheral nerve sheath tumors (MPNSTs).

This investigator-initiated, phase II, multicenter, single-arm trial enrolled patients with unresectable MPNSTs. Patients were treated with pexidartinib 1000 mg and sirolimus 2 mg orally daily. The primary end point was progression-free survival (PFS). Secondary end points included objective response, safety profile, and overall survival (OS). Pretreatment and on-treatment tumor biopsies were obtained to evaluate changes in the tumor microenvironment (TME) using multiplex immunofluorescence and differential transcriptional profiling.

Fifteen patients with MPNSTs were enrolled and 14 initiated therapy. Eight had neurofibromatosis type 1, five were sporadic, and one was undetermined. Although the target sample size was 25, because of the lower-than-expected accrual during the COVID-19 pandemic, enrollment was halted on April 12, 2023. The median PFS and median OS were 6 weeks (95% CI, 6 to 19.1) and 17.9 weeks (95% CI, 13.7 to not applicable), respectively. One patient achieved confirmed stable disease. Three patients experienced PFS ≥12 weeks. Grade 3 treatment-related toxicities (rash and leukopenia) occurred in four (28.6%) patients. Although the study did not meet its primary end point, correlative analysis demonstrated that four of the five long-term survivors had an immune-rich pretreatment TME, three of whom had a reduction in M2-tumor-associated macrophage signal with treatment.

Further studies of combination of pexidartinib and sirolimus and/or immunotherapy should be performed in the subset of patients with advanced MPNST with an immune-rich TME.

Dedifferentiated liposarcoma (DDLPS) is a rare and aggressive subtype of soft tissue sarcoma, characterized by limited treatment options and poor prognosis. Despite surgical resection being the only potentially curative treatment for localized DDLPS, the recurrence rate remains high, and systemic chemotherapy, typically anthracycline-based, shows limited efficacy in advanced stages. While immune checkpoint inhibitors (ICIs) have shown promise in various sarcoma subtypes, including DDLPS, their role as a first-line treatment remains unclear.

We conducted a systematic meta-analysis to evaluate the efficacy of ICIs in treating patients with DDLPS. A total of 25 studies encompassing 245 patients were included. Data on overall response rate (ORR), progression-free survival, and grade III-V treatment-related adverse events were analyzed. We assessed treatment efficacy based on the line of therapy and treatment regimens, including ICI monotherapy, dual ICI therapy, and ICI combinations with other modalities.

The pooled ORR for all ICI-based treatments was 7%. First-line ICI therapy yielded a significantly higher ORR of 22%, compared to 4% in later-line treatment. The combination of ICI with anthracyclines demonstrated the highest ORR of 52%. In contrast, ICI regimens combined with trabectedin or other agents showed limited efficacy. Sensitivity analysis confirmed the stability of results, and publication bias was not detected.

This meta-analysis supports the potential role of ICIs, particularly in combination with anthracyclines, as a first-line therapeutic strategy for DDLPS. These results provide a foundation for future prospective studies aimed at optimizing immunotherapy approaches for this rare and challenging malignancy.

Mesenchymal tumors of the breast constitute a rare and heterogeneous group of neoplasms, representing only 0.5% to 1% of all breast tumors. Originating from mesenchymal tissues, these tumors include various histological subtypes. They are particularly aggressive, characterized by a high propensity for local recurrence and an overall poor prognosis. The rarity of these cases has impeded the development of comprehensive clinical studies, leading to a lack of standardized diagnostic protocols and treatment guidelines. This review provides a thorough synthesis of current knowledge on breast mesenchymal tumors with a specific focus on malignant variants such as phyllodes tumors and breast sarcomas. It also addresses the diagnostic challenges faced by clinicians, evaluates current therapeutic strategies, and emphasizes the crucial role of surgical treatment. Additionally, it examines the evolving roles of chemotherapy and radiotherapy in enhancing patient outcomes.

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.

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.

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.

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.

Soft-tissue sarcomas are rare, diverse malignant tumors of mesenchymal origin, requiring diagnosis and treatment by a specialized multidisciplinary team. Initial assessment includes radiology and biopsy, followed by wide surgical resection with clear margins for localized cases. Radiotherapy is recommended for large, deep, high-grade tumors or after incomplete resection, while perioperative chemotherapy may be considered for high-risk cases. In oligometastatic disease, combining local and systemic therapies is an option. Anthracycline-based chemotherapy is the first-line treatment in advanced disease, though other drugs show efficacy in certain subtypes. Given the limited options, enrolling in clinical trials is advised for patients needing further treatment.

The rarity and heterogeneity of liposarcomas (LPS) pose significant challenges in their diagnosis and management. In this work, a series of metal-organic frameworks (MOFs) engineering is designed and implemented. Through comprehensive characterization and performance evaluations, such as stability, thermal-driven desorption efficiency, as well as energy- and charge-transfer capacity, the engineering of group IV bimetallic MOFs emerges as particularly noteworthy. This is especially true for their derivative products, which exhibit superior performance across a range of laser desorption/ionization mass spectrometry (LDI MS) performance tests, including those involving practical sample assessments. The top-performing product is utilized to enable high-throughput recording of LPS metabolic fingerprints (PMFs) within seconds using LDI MS. With machine learning on PMFs, both the LPSrecognizer and LPSclassifier are developed, achieving accurate recognition and classification of LPS with area under the curves (AUCs) of 0.900-1.000. Simplified versions are also developed of the LPSrecognizer and LPSclassifier by screening metabolic biomarker panels, achieving considerable predictive performance, and conducting basic pathway exploration. The work highlights the MOFs engineering for the matrix design and their potential application in developing metabolic analysis and screening tools for rare diseases in clinical settings.

Despite conventional cytotoxic chemotherapy treatments, soft tissue sarcoma continues to remain a terminal diagnosis for most patients. Numerous chemotherapeutic agents have been trialed in soft tissue sarcoma, with marginal improvement in overall survival. Novel therapeutic approaches are needed to improve outcomes for this entity.

the literature was reviewed, including a summary of pertinent adjuvant/neoadjuvant clinical trials and trials for metastatic disease.

Chemotherapeutic agent use in adjuvant/neoadjuvant trials provided limited if any evidence of the benefit of chemotherapy in this space. Despite multiple trials in the metastatic space, novel chemotherapeutic agents appear to have limited long-term benefits for the management of soft tissue sarcoma. Suggestions for further research, particularly with neoadjuvant clinical trials, were made.

Chemotherapy remains an inadequate treatment option for soft tissue sarcoma, and novel therapies are needed. The neoadjuvant space provides an excellent opportunity to study the effects of innovative treatments in soft tissue sarcoma.

Background: The heterogeneity of sarcomas and resulting distinct sub-type specific characteristics, their high recurrence rates, and tendency for distant metastasis, continue to present significant challenges to providing optimal treatments. Objective: To provide a comprehensive review of current literature and clinical trials in gene and cell therapies for sarcomas. Methods: A comprehensive literature search was conducted utilizing the following databases: PubMed, Medline, Google Scholar and clinicaltrials.gov. Search terms included "gene therapy", "cell therapy", "NK cell therapy, "CAR-T therapy", "virotherapy", "sarcoma", "gene therapy", and "solid tumors". Additional sources were identified through manual searching for references of relevant studies. No language restrictions were set. The NCT number, study status, condition, and phase were noted for clinical trials. Results: There are only three gene and cell therapies for sarcomas that have been approved by a federal regulatory agency. Rexin-G: the first tumor-targeted gene therapy vector designed to target all advanced solid malignancies, including chemo-refractory osteosarcomas and soft tissue sarcomas, was approved by the Philippine FDA in 2007. Gendicine was the first oncolytic virus approved for intratumoral delivery in China in 2003. Afami-cel, an innovative chimeric antigen receptor (CAR) T cell therapy, was approved for synovial sarcoma in the United States in 2024. Other promising therapies are discussed in the text. Conclusions: The future of gene and cell therapy for sarcomas holds great promise, as research moves to late-stage clinical development. The integration of gene and cell therapies into standard sarcoma treatment protocols has the potential to significantly improve the quality of life and outcomes for patients with this rare and challenging group of cancers.

Prostate-specific membrane antigen (PSMA) expression has been observed in a subset of soft tissue sarcomas, mainly in the neovascular endothelial cells. This feasibility study aimed to evaluate PSMA expression and PSMA PET/CT imaging in metastatic soft tissue sarcoma, providing important insights for potential future exploration of PSMA-targeted radioligand therapy.

This prospective single-center study included adult patients with metastatic soft tissue sarcoma, with measurable disease (lesion diameter > 1 cm), available biopsy/resection material, ECOG/WHO performance status of 0-2 and either no prior systemic treatment, progressive disease during/after treatment, or stable disease/partial response with the last dose > 8 weeks prior. Immunohistochemical PSMA staining was performed on previously obtained biopsy or resection material. In case of high PSMA expression, a [18F]-JK-PSMA-7 PET/CT scan evaluated tracer uptake, with adequate uptake defined as SUVmax > 8.

Of 25 included patients, 11 (44%) had high PSMA expression: 4/11 leiomyosarcomas, 3/4 dedifferentiated liposarcomas, 2/5 undifferentiated pleomorphic sarcomas, 1/2 myxofibrosarcomas and 1/1 malignant peripheral nerve sheath tumour. Five of 11 patients agreed to a [18F]-JK-PSMA-7 PET/CT, of which 3 had lesions that showed adequate tracer uptake (SUVmax 10.7-16.7). However, uptake across all metastatic lesions was highly heterogeneous (median SUVmax = 3.8; range 0.5-16.7), indicating that these patients are unlikely to benefit sufficiently from PSMA-targeted therapy. The study was therefore terminated prematurely.

PSMA expression and PSMA tracer uptake in metastatic soft tissue sarcoma were highly heterogeneous. A deeper understanding of PSMA biology and improved patient selection criteria are essential for future application of PSMA-targeted radioligand therapy in this disease.

clinicaltrials.gov, NCT05522257. Registered 31-08-2022.

Soft tissue sarcomas (STS) are rare, heterogeneous tumors with poor survival outcomes, primarily due to reliance on cytotoxic chemotherapy and lack of targeted therapies. Given the uniquely individualized nature of STS, we hypothesized that the ex vivo drug sensitivity platform, quadratic phenotypic optimization platform (QPOP), can predict treatment response and enhance combination therapy design for STS. Using QPOP, we screened 45 primary STS patient samples, and showed improved or concordant patient outcomes that are attributable to QPOP predictions. From a panel of approved and investigational agents, QPOP identified AZD5153 (BET inhibitor) and pazopanib (multi-kinase blocker) as the most effective combination with superior efficacy compared to standard regimens. Validation in a panel of established patient lines and in vivo models supported its synergistic interaction, accompanied by repressed oncogenic MYC and related pathways. These findings provide preliminary clinical evidence for QPOP to predict STS treatment outcomes and guide the development of novel therapeutic strategies for STS patients.

Dedifferentiated liposarcoma (DDLPS) is a fairly common subtype of soft tissue sarcoma, but relatively little is known about the clinical course and prognostic factors of this mesenchymal malignancy.

We performed a retrospective analysis of patients diagnosed with DDLPS at the University Hospital Leuven, Belgium between 1991 and 2022 based on an established clinical database and patient records.

We identified 259 patients with DDLPS, with the retroperitoneum as most common location of the primary tumor (47.5%). 204/259 patients (78.8%) patients had primary surgery. Radiotherapy was administered in the pre- (46/259, 17.8%) or postoperative setting (51/259, 19.7%). At diagnosis 28/259 (10.8%) patients presented with locally inoperable disease and 26/259 (10.0%) with synchronous metastasis. In patients who had primary surgery, local relapses were seen in 114/259 (44.0%) patients and 80/259 (30.9%) patients developed metachronous metastasis. A total of 48/259 (18.5%) patients developed both local relapse and metastasis. Patients with inoperable or metastatic disease were often treated with systemic therapy. The most common first-line systemic therapies were doxorubicin (51/98, 52.0%), doxorubicin combined with ifosfamide (12/98, 12.2%) and different types of experimental treatments (18/98, 18.4%). The median overall survival from first diagnosis of DDLPS to death of all causes was 70.5 months (95% confidence interval [CI] 56.6-98.6) for all patients, 10.9 months (95% CI 3.6-29.2) in patients with inoperable disease, 28.4 months (95% CI 1.3-199.3) for patients with local relapse and only 9.4 months (95% CI 1.2-25.9) for patients with metastatic disease. We identified lower age, primary surgery, absence of synchronous metastasis, absence of local relapse and treatment with experimental therapy as statistically significant favorable prognostic factors.

DDLPS is a subtype of soft tissue sarcoma with an aggressive clinical course and very poor prognosis, especially in patients with inoperable or metastatic disease. The results with classic chemotherapy are poor, and experimental treatments may be a preferred choice for individual patients. Data from this retrospective series can inform the design of future prospective and ongoing trials in this setting.

Several patient-derived tumor models have emerged recently. However, soft tissue sarcomas (STSs) present a challenge in developing preclinical drug-testing models due to their non-epithelial and complex nature. Here, we report a model termed patient-derived tumor-like cell clusters (PTCs) derived from STS patients. PTCs result from the self-assembly and proliferation of mesenchymal stem cells (MSCs), epithelial cells, and immune cells, faithfully recapitulating the morphology and function of the original tumors. Through standardized culture and drug-response assessment protocols, PTCs facilitate personalized drug testing, evaluating hundreds of therapies within two weeks. Notably, PTCs exhibit 100% accuracy in distinguishing between complete or partial response and disease progression. We demonstrate the utility of PTCs in guiding chemotherapy selection for a patient with relapse and metastases following conventional therapy, who exhibited a positive response after non-conventional therapy identified through PTC. These findings underscore the potential of PTCs for prospective use in clinical decision-making regarding therapy selection.

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.

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.

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).

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.

Retroperitoneal liposarcoma, especially dedifferentiated liposarcoma (DDL), is a rare tumor type primarily affecting middle-aged and older adults in the retroperitoneum or proximal extremities. This case report highlights an exceptionally large retroperitoneal DDL that had enveloped the entire right kidney and had adhered to nearby tissues. Diagnosing retroperitoneal liposarcoma is challenging due to its asymptomatic nature until it reaches a substantial size. Imaging, particularly contrast-enhanced computed tomography (CECT), play a vital role in diagnosis, staging, and preoperative planning. Surgical resection, with the goal of R0 resection, remains the cornerstone of treatment, albeit this can be challenging due to tumor location. First-line treatment for advanced DDL involves anthracycline-based therapy. Eribulin and pazopanib show promise in second-line treatment. Ongoing clinical trials suggest a shift towards multimodal therapy. This case report reports the largest retroperitoneal liposarcoma and underscores the complexity of managing retroperitoneal DDL.

Locally advanced and metastatic leiomyosarcoma (LMS) is an aggressive cancer with limited treatment options. This single-institution, retrospective study evaluated the efficacy of first-line chemotherapy regimens in patients with advanced or metastatic LMS treated at Stanford Medical Center.

Seventy-four patients with unresectable or metastatic LMS were deemed eligible and treated with first-line chemotherapy regimens, including gemcitabine plus docetaxel, dacarbazine, doxorubicin combinations (with evofosfamide or ifosfamide), and doxorubicin monotherapy. Progression-free survival (PFS), overall survival (OS), and disease control rate (DCR) were assessed using RECIST v1.1, with survival analyses performed using Kaplan-Meier and Cox proportional hazards methods.

The cohort consisted of 56 females (75.7%) and 18 males (24.3%), with a median age of 55.5 years. The majority (93.2%) had metastatic disease. The median PFS for the entire cohort was 4.9 months (range: 0.6-28.1 mo), and the median OS was 27.3 months (range: 1.9-140.2 mo). The doxorubicin combination (DC) group had the highest median PFS of 7.9 months (range: 0.6-15.8 mo). Doxorubicin alone had the highest median OS of 33.8 months (4.2-100.2 mo). Doxorubicin combinations demonstrated superior PFS in both uterine and non-uterine LMS subgroups.

These findings reaffirm the efficacy of doxorubicin-based combination regimens as a first-line treatment for locally advanced and metastatic LMS, particularly in non-uterine LMS.

Soft tissue sarcomas [STSs] are rare tumors of mesodermal origin that arise in diverse tissues such as muscles, fat, and nerves. There are over 100 subtypes of STS, each with distinct clinical behaviors and responses to treatment. Recent advances in treatment have moved towards histology-specific approaches, emphasizing the integration of pathological, immunohistochemical, and molecular features to guide treatment. Localized STS is primarily treated with surgery, often supplemented by neoadjuvant or adjuvant radiation and/or chemotherapy. However, about half of patients with localized disease will progress to an advanced stage, which is typically managed with systemic therapies including anthracycline-based chemotherapy such as doxorubicin or epirubicin. Despite these treatments, the survival rates for most subtypes of advanced metastatic STS remain relatively low. While anthracycline-based chemotherapy remains the mainstay of treatment, ongoing research into the biology of STSs is enhancing our understanding and approach to these complex tumors with an expansion beyond chemotherapy to include targeted therapy and immunotherapy to improve response rates and survival outcomes. This review focuses on STS other than gastrointestinal stromal tumors [GISTs], examines the current systemic treatment strategies, highlights recent advances, and explores future directions in the systemic therapy of sarcoma patients.

Follicular dendritic cell sarcoma (FDCS) is a rare sarcoma subtype, presenting as a relatively indolent disease in most cases. Given its rarity, clinicopathological characteristics and behavior as well as treatment, are reported in the literature through case reports and case series. Bone metastasis in FDCS is extremely rare and the outcome of the disease in this group of patients is unknown. We report one case of FDCS with bone involvement as the first site of metastasis. We present the progression of the disease over a period of almost a decade in a detailed manner, particularly the therapies used including immunotherapy with checkpoint inhibitors. In parallel, we provide a comparison with other cases of FDCS metastatic to the bone (total of eight cases) through a systematic review of the literature on the clinical and pathological manifestations as well as the outcomes of all such cases reported to date, to the best of our knowledge. These cases highlight the challenges associated with setting the correct diagnosis at presentation, the lack of evidence to support the role of adjuvant therapy following primary surgery but also the role and/or sequence of systemic options in the advanced setting.

Background/Objective: Anti-tumor effects of plasma-activated medium (PAM) were demonstrated using various malignant tumors. However, the anti-tumor effect of PAM on synovial sarcoma remains unclear. Therefore, we aimed to investigate the anti-tumor effects of PAM on synovial sarcoma and its underlying mechanisms, focusing on the quantitative analyses of both intracellular reactive oxygen species (ROS) and cell apoptosis. Methods: The human synovial sarcoma cell line HS-SY-II was used to investigate the cell viability after PAM treatment. We investigated the anti-tumor effects and side effects of local PAM injection in a synovial sarcoma xenograft murine model. Moreover, we observed PAM-induced intracellular ROS accumulation and cell apoptosis and assessed the involvement of intracellular ROS in the anti-tumor effects of PAM using an intracellular ROS scavenger. Results: PAM significantly decreased the viability of synovial sarcoma cells compared with untreated Dulbecco's modified Eagle medium. Local PAM injection into a synovial sarcoma xenograft murine model significantly suppressed tumor growth, including tumor volume (p < 0.001) and weight (p = 0.031), without side effects. Regarding anti-tumor mechanisms, PAM induced significant cell apoptosis and intracellular ROS accumulation (p < 0.001). The intracellular ROS scavenger significantly inhibited the anti-tumor effect of PAM (p < 0.001). Conclusions: We confirmed the anti-tumor effects of PAM on synovial sarcoma in vitro and in vivo, as well as the absence of side effects. The underlying mechanism was suggested to involve cell apoptosis induced by intracellular ROS accumulation. Considering the various clinical issues associated with the existing treatments of synovial sarcoma, PAM is a promising new option.

Soft tissue sarcomas (STS) are a heterogeneous group of tumors with diverse clinical and molecular characteristics, characterized by limited treatment options and poor prognosis. Immune checkpoint inhibitors (ICIs) have emerged as promising therapies for STS, yet comprehensive evaluations of their efficacy, especially in combination with other treatments, are scarce.

We conducted a systematic review and meta-analysis of clinical trials on ICIs in STS treatment, sourced from PubMed, Embase, and the Cochrane Central Register of Controlled Trials up to May 31, 2024. The studies included both monotherapy and combination therapies with ICIs. We assessed the methodological quality using the Cochrane Risk of Bias 2 tool and the Methodological Index for Non-Randomized Studies. Data synthesis involved random-effects meta-analysis to determine pooled proportions and 95% confidence intervals (CIs) for objective response rates (ORR), disease control rates (DCR), and high-grade treatment-related adverse events (TRAEs).

The analysis included 38 studies with 1349 patients covering 24 STS subtypes. The overall ORR was 16% (95% CI 0.12-0.21), DCR was 64% (95% CI 0.57-0.70), and the rate of Grade 3-5 TRAEs was 19% (95% CI 0.13-0.27). Treatments combining ICIs with tyrosine kinase inhibitors (TKIs) showed the highest efficacy (ORR 28%, 95% CI 0.18-0.40), albeit with increased adverse events. ORRs in first-line treatments were substantially higher (28%) compared to second-line treatments or beyond (11%). Subtypes like alveolar soft part sarcoma (ASPS), angiosarcoma (AS), and epithelioid sarcoma (ES) exhibited favorable responses exceeding 30%.

This systematic review and meta-analysis indicate that ICIs, particularly when combined with TKIs, provide substantial therapeutic benefits in treating STS, significantly enhancing response rates in specific subtypes such as ASPS and AS. The results underscore the transformative potential of ICIs in STS treatment strategies. However, the variability across subtypes and treatment lines emphasizes the need for further randomized controlled trials to refine and personalize therapeutic approaches, ensuring optimal outcomes for patients with these diverse malignancies.

The aim of our study is to evaluate the relationship between sarcopenia, overall survival (OS), and chemotherapy toxicity in patients with unresectable/metastatic soft tissue sarcoma (STS) treated with adriamycin and ifosfamide.

Patients with unresectable/metastatic STS over the age of 18, diagnosed between 2015 and 2023, were included in the study. The study was conducted retrospectively in a single center. Total muscle volume at the lumbar 3 (L3) vertebra level was measured from the patient's computer tomography (CT) images. The skeletal muscle index (SMI) was calculated for each patient. Additionally, the prognostic nutritional index (PNI) was calculated for each patient using blood values.

Fifty-eight patients were included in the study. The median age of the patients was 51 years, Thirty-six (62.1%) were female and 22 (37.9%) were male. The SMI median was 49 cm2/m2 in male patients. ROC analysis demonstrated a statistically significant prediction of OS when the SMI index was < 49.2 cm2/m2. In female patients, the median SMI was 40 cm2/m2. ROC analysis demonstrated a statistically significant prediction of OS when the SMI index was < 40.3 cm2/m2. Median OS in the SMI < 49 cm2/m2 male group was 9 months (95% CI 7.99-10.08). In the SMI ≥ 49 cm2/m2 male group, the median OS was 30.2 months (95% CI 0.0-66.66). OS was statistically significant between the two groups (p = 0.003). The median OS in the SMI < 40 cm2/m2 female group was 20.5 months (95% CI 7.69-33.30). In the SMI ≥ 40 cm2/m2 female group, the median OS was 59.1 months (95% CI 21.36-96.98). OS was statistically significant between the two groups (p = 0.025). The relationship of SMI, as well as PNI, age, and Eastern Cooperative Oncology Group performance status (ECOG PS) with OS, was assessed. The relationship between SMI and chemotherapy toxicity was also evaluated. Chemotherapy-related toxicity was found to be significantly higher in sarcopenic patients (male SMI < 49 cm2/m2, female SMI < 40 cm2/m2) (p = 0.025).

A significant relationship was found between SMI and OS, but no significant relationship was found between PNI and OS. A significant relationship was also detected between SMI and treatment toxicity. Our study reveals that evaluating ECOG PS and sarcopenia in addition to grade and histological subtype when making treatment decisions will be associated with longer survival and less toxicity.

Undifferentiated pleomorphic sarcoma (UPS) is the most frequent and the most aggressive sarcoma subtype for which therapeutic options are limited. The identification of new therapeutic strategies is therefore an important medical need. Epigenetic modifiers has been extensively investigated in recent years leading to the development of novel therapeutic agents. Dual BET/EP300 inhibitors have shown synergistic antitumor activity and have recently entered clinical development. To date, no data related to potential of BET/EP300 inhibition as a treatment in UPS have been reported. To investigate the therapeutic potential of BET/EP300 inhibition, we evaluated the antitumor activity of three compounds in vitro via MTT, apoptosis and cell cycle assays. The most potent inhibitor was evaluated in vivo in two animal models and the mechanisms of action were investigated by RNA sequencing, Western blotting and immunofluorescence staining. A CRISPR knockout screen was performed to identify resistance mechanisms. Among the three compounds tested, the dual inhibitor NEO2734 was the most potent, decreased the viability of UPS cells in vitro through a regulation of E2F targets and cell cycle and decreased the tumor growth in vivo. Moreover, we identified GPX4 as a gene involved in resistance and showed synergy between BET inhibition and ferroptosis induction. The present study demonstrated that dual BET/EP300 inhibitors have a relevant antitumor activity in a subgroup of UPS characterized by expression of MYC-targets pathway and identified a potent combination therapeutic strategy that deserves further investigation in the clinical setting.

Cardiac sarcomas are rare, aggressive malignancies originating from various cardiac cell types, presenting significant challenges in both diagnosis and treatment. This comprehensive review explores recent advancements in diagnosis and treatment of cardiac angiosarcoma, fibrosarcoma, leiomyosarcoma, and rhabdomyosarcoma. And we briefly discuss the exceedingly rare occurrence of cardiac osteosarcoma and present our perspectives on its treatment. Development of these tumors is influenced by genetic mutations, environmental factors, and chromosomal abnormalities, necessitating a multidisciplinary approach for accurate diagnosis and management. Advanced imaging techniques, biomarkers, and immunohistochemical analysis assist in confirming the diagnosis and guiding treatment decisions. Surgical resection, adjuvant therapies, and personalized treatment strategies based on genetic profiling offer promising avenues for improving patient outcomes. Emerging therapeutic approaches, such as targeted therapies and immunotherapies, have shown promising progress in recent years. Despite these advancements, the prognosis for patient with cardiac sarcomas remains poor, highlighting the urgent need for continued research to refine treatment methods and enhance long-term survival outcomes. Ongoing efforts and clinical trials are essential for advancing the management of these rare and aggressive tumors, ultimately improving quality of life for affected patients.

Doxorubicin, alongside a select group of cytotoxic agents, is capable of inducing an adaptive immune response via a well-established peculiar type of tumor cell death called immunogenic cell death (ICD). We hypothesize that combining doxorubicin and dacarbazine with nivolumab may enhance therapeutic efficacy by exerting synergy in the ICD circuit. We hereby present a phase Ib trial with this combination.

Patients with advanced leiomyosarcoma and anthracycline-naïve were eligible. The initial dose level consisted of doxorubicin 75 mg/m2 once on day 1, once every three weeks, followed by dacarbazine 400 mg/m2 once on days 1 and 2, once every three weeks, plus nivolumab 360 mg once on day 2, once every 3 weeks, for six courses and then 1 year of nivolumab. A (-1) dose level was the same regimen but with nivolumab 240 mg. A classic 3 + 3 phase-I design was used to determine the recommended phase-II dose (RP2D). Secondary end points included overall response rate, safety profile, survival, and translational research.

From January 2002 to July 2023, 24 patients were enrolled and 23 were evaluable for efficacy, excluding one patient because of noncompliant dose. All patients were treated with the initial dose level, then the RP2D. Toxicity was mild, with the most frequent being grade 4 toxicity neutropenia (16.7%) and thrombocytopenia (8.3%), while no grade 5 toxicity occurred. The centrally reviewed objective response rate was as follows: partial response 56.5%, stable disease 39.1%, and progression 4.4%. The 6-month progression-free survival (PFS) rate was 80% (95% CI, 63 to 98). Dynamic increases of HMGB1 in blood significantly correlated with longer PFS.

This scheme of doxorubicin, dacarbazine, and nivolumab is feasible and well tolerated. Clinical activity is encouraging and the prognostic impact of HMGB1 supports the relevance of ICD activation. Further clinical research is already underway with this concept in leiomyosarcoma.

The prognosis of patients with advanced soft tissue sarcoma (STS) remains dismal. Trofosfamide (TRO) has been proposed as a well-tolerated oral maintenance therapy. This retrospective analysis aims to determine the value of this therapy.

Fifty-nine patients with advanced STS who received TRO maintenance therapy between 2016 and 2022 were reviewed and analysed regarding clinical parameters and outcomes.

The median age was 48 years; the most common histological subtype was synovial sarcoma (n = 22, 37%), and 71% of patients (n = 42) presented with metastatic disease. No radiological evidence of disease (NED) before the start of maintenance was reported in 36% of patients (n = 21). The median follow-up was 38.2 months with a median maintenance duration of 9.0 months. The median event-free survival (EFS) and overall survival (OS) were 9.5 and 33.2 months, respectively. In metastatic patients achieving NED before the initiation of TRO, the median EFS was 29.4 months, while the median OS was not reached. In metastatic patients with anthracycline + ifosfamide (AI) as first-line induction therapy without prior metastasis-directed local therapy, the median EFS and OS from the start of AI were 13.9 and 26.8 months, respectively. Multivariate analysis of the overall cohort demonstrated that NED before the start of maintenance was significantly associated with a prolonged EFS (p = 0.024, hazard ratio [HR] = 0.26), and G2 histology correlated with longer OS (p = 0.030, HR = 0.16, reference: G3).

Oral maintenance therapy with TRO appears to improve outcomes in patients with advanced STS. Metastatic patients who achieve NED through prior metastasectomy may particularly benefit from TRO maintenance.

To observe the efficacy of combination therapy with Penpulimab and Anlotinib in the treatment of retroperitoneal well-differentiated liposarcoma. Retrospective analysis of clinical data of a patient with retroperitoneal well-differentiated soft tissue sarcoma admitted to Shaoxing People's Hospital, and review of relevant literature. The patient is a young male who experienced recurrence of retroperitoneal well-differentiated liposarcoma after two surgeries. After first-line treatment with Anlotinib combined with Penpulimab, the patient achieved almost complete remission with a progression free survival period of about 16 months. The first-line treatment of retroperitoneal well-differentiated soft tissue sarcoma using Anlotinib combined with Penpulimab resulted in a good prognosis.

Ursodeoxycholic acid (UDCA) is a naturally occurring, low-toxicity, and hydrophilic bile acid (BA) in the human body that is converted by intestinal flora using primary BA. Solute carrier family 7 member 11 (SLC7A11) functions to uptake extracellular cystine in exchange for glutamate, and is highly expressed in a variety of human cancers. Retroperitoneal liposarcoma (RLPS) refers to liposarcoma originating from the retroperitoneal area. Lipidomics analysis revealed that UDCA was one of the most significantly downregulated metabolites in sera of RLPS patients compared with healthy subjects. The augmentation of UDCA concentration (≥25 μg/mL) demonstrated a suppressive effect on the proliferation of liposarcoma cells. [15N2]-cystine and [13C5]-glutamine isotope tracing revealed that UDCA impairs cystine uptake and glutathione (GSH) synthesis. Mechanistically, UDCA binds to the cystine transporter SLC7A11 to inhibit cystine uptake and impair GSH de novo synthesis, leading to reactive oxygen species (ROS) accumulation and mitochondrial oxidative damage. Furthermore, UDCA can promote the anti-cancer effects of ferroptosis inducers (Erastin, RSL3), the murine double minute 2 (MDM2) inhibitors (Nutlin 3a, RG7112), cyclin dependent kinase 4 (CDK4) inhibitor (Abemaciclib), and glutaminase inhibitor (CB839). Together, UDCA functions as a cystine exchange factor that binds to SLC7A11 for antitumor activity, and SLC7A11 is not only a new transporter for BA but also a clinically applicable target for UDCA. More importantly, in combination with other antitumor chemotherapy or physiotherapy treatments, UDCA may provide effective and promising treatment strategies for RLPS or other types of tumors in a ROS-dependent manner.

Soft tissue sarcomas (STS) are rare tumours arising in mesenchymal tissues and can occur almost anywhere in the body. Their rarity, and the heterogeneity of subtype and location, means that developing evidence-based guidelines is complicated by the limitations of the data available. This makes it more important that STS are managed by expert multidisciplinary teams, to ensure consistent and optimal treatment, recruitment to clinical trials, and the ongoing accumulation of further data and knowledge. The development of appropriate guidance, by an experienced panel referring to the evidence available, is therefore a useful foundation on which to build progress in the field. These guidelines are an update of the previous versions published in 2010 and 2016 [1, 2]. The original guidelines were drawn up by a panel of UK sarcoma specialists convened under the auspices of the British Sarcoma Group (BSG) and were intended to provide a framework for the multidisciplinary care of patients with soft tissue sarcomas. This iteration of the guidance, as well as updating the general multidisciplinary management of soft tissue sarcoma, includes specific sections relating to the management of sarcomas at defined anatomical sites: gynaecological sarcomas, retroperitoneal sarcomas, breast sarcomas, and skin sarcomas. These are generally managed collaboratively by site specific multidisciplinary teams linked to the regional sarcoma specialist team, as stipulated in the recently published sarcoma service specification [3]. In the UK, any patient with a suspected soft tissue sarcoma should be referred to a specialist regional soft tissues sarcoma service, to be managed by a specialist sarcoma multidisciplinary team. Once the diagnosis has been confirmed using appropriate imaging and a tissue biopsy, the main modality of management is usually surgical excision performed by a specialist surgeon, combined with pre- or post-operative radiotherapy for tumours at higher risk for local recurrence. Systemic anti-cancer therapy (SACT) may be utilised in cases where the histological subtype is considered more sensitive to systemic treatment. Regular follow-up is recommended to assess local control, development of metastatic disease, and any late effects of treatment.

Ifosfamide is used clinically with doxorubicin as first-line chemotherapy for soft-tissue sarcoma. However, ifosfamide efficacy for soft-tissue sarcoma is limited due to frequent occurence of ifosfamide resistance and thus more effective therapy is needed. The present study aimed to determine the synergy of recombinant methioninase (rMETase) plus ifosfamide against HT1080 human fibrosarcoma cells in vitro. Additionally, the present study also investigated the efficacy of a methionine-restricted diet combined with ifosfamide in nude-mouse models of ifosfamide-resistant HT1080 (IR-HT1080).

Cell viability for HT1080 human fibrosarcoma cells was determined in four groups in vitro: No treatment control; ifosfamide alone; rMETase alone; and a combination of ifosfamide plus rMETase. HT1080 tumors were established in nude mice subcutaneously. The HT1080 tumor models were treated by administering ifosfamide by intraperitoneal injection twice a week, for a total of 11 doses. Surviving tumors were considered ifosfamide resistant (IR-HT1080). Four groups of IR-HT1080 nude-mouse models were subsequently established: Group 1 was a no-treatment control, Group 2 received ifosfamide, Group 3 was given a methionine-restricted diet (MR), and Group 4 received ifosfamide plus MR. Additionally, two groups of nude mice with parental HT1080 subcutaneous tumors were included: Group 5 was a no-treatment control, and Group 6 received ifosfamide for comparison.

The 50% inhibitory concentration (IC50) for ifosfamide against HT1080 cells was 0.38 mM. The IC50 for rMETase was 0.75 U/ml for HT1080 cells (data from [4]). The combination of rMETase (0.75 U/ml) plus ifosfamide (0.38 mM) was synergistic against HT1080 fibrosarcoma cells in vitro. The combination of ifosfamide plus MR eradicated the IR-HT1080 tumors in nude-mouse models, while each treatment alone achieved limited tumor inhibition.

The present results suggest the combination of MR and ifosfamide has promising potential for overcoming ifosfamide resistance in future clinical applications.

Trabectedin binds covalently to the DNA minor groove and causes DNA to bend toward the main groove, then trabectedin regulates the transcription of the involved genes in cell proliferation or acts on the mononuclear phagocyte system in tumors, which contributes to its antitumor effects. Several clinical trials confirmed the efficacy of trabectedin for patients with advanced soft tissue sarcoma (STS) although clinically useful biomarkers remained unidentified. This study aimed to identify prognostic factors of trabectedin treatment, especially focusing on the systemic inflammatory, immune response, and nutritional status.

This study included 44 patients with advanced STS treated with trabectedin from January 2018 to August 2022. We evaluated the associations of clinical factors that influence the efficacy of trabectedin treatment with progression-free survival (PFS) and overall survival (OS), focusing on systemic inflammatory, immune response, and nutritional status represented by the absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammation response index (SIRI), prognostic nutrition index (PNI), and C-reactive protein (CRP) using the Kaplan-Meier method and the log-rank test.

ALC, LMR, PNI, NLR, PLR, and SIRI demonstrated no association with PFS. Patients with CRP of ≥0.3 had a significantly shorter PFS than those with CRP of <0.3 (median PFS: 863 vs. 105 days, P = 0.045). PNI of ≥44 (median: 757 days vs. 232 days, P = 0.021) and CRP of <0.3 (median: 877 days vs. 297 days, P = 0.043) were significantly good prognostic factors in terms of OS.

The study results indicate pretreatment PNI and CRP levels as prognostic factors for trabectedin treatment in advanced STS.