Adult Soft Tissue Sarcomas Research Articles

Role of Adjuvant Treatment in Resected Adult Extremity Soft Tissue Sarcoma

Role of Adjuvant Treatment in Resected Adult Extremity Soft Tissue Sarcoma

Analysis of metastasis‑related risk factors and clinical relevance in adult soft‑tissue sarcoma.

Metastasis occurs in nearly 50% of cases of adult soft-tissue sarcoma (ASTS), leading to a dismal prognosis, with a 2-year survival rate of ~30%. Consequently, a prognostic model that incorporates metastatic characteristics may be instrumental in predicting survival time and in crafting optimal personalized therapeutic strategies for patients with ASTS. In the present study, a prognostic prediction model for ASTS was developed by examining genes that are differentially expressed between non-metastatic and metastatic patients in the Gene Expression Omnibus dataset. The prognostic model, which includes five featured genes [actin γ2 (ACTG2), apolipoprotein D, coatomer protein complex subunit γ2 imprinted transcript 1, collagen type VI α6 chain and osteomodulin], was further validated in patients with ASTS from the Cancer Genome Atlas dataset. Based on these five-gene signatures, patients were categorized into high- and low-risk groups. Functional and pathway analyses revealed disparities in stemness, extracellular matrix and cell adhesion-related pathways between the two risk groups, particularly noting the activation of the PI3K-Akt pathway in high-risk cases. Analysis of immune infiltration also revealed variations in immune microenvironment changes between the two risk groups. Immunohistochemical staining substantiated the prognostic significance of these gene signatures in a specific sarcoma subtype. Additionally, wound-healing and Transwell assays demonstrated that inhibition of ACTG2 by shRNAs curbed cell migration and invasion in a sarcoma HOS cell line, underscoring its role in sarcoma metastasis. In conclusion, the present study successfully developed and validated a metastasis-based prognosis prediction model. This model not only reliably forecasts the survival of patients with ASTS, but also may pave the way for further investigation into the processes underlying sarcoma metastasis, ultimately aiding in the design of tailored therapeutic regimens.

Enhancing Diagnosis and Prognosis by Assessing the Clinical, Morphological, and Behavior Aspects in Soft Tissue Sarcomas.

Soft-tissue sarcomas (STSs) are an uncommon and diverse group of cancers, consisting of more than 80 different kinds, each showing unique mesenchymal differentiation as described by the World Health Organization (WHO). The prognostic factors at the time of diagnosis mostly depend on the size, depth, and histological grade of the lymphatic involvement. Improved prognostic indicators are necessary to identify patients at high risk who may derive advantages from adjuvant therapy and those at low risk who might avoid treatment-related side effects. Over a period of five years, a considerable number of patients experience the recurrence of the tumor in the same area or the metastasis of the disease to other parts of the body, even after the complete removal of the localized tumor through surgery. To further personalize and focus medicines, it is critical to enhance prediction accuracy and uncover new therapy targets. This is particularly important considering the high mortality and morbidity rate associated with metastatic STS. The significant diversity of STS poses difficulty in comprehending its pathobiology and in converting biological progress into therapeutic application. This prospective cohort study was carried out at a major university hospital to ascertain adult patients who were diagnosed with STS of the extremities between the period from 2018 to 2023. The inclusion criteria were individuals who were 18 years of age or older with a histological diagnosis of STS. The exclusion criteria encompassed individuals with malignancies other than STS and those with inadequate data on essential factors. Thorough assessments were conducted to analyze patient demographics, tumor features (including site, size, depth, neurovascular or bone invasion), and histologic type and grade (according to the French Federation of Cancer Centers (FNCLCC) grading system). The purpose was to find predictive markers and evaluate results. The results are consistent with previous research and enhance our current knowledge of STS prognosis. Key prognostic markers for metastasis and mortality risk include tumor size larger than 5 cm, histologic grade, and sarcoma subtype. Radical surgical procedures, such as amputation or disarticulation, did not show any survival advantage, probably because they were used in situations where the disease had already progressed locally and had significant involvement in the blood vessels. Histologic grading has been identified as the most important factor in predicting the likelihood of metastasis in adult STSs. The study found that most tumors were of high grade, and there was a statistically significant association between tumor grade, Ki67 levels, and overall survival. A small proportion of patients experienced prolonged longevity beyond five years, emphasizing the connection between early detection, tumors of lesser severity, and enhanced results. These observations emphasize the significance of accurate prognostic assessments and customized therapeutic approaches in the treatment of STS.

P53 as a Potential Actionable Target in Myxofibrosarcoma: A Molecular and Pathologic Review of a Single-Institute Series

Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by high-local recurrence rate, poorly understood molecular pathogenesis, lack of specific prognostic markers, and effective targeted therapies. To gain further insights into the disease, we analyzed a well-defined group of 133 primary MFS cases. Immunohistochemical (IHC) staining for p53, MET, RET, and RB was performed. Twenty-five cases were analyzed by targeted resequencing of known cancer driver hotspot mutations, whereas 66 and 64 MFSs were examined for the presence of genetic variants in TP53 and MET gene, respectively. All clinical, histologic, immunostaining, and genetic variables were analyzed for their impact on 5-years overall survival (OS) and 5-years event-free survival (EFS). In our series, no grade I tumors relapsed and high grade are related to a positive MET immunostaining (P = .034). Both local recurrence (P = .038) and distal metastases (P = .016) correlated to the presence of “single nucleotide variant (SNV) plus copy number variation (CNV)” in TP53. Multivariate analysis revealed that age (>60 years), metastasis at presentation, and positive IHC-p53 signal are risk factors for a poor OS (P = .003, P = .000, and P = .002), whereas age (>60 years), synchronous metastasis, and tumor size (>10 cm) predict an unfavorable 5-years EFS (P = .011, P = .000, and P = .023). Considering the smaller series (n = 66) that underwent molecular screening, the presence of “SNV+CNV” in TP53 represents a risk factor for a worse 5-years EFS (hazard ratio, 2.5; P = .017). The present series confirms that TP53 is frequently altered in MFS (86.4% of cases), appearing to play an important role in MFS tumorigenesis and being a potentially drugable target. A positive p53 immunostainings is related to a poor diagnosis, and it is the presence of a single nucleotide genetic alterations in TP53 that is essential in conferring MFS an aggressive phenotype, thus supporting the use of molecular profiling in MFS to better define the role of p53 as a prognostic factor.

Disaggregation-Activated pan-COX Imaging Agents for Human Soft tissue Sarcoma.

Cancer stem cells are pivotal players in tumors initiation, growth, and metastasis. While several markers have been identified, there remain challenges particularly in heterogeneous malignancies like adult soft tissue sarcomas, where conventional markers are inherently overexpressed. Here, we designed BODIPY scaffold fluorescence probes (BD-IMC-1, BD-IMC-2) that activate via disaggregation targeting for cyclooxygenase (COX), a potential marker for CSCs in sarcoma in clinical pathology. Based on their structures, BD-IMC-1 showcased higher susceptibility to disaggregation compared to BD-IMC-2, consistent with their selective interaction with COX. Notably, the BD-IMC-1 revealed positive cooperativity binding to COX-2 at sub-micromolar ranges. Both probes showed significant fluorescence turn-on upon LPS or PMA triggered COX-2 upregulation in live RAW264.7, HeLa, and human sarcoma cell line (Saos-LM2) up to 2-fold increase with negligible toxicity. More importantly, the BD-IMC-1 demonstrated their practical imaging for COX-2 positive cells in paraffin-fixed human sarcoma tissue. Considering the fixed tissues are most practiced pathological sample, our finding suggests a potential of disaggregation activated chemosensor for clinical applications.

Disaggregation‐Activated pan‐COX Imaging Agents for Human Soft tissue Sarcoma

AbstractCancer stem cells are pivotal players in tumors initiation, growth, and metastasis. While several markers have been identified, there remain challenges particularly in heterogeneous malignancies like adult soft tissue sarcomas, where conventional markers are inherently overexpressed. Here, we designed BODIPY scaffold fluorescence probes (BD‐IMC‐1, BD‐IMC‐2) that activate via disaggregation targeting for cyclooxygenase (COX), a potential marker for CSCs in sarcoma in clinical pathology. Based on their structures, BD‐IMC‐1 showcased higher susceptibility to disaggregation compared to BD‐IMC‐2, consistent with their selective interaction with COX. Notably, the BD‐IMC‐1 revealed positive cooperativity binding to COX‐2 at sub‐micromolar ranges. Both probes showed significant fluorescence turn‐on upon LPS or PMA triggered COX‐2 upregulation in live RAW264.7, HeLa, and human sarcoma cell line (Saos‐LM2) up to 2‐fold increase with negligible toxicity. More importantly, the BD‐IMC‐1 demonstrated their practical imaging for COX‐2 positive cells in paraffin‐fixed human sarcoma tissue. Considering the fixed tissues are most practiced pathological sample, our finding suggests a potential of disaggregation activated chemosensor for clinical applications.

Demographic and clinical profile of 1106 adult soft tissue sarcoma patients: A single institutional prospective database experience from India.

Adult soft tissue sarcomas (STS) are rare and diverse. Current management is based on limited literature from the West. Therefore, data from different geographical regions is required, including the low-middle-income countries. This is our experience managing adult sarcomas in the tertiary cancer center of North India. This is a retrospective analysis of the structured sarcoma database of patients treated in the surgical oncology department between 1992 and 2020. The descriptive analysis includes demography, site distribution, diagnosis, histopathology variations, prior surgical interventions, and stage. A total of 1106 soft tissue sarcoma patients were treated in three decades. Age distribution was 13%, 43%, 31%, and 11% in <20, 21-40, and 41-60 and >60 years, respectively. The male-to-female ratio was 1.73. The anatomical distribution was 17%, 42%, 23%, 7%, 7%, and 3% in upper extremity, lower extremity, trunk, retroperitoneum, head and neck, and viscera, respectively. Overall, 49% of patients had undergone prior suboptimal surgeries at community hospitals. Common histology subtypes were synovial sarcoma (18%), undifferentiated pleomorphic sarcoma (UPS) (13%), dermatofibrosarcoma protuberans (12%), and liposarcoma (9%). A pathological discordance of 13% was identified between the initial and the final histologies. Overall, 61% of tumors were high-grade. Memorial Sloan Kettering Stages II and III were present in 33% and 35% of patients, respectively. This is one of the largest single institutional experiences of STS from the Asian population. Mostly young adults were affected with male preponderance. The lower extremity and trunk were common subsites. Frequent histologies were synovial sarcoma and UPS. A high rate of suboptimal surgical intervention at the community level and pathological discordance was noted. This study highlights the need to establish prospective structured databases for capturing quality information related to rare malignancies and providing insights for future research.

Trabectedin and Lurbinectedin Modulate the Interplay between Cells in the Tumour Microenvironment-Progresses in Their Use in Combined Cancer Therapy.

Trabectedin (TRB) and Lurbinectedin (LUR) are alkaloid compounds originally isolated from Ecteinascidia turbinata with proven antitumoral activity. Both molecules are structural analogues that differ on the tetrahydroisoquinoline moiety of the C subunit in TRB, which is replaced by a tetrahydro-β-carboline in LUR. TRB is indicated for patients with relapsed ovarian cancer in combination with pegylated liposomal doxorubicin, as well as for advanced soft tissue sarcoma in adults in monotherapy. LUR was approved by the FDA in 2020 to treat metastatic small cell lung cancer. Herein, we systematically summarise the origin and structure of TRB and LUR, as well as the molecular mechanisms that they trigger to induce cell death in tumoral cells and supporting stroma cells of the tumoral microenvironment, and how these compounds regulate immune cell function and fate. Finally, the novel therapeutic venues that are currently under exploration, in combination with a plethora of different immunotherapeutic strategies or specific molecular-targeted inhibitors, are reviewed, with particular emphasis on the usage of immune checkpoint inhibitors, or other bioactive molecules that have shown synergistic effects in terms of tumour regression and ablation. These approaches intend to tackle the complexity of managing cancer patients in the context of precision medicine and the application of tailor-made strategies aiming at the reduction of undesired side effects.

Genetic, Epigenetic and Transcriptome Alterations in Liposarcoma for Target Therapy Selection.

Liposarcoma (LPS) is one of the most common adult soft-tissue sarcomas (STS), characterized by a high diversity of histopathological features as well as to a lesser extent by a spectrum of molecular abnormalities. Current targeted therapies for STS do not include a wide range of drugs and surgical resection is the mainstay of treatment for localized disease in all subtypes, while many LPS patients initially present with or ultimately progress to advanced disease that is either unresectable, metastatic or both. The understanding of the molecular characteristics of liposarcoma subtypes is becoming an important option for the detection of new potential targets and development novel, biology-driven therapies for this disease. Innovative therapies have been introduced and they are currently part of preclinical and clinical studies. In this review, we provide an analysis of the molecular genetics of liposarcoma followed by a discussion of the specific epigenetic changes in these malignancies. Then, we summarize the peculiarities of the key signaling cascades involved in the pathogenesis of the disease and possible novel therapeutic approaches based on a better understanding of subtype-specific disease biology. Although heterogeneity in liposarcoma genetics and phenotype as well as the associated development of resistance to therapy make difficult the introduction of novel therapeutic targets into the clinic, recently a number of targeted therapy drugs were proposed for LPS treatment. The most promising results were shown for CDK4/6 and MDM2 inhibitors as well as for the multi-kinase inhibitors anlotinib and sunitinib.

Delays in diagnosis and surgery of sarcoma patients during the COVID-19 outbreak in Spain.

Social distancing and quarantine implanted during the COVID-19 outbreak could have delayed the accession of oncologic patients to hospitals and treatments. This study analysed the management of sarcoma patients during this period in five Spanish hospitals. Clinical data from adult sarcoma patients, soft tissue and bone sarcomas, managed during the COVID-19 outbreak, from 15 March to 14 September 2020 (Covid cohort), were retrospectively collected and time for diagnosis, surgery and active treatments were compared with sarcoma patients managed during the same pre-pandemic period in 2018 (Control cohort). A total of 126 and 182 new sarcoma patients were enrolled in the Covid and Control cohorts, respectively, who were mainly diagnosed as soft tissue sarcomas (81.0% and 80.8%) and at localized stage (80.2% and 79.1%). A diagnostic delay was observed in the Covid cohort with a median time for the diagnosis of 102.5 days (range 6-355) versus 83 days (range 5-328) in the Control cohort (p = 0.034). Moreover, a delay in surgery was observed in cases with localized disease from the Covid cohort with a median time of 96.0 days (range 11-265) versus 54.5 days (range 2-331) in the Control cohort (p = 0.034). However, a lower delay for neoadjuvant radiotherapy was observed in the Covid cohort with a median time from the diagnosis to the neoadjuvant radiotherapy of 47 days (range 27-105) versus 91 days (range 27-294) in the Control cohort (p = 0.039). No significant differences for adjuvant radiotherapy, neoadjuvant/adjuvant chemotherapy and neoadjuvant/adjuvant palliative chemotherapy were observed between both cohorts. Neither progression-free survival (PFS) nor overall survival (OS) was significantly different. Delays in diagnosis and surgery were retrospectively observed in sarcoma patients during the COVID-19 outbreak in Spain, while the time for neoadjuvant radiotherapy was reduced. However, no impact on the PFS and OS was observed.

Impact of Consolidative Radiation on Overall and Progression-Free Survival in Pediatric, Adolescent, and Young Adult Metastatic Bone and Soft Tissue Sarcoma

To determine the association between consolidative radiation (RT) and survival in children, adolescents, and young adults with metastatic sarcoma. Eligibility criteria included patients aged ≤39 years with newly diagnosed metastatic bone or soft tissue sarcoma who completed local control of the primary tumor without disease progression. Consolidative RT was defined as RT to all known sites of metastatic disease. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). The least absolute shrinkage and selection operator Cox provided adjusted estimates. To account for immortal time bias, consolidative RT was used as a time-varying covariate in a time dependent Cox model. Distant failure was estimated using the Fine-Gray model. Patients (n=85) had a median age at diagnosis of 14.8 years. Most common histology was Ewing Sarcoma (45.9%) followed by rhabdomyosarcoma (40.0%). Receipt of consolidative RT was associated with Ewing Sarcoma (P < .001) and local control modality as those who underwent local control with surgery and RT compared with surgery alone were more likely to be treated with consolidative RT (P=.034). Consolidative RT was independently associated with improved OS (hazard ratio [HR], 0.41; 95% CI, 0.17-0.98; P=.045) and improved PFS (HR, 0.37; 95% CI, 0.16-0.88; P=.024) after adjusting for confounding variables and immortal time bias. Patients treated with consolidative RT also experienced a lower risk of distant failure (HR, 0.33; 95% CI, 0.17-0.64; P=.001). In an independent data set of patients with metachronous progression (n=36), consolidative RT remained independently associated with improved OS. Consolidative RT was independently associated with improved OS and PFS and decreased risk of distant failure in child, adolescent, and young adult patients with metastatic sarcoma. Future work should evaluate biomarkers to optimize patient selection, timing, and dose for consolidative RT.

Dawn of Staging for Head and Neck Soft Tissue Sarcoma: Validation of the Novel 8th Edition AJCC T Classification and Proposed Stage Groupings

After decades of stagnation, the 8th edition TNM (TNM8) introduced a new T classification for head and neck (HN) soft tissue sarcomas (STS). New size cutoffs of 2 and 4 cm define T1-3, and a novel T4 category is defined by local invasion of adjoining structures. These size cutoffs had been chosen arbitrarily to advance data collection in this unique disease site since literature showed approximately 70% of HN STS did not reach the previous size threshold (5 cm) for the existing T1 category. The definition of the TNM8 T categories also align with mucosal HN cancers. No stage grouping for HN STS was defined since this new classification required more data collection to derive stage groups. This study aims to validate the TNM8 T classification and to propose stage groupings. Clinical data of all adult (>16 years) HN STS patients treated from 1988 - 2019 with curative intent in our tertiary cancer center were retrieved from a prospective database, and supplemented with chart review. As per TNM8, cutaneous angiosarcoma, embryonal and alveolar rhabdomyosarcoma, Kaposi sarcoma, and dermatofibrosarcoma protuberans were excluded due to their different behavior. Multivariate analysis (MVA) identified prognostic factors for overall survival (OS). Adjusted hazard ratios (AHR) and recursive partitioning analysis (RPA) were used to derive stage groupings. Stage grouping performance for OS was assessed and also compared against the existing TNM8 groups for non-HN STS. A total of 221 patients (N1: 2; M1: 2) were included. Of the 219 M0 patients, 63% were males; median tumor size was 3.0 cm (range: 0.3-14.0); the proportion of TNM8 T1-T4 were 35%, 34%, 26%, and 5%, respectively. Median follow up was 5.9 years. Five-year OS was 79%. MVA confirmed the prognostic value of T category (T4 HR 7.73, 95% CI 3.62-16.5) and grade (G2/3 vs G1 HR 3.7, 95% CI 1.82-7.53), in addition to age (HR 1.03, 95% CI 1.01-1.04) (all p<0.001) for OS. AHR model derived T1-3_Grade 1 as stage 1; T1-3_Grade 2/3 as stage II; and T4_any Grade or any T_N1 as stage III (Table 1); the corresponding 5-year OS was 93%, 73%, and 38%, respectively. Both patients with M1 died within 1.5 years after diagnosis and M1 disease was designated stage IV. The AHR-grouping outperformed the RPA and non-HN TNM8 stage grouping for hazard consistency, hazard discrimination, percent variance explained, hazard difference, and sample size balance. The novel T4 category introduced in TNM8 is associated with a >7 fold increased risk of death. Grade continues to be a critical prognostic factor in HN STS. The TNM8 HN STS T classifications have been validated, and the proposed new stage groupings with TNM8 incorporating grade have excellent performance for OS.

Biology and Management of High-Grade Myxofibrosarcoma: State of the Art and Future Perspectives.

Myxofibrosarcoma (MFS) is one of the most common adult soft tissue sarcomas, typically arising in the extremities. Histologically, MFS is classified into three grades: low, intermediate, and high. Histological grades correlate with distant metastases and tumor-associated mortality. The diagnosis of MFS is challenging due to a lack of well-characterized immunohistochemical markers. High-grade MFS displays highly complex karyotypes with multiple copy number alterations. Recent integrated genomic studies have shown the predominance of somatic copy number aberrations. However, the molecular pathogenesis of high-grade MFS remains poorly understood. The standard treatment for localized MFS is surgical resection. The systemic treatment options for advanced disease are limited. This review provides an updated overview of the clinical and imaging features, pathogenesis, histopathology, and treatment of high-grade MFS.

Malignant Fibrous Histiocytoma

Malignant fibrous histiocytoma is the most common soft tissue sarcoma in adults but is rare as a primary cutaneous tumor. It has a male predilection with a peak incidence between the fifth and sixth decades of life. Malignant fibrous histiocytoma predominantly occurs in the extremities. We report a case of malignant fibrous histiocytoma presenting in the hallux of the right foot.

Efficacy of eribulin administered in combination with an immune checkpoint inhibitor (ICI) and anlotinib as salvage treatment for patients (pts) with advanced adult soft tissue sarcoma (STS).

11572 Background: Eribulin combined with a multi-targeted antiangiogenic tyrosine kinase inhibitor has shown efficacy in STS. ICIs have also exhibited improved survival in some STS subtypes. We investigated the efficacy and safety of triple combination therapy with eribulin, an ICI and anlotinib in the treatment of advanced STS in an adult Chinese population. Methods: This study retrospectively analyzed data from patients diagnosed with advanced STS who received combination therapy with eribulin, an ICI and anlotinib at the Department of Oncology, Zhongshan Hospital affiliated to Fudan University. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) by RECIST v1.1, disease control rate (DCR), and treatment-related adverse events (TRAEs) by CTCAE v5.0. Results: Medical records from 32 pts treated between August 15, 2020 and January 31, 2023 were included; the median age was 56 years, 71.8% (23/32) were female, 75.0% (24/32) had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1, and 25.0% (8/32) had an ECOG PS of 2. Pts had received a median of 2 (range 0-6) prior regimens and the median follow-up was 4.1 months. Among the patients, 50.0% (16/32) had liposarcomas (including 1 with pleomorphic liposarcoma and 15 with dedifferentiated liposarcoma [DDLPS]), 31.3% (10/32) had leiomyosarcomas (LMS), 3 had undifferentiated pleomorphic sarcoma (UPS), and 1 each had angiosarcoma, rhabdomyosarcoma and desmoplastic small round cell tumor. In a preliminary analysis, 29 pts were evaluable for clinical activity; partial responses (PRs) were achieved in 3 pts (2 DDLPS, 1 UPS), the ORR and DCR were 10.3% (3/29) and 62.1% (18/29) respectively, and the median PFS was 5.7 months (95% CI 2.7-9.8). Of the 15 pts with DDLPS (median 1 prior line of therapy; median follow-up 6.3 months), 13 were evaluable for clinical activity; a PR was achieved by 15.4% (2/13), the DCR was 61.5% (8/13), the median PFS was 9.8 months (95% CI 1.8-28.5) and treatment was ongoing in 46.7% of pts (n = 7). Among the 9 evaluable pts with LMS, 0 achieved a PR, the DCR was 44.4% (4/9), median PFS was 3.9 months and 3 pts were still receiving treatment. In the overall cohort (n = 32), TRAEs of any grade occurred in 56.3% of pts (n = 18), the most common were myelosuppression (28.1%), fatigue (15.6%), fever (12.5%) and rash (12.5%). Grade 3/4 TRAEs occurred in 12.5% of pts, with no grade 5 events. Conclusions: This study demonstrates the potential efficacy of combination therapy with eribulin, an ICI and anlotinib in patients with advanced STS, especially in those with the DDLPS subtype. Our data suggest that this combination has good tolerability and a prospective trial is warranted. Clinical trial information: ChiCTR2100053594.

PRIMARY PARASPINAL LEIOMYOSARCOMA INVADING THE DORSAL SPINAL CANAL:A CASE REPORT AND REVIEW OF THE LITERATURE

Leiomyosarcoma (LMS) is one of the most common subtypes of soft tissue sarcoma in adults and can occur in almost any part of the body, which presents a high propensity to metastasize to various locations. Primary leiomyosarcomas of the paraspinal soft tissues are exceedingly rare. We report a case of a primary leiomyosarcoma of the dorsal paraspinal musculature invading the spinal canal in a 36-year-old man, successfully treated with surgery.

Mesenchymal loss of p53 alters stem cell capacity and models human soft tissue sarcoma traits.

Soft tissue sarcomas (STSs) are a heterogeneous group of tumors that originate from mesenchymal cells. p53 is frequently mutated in human STS. In this study, we found that the loss of p53 in mesenchymal stem cells (MSCs) mainly causes adult undifferentiated soft tissue sarcoma (USTS). MSCs lacking p53 show changes in stem cell properties, including differentiation, cell cycle progression, and metabolism. The transcriptomic changes and genetic mutations in murine p53-deficient USTS mimic those seen in human STS. Furthermore, single-cell RNA sequencing revealed that MSCs undergo transcriptomic alterations with aging-a risk factor for certain types of USTS-and that p53 signaling decreases simultaneously. Moreover, we found that human STS can be transcriptomically classified into six clusters with different prognoses, different from the current histopathological classification. This study paves the way for understanding MSC-mediated tumorigenesis and provides an efficient mouse model for sarcoma studies.

Treatment with doxorubicin and PD-1/CTLA-4 blockade improves T cell activation and anti-tumor efficacy in MCA-205 murine fibrosarcoma

Abstract Immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 produce responses in about 20% of adult soft tissue sarcomas (STSs), however, most patients do not respond, potentially from poor T cell activation. Standard chemotherapy for STSs includes the anthracycline doxorubicin (DOX) which has been shown in preclinical cancer models to induce immunogenic cell death (ICD) via tumor production of type I interferons (IFN). We hypothesized that induction of ICD and IFN release by doxorubicin would enhance T cell activation, infiltration, and boost anti-tumor efficacy when combined with dual anti-PD-1/CTLA-4 blockade in the MCA-205 murine fibrosarcoma model. MCA-205 tumors were generated in C57BL/6 mice and were treated with DOX, anti-PD1 (RMP1–14), anti-CTLA4 (9D9 mouse IgG2b) or a mouse surrogate of botensilimab, an anti-CTLA4 (9D9 mouse IgG2b.DLE) antibody with enhanced binding to FcγR, or combination DOX plus anti-PD-1/CTLA-4. We found reduction of tumor growth and improved survival (median survival not reached) with DOX/PD-1/CTLA-4 compared to DOX (median survival 29.5 days). This correlated with a 2-fold increased influx of TILs as measured by flow cytometry and immunohistochemistry, with a marked increase in CD8:CD4 T cell ratio with increased expression of activation markers (PD-1, 4–1BB and TIM3). TCR Vβ clonotyping revealed a shift in clonotype frequency with DOX/PD-1/CTLA-4 relative to other treatment groups. Pathway analysis from bulk RNA sequencing demonstrated upregulation of T cell activation in DOX/PD-1/CTLA-4 tumors compared to control tumors. Further work will correlate these findings with human STS patients receiving DOX plus CTLA-4/PD-1 blockade in an ongoing clinical trial (NCT04028063). This work was supported by grants from the University of Colorado Cancer Center (P30CA046934) and the University of Colorado School of Medicine.

The Evolutionary Profile of Dermatofibrosarcoma of Darier and Ferrand: Study of 23 Cases in Bamako

Introduction: Darier and Ferrant dermatofibrosarcoma is a rare malignant cutaneous mesenchymal tumour, representing less than 0.1% of malignant tumours and less than 5% of soft tissue sarcomas in adults. The aim of this study was to describe the evolutionary profile of cases of dermato fibrosarcoma of Darier et Ferrant reported in the dermato-venereology department of the National Centre for Disease Control (CNAM). Patients and methods: This was a descriptive cross-sectional study conducted in the dermatology department of the National Centre for Disease Control Support between 1991 and 2016, a period of 25 years. Was included, all patient with a histologically confirmed dermatofibrosarcoma notified in the registers of the CNAM histology laboratory or in the patient's medical file during the study period. Results: In total we collected 23 cases out of 5520 biopsied patients, i.e. a proportion of 0.41%. Males represented 60.8% with an average age of 40 years. The lesions were simple nodular in 12 of the 23 patients (52.2%), multi-nodular in 7 of the 23 patients (30.4%), nodulo-ulcerous and in patches in 4 of the 23 patients (17.4%). The lesions were located on the trunk in 60.8% of cases (image 1), on the head in 21.7% of cases and on the limbs in 17.5% of cases. The mean size of the lesions was 10×8cm with extremes of 3cm×3cm to 25cm×20cm. Management was exclusively surgical. Conclusion: DFSP is a rare tumour with a slow evolution, characterised by its rare metastasis but above all by its strong tendency to recurrence. The diagnosis is often evoked clinically and confirmed by histological study. The treatment of DFSP is surgical based on a large and deep lesion removal. Clinical monitoring allows early detection of recurrence, which is frequent in this disease.

Multimodal treatment of localized high-grade soft tissue sarcomas of the extremities : Summary and discussion of the current S3 guidelines on adult soft tissue sarcomas and the ESMO guidelines on soft tissue and visceral sarcomas

Soft tissue sarcomas are rare, heterogeneous tumors that are frequently in the extremities. Treatment includes surgical resection, combination chemotherapy and/or radiotherapy, as well as supplementary procedures such as isolated limb perfusion and regional deep hyperthermia. The prognosis depends on the tumor stage and the approximately 70 histological subtypes, with specific treatment approaches existing only for some subtypes. This review summarizes the recommendations of the German S3 guideline "Adult Soft Tissue Sarcomas" and the European Society for Medical Oncology (ESMO) guideline "Soft tissue and visceral sarcomas" regarding the diagnostic workup and therapy of soft tissue sarcomas of the extremities.