Soft Tissue Sarcoma Subtypes Research Articles

Myxoid liposarcoma: treatment outcomes, metastatic pattern and volumetric analysis.

Myxoid liposarcoma (MLPS) is arare subtype of soft tissue sarcoma. This entity has aspecific clinical behavior, characterized with adistinct pattern of hematogenous spread, as well as with aunique radiosensitivity and chemosensitivity. Oncologic results, metastatic patterns and treatment response after multimodal therapy were evaluated in aunicentric patient cohort. Patients with myxoid liposarcoma were retrospectively analyzed in asingle institution analysis (n = 31). Oncologic outcomes were evaluated in 28patients with localized MLPS treated with multimodal therapy in curative intent. Metastatic pattern was analyzed in additional 3patients with initially metastatic disease. In patients treated with concomitant MR-guided hyperthermia in the preoperative setting (n = 7), tumor size response was evaluated longitudinally during radio(-chemo)therapy in thermometry MRIs and before surgery (based on preoperative imaging). The median follow-up was 4.1 ± 1.0years. The most common anatomic localization was the lower extremity (78.6%). The 5‑year rates for oncologic outcomes in 28patients treated in curative intent were 91.7% (± 8.0%) for overall survival (OS), 77.4% (± 11.0%) for local control (LC), 60.1% (± 10.6%) for distant metastasis-free survival (DMFS) and 55.4% (± 11.1%) for disease free survival (DFS). Excellent 5‑year LC (94.7 ± 5.1%) was demonstrated for the cohort excluding 5patients treated for local recurrences. Most patients had good pathologic response (< 10% vital tumor tissue) following neoadjuvant treatment (82.4%, 14/17). However, this did not correlate with oncologic outcomes. Aspecific pattern of distant metastases has been observed, with predilection for soft tissues as the most common metastatic site. Furthermore, no isolated pulmonary metastases were observed. The MR analysis demonstrated asignificant tumor size reduction (≥ 25%) of the initial tumor volume in 85.7% (n = 6/7) patients. No local recurrences and no distant metastases were observed in patients with significant MR size reduction. Sequential MRIs during preoperative radiotherapy of myxoid liposarcoma show distinct patterns of the known size reduction of this specific subentity. Our analysis of metastatic patterns demonstrate mostly soft tissue metastases, no patient experienced isolated pulmonary metastases.

Efficacy of immune checkpoint inhibitors in the treatment of soft tissue sarcoma: A systematic review and meta-analysis of clinical trials.

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.

Incidence and survival of European adolescents and young adults diagnosed with sarcomas: EUROCARE-6 results.

Epidemiological data for sarcoma in adolescents and young adults (AYAs) and across age groups are limited. We aim to: 1) update sarcoma incidence, survival, and changes over time in European AYAs; 2) provide an updated comparison of sarcoma survival in AYAs versus children and mature adults. We calculated crude incidence rates (IR) per 100,000 European population per year from 2006 to 2013. Using the period approach, we calculated 5-year relative survival (RS) for the follow-up period 2010-2014. We estimated changes in incidence and survival for bone sarcoma (BS) and soft tissue sarcoma (STS) subtypes in AYAs in the years 2000-2013. In European AYAs, the IR was 0.81/100,000 for BS and 1.45/100,000 for STS. Five-year RS was 69 % and 65 % for BS and STS, respectively. Compared to children, AYAs had poorer survival for Ewing sarcoma of bone, synovial sarcoma, Ewing sarcoma of soft tissue and rhabdomyosarcoma. Compared to mature adults, AYAs had higher 5-year RS for all BS and for most of the STS subtypes. In AYAs, incidence increased for a few bone and soft tissue subtypes. Survival increased mainly for BS. The reason for the better survival observed in AYAs compared to mature adults is probably multifactorial. The limited improvement of STS survival in AYAs may reflect the relative absence of new drugs for STS during the study period. The increase in RS for BS might relate to general improvements in radiological and surgical approaches and radiotherapy techniques.

Oncogenic Functions of Alternatively Spliced MDM2-ALT2 Isoform in Retroperitoneal Liposarcoma.

Retroperitoneal liposarcoma (RPLPS) is one of the most common histologic subtypes of soft tissue sarcoma (STS). Complete surgical resection remains the mainstay treatment, while the high rate of locoregional recurrence constitutes the predominant cause of mortality. Well-differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are the most frequent subtypes of RPLPS and present amplified MDM2 gene as a hallmark. However, there are few reports evaluating the role of alternatively spliced MDM2 transcripts in RPLPS. In this study, we assessed MDM2-ALT2 expression levels in a cohort of RPLPS patients and evaluated the biological functions of the MDM2-ALT2 isoform in vitro in DDLPS cell lines. Using BaseScope™ and qPCR, we demonstrated that MDM2-Full Length (MDM2-FL) and MDM2-ALT2 expression levels were upregulated in RPLPS patient-derived tissue samples compared to normal adjacent to tumor tissue (NAT). DDLPS cells overexpressing MDM2-FL or MDM2-ALT2 had higher proliferation rates and increased migration and invasion capacities, as well as increased protein levels of p-AKT, mTOR, p70S6K, MMP2, and cJun. Simultaneous overexpression of MDM2-ALT2 and AKT silencing showed that AKT inhibition impaired p-p70S6K and MMP2 protein increased levels and led to significantly decreased proliferation and migration rates compared to cells overexpressing MDM2-ALT2 only. Taken together, our data suggest that MDM2-ALT2 may promote RPLPS progression.

Descriptive analysis of incidence, demographic characteristics, and survival outcomes of soft-tissue sarcoma of the extremities in Saudi Arabia

Soft-tissue sarcomas are uncommon, aggressive, and histologically heterogeneous, malignant tumors. Soft-tissue tumor types have different age and anatomical site distributions. This study aimed to assess the prevalence and incidence of soft-tissue sarcomas of the extremities to facilitate early diagnosis and intervention in the Kingdom of Saudi Arabia. This retrospective study included all patients diagnosed with primary soft-tissue sarcomas of the extremities and pelvis between January 2006 and December 2015. The data were obtained from the Saudi Cancer Registry. Means and confidence intervals were reported for numerical variables, whereas the frequencies and percentages were reported for categorical variables. The chi-squared test and analysis of variance were used to test the associations between categorical numerical variables. Cox regression analysis was used to determine the hazard ratios for each sarcoma type. Of the 659 patients, 145 (22%) were aged 19–30 years, 365 (55.4%) were men, and 411 (62.4%) had lower limb sarcoma. Most of the tumors (54.3%) were localized. The incidence of sarcoma ranged from 2 to 2.9 cases per one million (average, 2.4 cases per one million). Moreover, liposarcoma was the most commonly diagnosed (n = 135; 20.5%), followed by undifferentiated pleomorphic sarcoma (n = 87; 13.2%). The incidence of soft-tissue sarcomas in the Kingdom of Saudi Arabia were lower than those in Western countries. However, the distribution of soft-tissue sarcoma subtypes was similar to those in other countries. The survival rates in this study highlight the need for continued research and targeted interventions to improve the outcomes of patients with soft-tissue sarcomas, especially those with more aggressive subtypes, such as sarcoma not otherwise specified and rhabdomyosarcoma.

Abstract A054: Oncogenic functions of alternatively spliced MDM2-ALT2 isoform in retroperitoneal liposarcoma

Abstract Retroperitoneal liposarcoma (RPLPS) is one of the most common histologic subtypes of soft tissue sarcoma (STS). Complete surgical resection remains the mainstay treatment while the high rate of locoregional recurrence constitutes the predominant cause of mortality. Well- differentiated (WDLPS) and dedifferentiated (DDLPS) liposarcoma are the most frequent subtypes of RPLPS and present amplified MDM2 gene as a hallmark. However, there are few reports evaluating the role of alternatively spliced MDM2 transcripts in RPLPS. In this study, we assessed MDM2-ALT2 expression levels in a cohort of RPLPS patients and evaluated biological functions of MDM2-ALT2 isoform in vitro in DDLPS cell lines. Using BaseScope™ and qPCR, we demonstrated that MDM2-Full Length (MDM2-FL) and MDM2-ALT2 expression levels were upregulated in RPLPS patient-derived tissue samples compared to normal adjacent to tumor tissue (NAT). DDLPS cells overexpressing MDM2-FL or MDM2-ALT2 had higher proliferation rates and increased migration and invasion capacities, as well as increased protein levels of p- AKT, mTOR, p70S6K, MMP2 and cJun. Simultaneous overexpression of MDM2-ALT2 and AKT silencing showed that AKT inhibition impaired p-p70S6K and MMP2 protein increased levels and led to significantly decreased proliferation and migration rates compared to cells overexpressing MDM2-ALT2 only. Taken together, our data suggest that MDM2-ALT2 may promote RPLPS progression. Citation Format: Fernanda Costas C. de Faria, Safiya Khurshid, Patricia Sarchet, Sayumi Tahara, Lucia Casadei, Valerie Grignol, Roma Karna, Sydney Rentsch, Nippin Sp, Joal D Beane, Luciano Mazzoccoli, Matias Montes, Giovanni Nigita, Joe T Sharick, Jennifer L Leigth, Federica Calore, Dawn Chandler, Raphael E Pollock. Oncogenic functions of alternatively spliced MDM2-ALT2 isoform in retroperitoneal liposarcoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A054.

Dysregulation of miRNAs in Soft Tissue Sarcomas.

MicroRNAs (miRNAs) are pivotal regulators of gene expression, influencing key cellular processes such as proliferation, differentiation, apoptosis, and metastasis. In the realm of sarcomas-a diverse group of malignant tumors affecting soft tissues and bone sarcomas-miRNAs have emerged as crucial players in tumorigenesis and tumor progression. This review delves into the intricate roles of miRNAs across various soft tissue sarcoma subtypes, including rhabdomyosarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, fibrosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS), and malignant peripheral nerve sheath tumor (MPNST). We explore how dysregulated miRNAs function as oncogenes or tumor suppressors, modulating critical pathways that define the aggressive nature of these cancers. Furthermore, we discuss the diagnostic and prognostic potential of specific miRNAs and highlight their promise as therapeutic targets. By understanding the miRNA-mediated regulatory networks, this review aims to provide a comprehensive overview of current research while pointing towards future directions for miRNA-based therapies. Our findings underscore the potential of miRNAs to transform the landscape of sarcoma treatment, offering hope for more precise, personalized, and effective therapeutic strategies.

Transcriptomic profiles of myxofibrosarcoma and undifferentiated pleomorphic sarcoma correlate with clinical and genomic features.

Myxofibrosarcoma (MFS) and undifferentiated pleomorphic sarcoma (UPS) are two common and aggressive subtypes of soft tissue sarcoma. The aim of this study was to assess potential transcriptomic differences between MFS and UPS tumours and to evaluate the extent to which differences in gene expression profiles were associated with genomic and clinical features. The study included 162 patients with tumours diagnosed as MFS (N = 62) or UPS (N = 100). The patients had been diagnosed and treated at two Swedish sarcoma centres during a 30-year period. For gene expression profiling and gene fusion detection all tumours were analysed using RNA-sequencing and could be compared with data on clinical outcome (N = 155), global copy number profiles (N = 145), and gene mutations (N = 128). Gene expression profiling revealed three transcriptomic clusters (TCs) without any clear separation of MFS and UPS. One TC was associated with longer metastasis-free survival. These tumours had lower tumour mutation burden (TMB), were enriched for a copy number signature representative of focal LOH and chromosomal instability on a diploid background, and were relatively immune-depleted. MFS and UPS showed extensive genomic overlap, with whole genome doubling occurring more frequently among the latter. The results support the idea that MFS and UPS tumours have largely overlapping genomic and transcriptomic features, with UPS tumours showing more aggressive behaviour and more complex genomes. Independently of the tumour type, clinically relevant subgroups were revealed by gene expression analysis, and the finding of multiple genomic subgroups strongly suggest the existence of subgroups of relevance to treatment stratification. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

B7-H3 is widely expressed in soft tissue sarcomas

PurposeTargeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS.Patients and methodsThis retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature.ResultsSpecimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93–0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61–0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1.ConclusionThese data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.

Case Report : Undifferentiated Synovial Sarcoma Presenting as a Large Thoracic Mass: A Rare and Challenging Diagnosis

Background: Undifferentiated synovial sarcoma (USS) is a rare and aggressive subtype of soft tissue sarcoma. Its presentation as a large thoracic mass poses significant diagnostic and therapeutic challenges.  Case Presentation: A 34-year-old male presented with a three-month history of progressive chest pain and hemoptysis. Imaging studies revealed a large, cystic thoracic mass with pleural effusion. Initial serological testing suggested hydatid cyst, but subsequent testing revealed negative Echinococcus (Hydatid) IgG antibodies.  Diagnostic and Therapeutic Interventions: Repeat fine-needle aspiration cytology (FNAC) was deferred due to revised ultrasound findings indicating a solid fibrocystic vascular lesion. Bronchial artery embolization (BAE) was performed to control life- threatening hemorrhage. Thoracotomy and en-bloc mass excision were subsequently undertaken.  Histopathological Diagnosis: Histopathological examination of the resected specimen revealed undifferentiated synovial sarcoma and spindle cell sarcoma.  Clinical Implications: This case highlights the importance of correlating imaging and serological findings, managing vascular complications, and the efficacy of BAE in controlling hemorrhage. The significance of thoracotomy and mass excision in achieving diagnostic clarity and therapeutic success is underscored.  Conclusion: Undifferentiated synovial sarcoma presenting as a large thoracic mass poses significant diagnostic and therapeutic challenges. A multidisciplinary approach, incorporating imaging, serological testing, and surgical intervention, is crucial for achieving optimal patient outcomes.

High-Throughput Transcriptomics Identifies Chemoresistance-Associated Gene Expression Signatures in Human Angiosarcoma

Angiosarcomas, clinically aggressive cancers of endothelial origin, are a rare subtype of soft-tissue sarcomas characterized by resistance to chemotherapy and dismal prognosis. In this study, we aim to identify the transcriptomic biomarkers of chemoresistance in angiosarcoma. We examined 72 cases of Asian angiosarcomas, including 35 cases treated with palliative chemotherapy, integrating information from NanoString gene expression profiling, whole transcriptome profiling (RNA-seq), immunohistochemistry, cell line assays, and clinicopathological data. In the chemoresistant cohort (defined as stable disease or progression), we observed the significant overexpression of genes, including SPP1 (log2foldchange 3.49, adj. p = 0.0112), CXCL13, CD48, and CLEC5A, accompanied by the significant enrichment of myeloid compartment and cytokine and chemokine signaling pathways, as well as neutrophils and macrophages. RNA-seq data revealed higher SPP1 expression (p = 0.0008) in tumor tissues over adjacent normal compartments. Immunohistochemistry showed a significant moderate positive correlation between SPP1 protein and gene expression (r = 0.7016; p &lt; 0.00110), while higher SPP1 protein expression correlated with lower chemotherapeutic sensitivity in patient-derived angiosarcoma cell lines MOLAS and ISOHAS. In addition, SPP1 mRNA overexpression positively correlated with epithelioid histology (p = 0.007), higher tumor grade (p = 0.0023), non-head and neck location (p = 0.0576), and poorer overall survival outcomes (HR 1.84, 95% CI 1.07–3.18, p = 0.0288). There was no association with tumor mutational burden, tumor inflammation signature, the presence of human herpesvirus-7, ultraviolet exposure signature, and metastatic state at diagnosis. In conclusion, SPP1 overexpression may be a biomarker of chemoresistance and poor prognosis in angiosarcoma. Further investigation is needed to uncover the precise roles and underlying mechanisms of SPP1.

Rhabdomyosarcoma Presenting as an Infective Midline Nodule on the Chin in an Eight-year-old Child

Background and Aims: Rhabdomyosarcoma (RMS) is the most common subtype of soft tissue sarcoma (STS) in children. Early diagnosis is the most favourable prognostic factor and thus physicians need to include RMS in the differential diagnosis of more common diseases developing within the head and neck region. This report highlights the same while describing a case of an eight-year-old child who presented with a chin swelling which turned out to be an RMS. Methods: We present a rare case of an eight-year-old child with a midline painless mass. Results: This child had a transoral resection of the mass. He undertook further chemotherapy and was completely cured with no tumour recurrence. Conclusion: In a painless rapidly increasing mass in the head and neck area, despite rare, but RMS should be included as a differential diagnosis. This is important as early diagnosis and proper resection and treatment are paramount in the prognosis of the disease.

MEK Inhibitors Lead to PDGFR Pathway Upregulation and Sensitize Tumors to RAF Dimer Inhibitors in NF1-Deficient Malignant Peripheral Nerve Sheath Tumor.

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive subtype of soft-tissue sarcoma with a high propensity to metastasize and extremely limited treatment options. Loss of the RAS-GAP NF1 leads to sustained RAF/MEK/ERK signaling in MPNST. However, single-agent MEK inhibitors (MEKi) have failed to elicit a sustained inhibition of the MAPK signaling pathway in MPNST. We used pharmacological, biochemical, and genetic perturbations of the receptor tyrosine kinase and MAPK signaling pathway regulators to investigate the mechanisms of MEKi resistance and evaluated combination therapeutic strategies in various preclinical MPNST models in vitro and in vivo. Here, we report that MEKi treatment resistance in MPNST involves two adaptive pathways: direct transcriptional upregulation of the receptor tyrosine kinase PDGFRβ and MEKi-induced increase in RAF dimer formation and activation of downstream signaling. Although the pharmacologic combination of a MEKi with a PDGFRβ-specific inhibitor was more effective than treatment with the MEKi alone, the combination of the MEKi and RAF dimer inhibitors led to a robust inhibition of MAPK pathway signaling. This combination treatment was effective in vitro and in vivo, as demonstrated by the significant increase in drug synergism and its high effectiveness in decreasing MPNST viability. Our findings suggest that the combination of MEKis and PDGFR and/or RAF dimer inhibitors can overcome MEKi resistance and may serve as a novel targeted therapeutic strategy for patients with NF1-deficient MPNST, which in turn could impact future clinical investigations for this patient population.

Cellular origin and clonal evolution of human dedifferentiated liposarcoma

Dedifferentiated liposarcoma (DDLPS) is the most frequent high-grade soft tissue sarcoma subtype. It is characterized by a component of undifferentiated tumor cells coexisting with a component of well-differentiated adipocytic tumor cells. Both dedifferentiated (DD) and well-differentiated (WD) components exhibit MDM2 amplification, however their cellular origin remains elusive. Using single-cell RNA sequencing, DNA sequencing, in situ multiplex immunofluorescence and functional assays in paired WD and DD components from primary DDLPS tumors, we characterize the cellular heterogeneity of DDLPS tumor and micro-environment. We identify a population of tumor adipocyte stem cells (ASC) showing striking similarities with adipocyte stromal progenitors found in white adipose tissue. We show that tumor ASC harbor the ancestral genomic alterations of WD and DD components, suggesting that both derive from these progenitors following clonal evolution. Last, we show that DD tumor cells keep important biological properties of ASC including pluripotency and that their adipogenic properties are inhibited by a TGF-β-high immunosuppressive tumor micro-environment.

Real-world efficacy, safety data and predictive clinical parameters for treatment outcomes in advanced soft tissue sarcoma treated with combined immunotherapy and antiangiogenic therapy

BackgroundThe combination of immunotherapy and antiangiogenic therapy has shown potential in the treatment of numerous malignant tumors, but limited evidence was available for soft tissue sarcomas (STS). Therefore, the aim of the present study is to assess the efficacy and safety of immunotherapy in conjunction with antiangiogenic therapy in patients diagnosed with advanced STS (aSTS).MethodsThe study enrolled patients with aSTS from January 2014 to October 2022. Eligible participants had previously received anthracycline-based chemotherapy, presented with an anthracycline-resistant sarcoma subtype, or were ineligible for anthracycline treatment due to medical conditions. Following enrollment, these patients received a combination of immunotherapy and antiangiogenic therapy. The primary endpoints were the objective response rate (ORR) and progression-free survival (PFS), while the secondary endpoints included the disease control rate (DCR), overall survival (OS), and the incidence of adverse events.ResultsFifty-one patients were included in this cohort study. The median duration of follow-up was 15.8 months. The ORR and DCR were 17.6%, and 76.5%, respectively. The median PFS (mPFS) was 5.8 months (95% CI: 4.8–6.8) for all patients, and the median OS had not been reached as of the date cutoff. Multivariate analysis indicated that Eastern Cooperative Oncology Group performance status of 0–1 and ≤ second-line treatment were positive predictors for both PFS and OS. Patients with alveolar soft part sarcoma or clear cell sarcoma had longer mPFS (16.2 months, 95% CI: 7.8–25.6) when compared to those with other subtypes of STS (4.4 months, 95% CI: 1.4–7.5, P < 0.001). Among the observed adverse events, hypertension (23.5%), diarrhea (17.6%), and proteinuria (17.6%) were the most common, with no treatment-related deaths reported.ConclusionThe combination of immunotherapy and antiangiogenic agents showed promising efficacy and acceptable toxicity in patients with aSTS, especially those with alveolar soft part sarcoma or clear cell sarcoma.

Radiological evaluation of response in patients with locally advanced/metastatic soft tissue sarcoma treated with trabectedin.

Background: Trabectedin is an antineoplastic drug approved for patients (pts) with advanced soft tissue sarcomas (STS). Interestingly, the radiological evaluation of response during trabectedin therapy is peculiar. Methods: The aim of this single-center retrospective study is to analyze the concordance of response assessment according to RECIST compared with Choi criteria in patients with STS treated with trabectedin between 2009 and 2020 at Regina Elena National Cancer Institute in Rome. Results: We present the preliminary data collected in the last 2months (mos) on 37pts who received the diagnosis between 2015 and 2020, with a median age of 52.5years (range 32-78). The median number of trabectedin cycles administered was four (range 2-50) for a median follow up of 5.83months (range 1-60). Histological subtypes of STS were five (13.5%) leiomyosarcoma, 14 (37.8%) liposarcoma, nine (24.3%) undifferentiated pleomorphic sarcoma, three (8.1%) synovial sarcoma, and six (16.2%) other rare histological subtypes. Eight pts (21.6%) received trabectedin in the first line setting, 21 (56.8%) in the second line, and seven (18.9%) received it in subsequent lines. One pt received trabectedin as neoadjuvant therapy in a clinical trial (ISG-STS 1001). Median progression-free survival was 3.6months (CI95% 2.7-4.6); median overall survival was 34.3months (CI95% 0-75.4). The radiological responses were evaluated with both RECIST and Choi criteria; responses matched in 33pts (89.2%) but not in four (10.8%). The best responses obtained according to RECIST criteria were two (5.4%) partial response (PR), 13 (35.1%) stable disease (SD), and 22 (59.5%) progressive disease (PD). Instead, two (5.4%), 13 (35.1%), and 22 (59.5%) pts obtained PR, SD, and PD respectively, according to Choi criteria. Cohen's kappa coefficient of concordance was 0.792 (p-value <0.002). A specialized radiologist performed all imaging examinations using a dedicated workstation in the same center. Conclusion: In this first analysis, the concordance between RECIST and Choi assessments demonstrates no statistically significant difference. Responses did not match for four pts. We are expanding the analysis to all pts included in the original cohort to confirm or deny these initial results.

The single cell transcriptional landscape of fibrosarcoma.

235 Background: Fibrosarcoma (FS) is a relatively uncommon subtype of soft tissue sarcoma, which predominantly occurs in the extremities and girdles of elderly individuals. FS are famous for its high recurrence and metastasis rate. However, the current treatment regimens have shown poor efficacy in treating these progressive lesions. Therefore, a deep understanding of the tumor microenvironment characteristics of fibrosarcoma is needed to develop more effective drugs.Therefore, a deeper understanding of the tumor microenvironment characteristics of fibrosarcoma is needed for further development of therapeutic drugs. Methods: We performed single-cell transcriptome sequencing for the first time on 6 patients bearing with FS. Bulk-seq data of soft tissue sarcoma was downloaded from public database including TCGA and GEO for prognostic analysis. What' s more, a cohort of 54 FS patients was retrospectively collected for protein detection. Results: The tumor microenvironment landscape was characterized by the presence of malignant fibroblast, diverse macrophages, limited T-cell presence, and high levels of vascular infiltration. The expression of siglec15 was significantly upregulated in the malignant cells. And the prognostic significance of siglec15 was confirmed by the TCGA public database. What’s more, the high expression of siglec15 protein was negatively related to overall survival of fibrosarcoma patients from our institution. We also explored the interactions among different cell subtypes, especially the interactions between malignant cells and endothelial cells, as well as macrophages and endothelial cells, which not only promote tumor progression but also inhibit T-cell infiltration and function. Conclusions: In total, our work has uncovered the low T cell infiltration landscape of FS. The primary reason of insufficient immune infiltration may be due to the blockage of T cell extravasation caused by the interaction between endothelial cells, malignant cells and macrophages.

Collagen modification remodels the sarcoma tumor microenvironment and promotes resistance to immune checkpoint inhibition.

Molecular mechanisms underlying immune checkpoint inhibitor (ICI) response heterogeneity in solid tumors, including soft tissue sarcomas (STS), remain poorly understood. Herein, we demonstrate that the collagen-modifying enzyme, procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (Plod2), which is over-expressed in many tumors relative to normal tissues, promotes immune evasion in undifferentiated pleomorphic sarcoma (UPS), a relatively common and aggressive STS subtype. This finding is consistent with our earlier observation that Plod2 promotes tumor metastasis in UPS, and its enzymatic target, collagen type VI (ColVI), enhances CD8+ T cell dysfunction. We determined that genetic and pharmacologic inhibition of Plod2 with the pan-Plod transcriptional inhibitor minoxidil, reduces UPS growth in an immune competent syngeneic transplant system and enhances the efficacy of anti-Pd1 therapy. These findings suggest that PLOD2 is an actionable cancer target and its modulation could augment immunotherapy responses in patients with UPS, and potentially other sarcomas and carcinomas.

Real-world outcomes of metastatic clear cell sarcoma sequential chemotherapy

Clear cell sarcoma is an ultra-rare chemoresistant subtype of soft tissue sarcoma. This retrospective analysis aimed to clarify the efficacy of palliative chemotherapy in CCS by assessing response rates, progression-free survival (PFS), and overall survival (OS) at a referral center. A retrospective analysis of palliative treatment was conducted on patients with CCS treated at the sarcoma unit from 1997 to 2023. Treatment responses were assessed using RECIST criteria, and the Kaplan–Meier method was used to calculate PFS and OS. The analysis covered 23 CCS chemotherapy-treated patients with 11 (47.8%) men. The median age at the palliative treatment start was 32 years (range 18-59). The median follow-up was 8.2 months. Four patients were referred to our centre for M1 disease, and 6 received perioperative chemotherapy and progressed during follow-up. In the first line, 14 patients received anthracycline-based chemotherapy (60.9%), five were treated with ifosfamide (HD-IFO), and four received other regimens. One patient (4.3%) achieved partial response (PR), and 12 patients (52.2%) achieved stable disease (SD) as the best response. Median PFS in 1 line was 2.79 months (95% CI: 2.04–8.38), and 1.76 months (95% CI: 0.72–6.97) in the second line. The median OS from first-line palliative chemotherapy was 8.2 months (95% CI: 6.2–14), and the second-line palliative chemotherapy mOS was 4.6 months (95% CI: 3.9–NA). Perioperatively anthracycline-pretreated worsened patients’ median PFS in the M1 setting. Poor responses to conventional chemotherapy were observed in CCS, indicating a need for further clinical trials in this indication.

Safety and Preliminary Efficacy of Once-Weekly Split-Dose Selinexor in Soft Tissue Sarcoma: Results of the Phase Ib METSSAR Clinical Trial.

The approved dose of Selinexor, 60 mg twice-weekly, is associated with several clinically relevant toxicities. Preclinical studies show that a sustained-release formulation of selinexor results in a lower toxicity profile. The phase 1b METSSAR trial assessed the safety and tolerability of an alternative dosing schedule of selinexor (to mimic the sustained-release formulation) in advanced soft tissue sarcoma (STS) patients. Selinexor was administered in a split-dose schedule (40 mg, 20 mg, 20 mg in the morning, afternoon, and evening, respectively) on days 1, 8, 15, and 22 of a 28-day cycle, until unacceptable toxicity or disease progression. The primary endpoint was the rate of grade ≥ 3 treatment-related adverse events (TRAEs). Secondary objectives were EORTC QLQ-C30 quality of life (QoL) assessment, and preliminary efficacy. Twenty patients with 12 STS subtypes were enrolled and received a median of four cycles of treatment. There were no grade ≥ 3 TRAEs. Dysgeusia, nausea, fatigue, and thrombocytopenia were the most common grade ≤ 2 TRAEs. No treatments were discontinued due to TRAE, but four patients (20%) required dose reduction. Median change in global health status (GHS) score from baseline to cycle 2 (by QLQ-C30 v3.0) was - 8.33, and only 39% of patients reported a clinically meaningful decline in GHS score (≥10 points). Median symptom scale scores on treatment were increased for fatigue (+12.35), nausea/vomiting (+18.52), and anorexia (+16.67), but reduced for pain (- 3.70). The median progression-free survival (PFS) was 4.0 months (95% confidence interval 1.9-7.5). Split-dose once-weekly selinexor was reasonably well tolerated in this heterogeneous group of advanced STS patients with a better, or at least similar, clinician- and patient-reported toxicity profile compared to the standard dosing regimen. Further clinical evaluation is warranted, as better dose delivery can lead to improved antitumor efficacy.