Neutrophils Driving Unconventional T Cells Mediate Resistance against Murine Sarcomas and Selected Human Tumors.

Neutrophils are a component of the tumor microenvironment and have been predominantly associated with cancer progression. Using a genetic approach complemented by adoptive transfer, we found that neutrophils are essential for resistance against primary 3-methylcholantrene-induced carcinogenesis. Neutrophils were essential for the activation of an interferon-γ-dependent pathway of immune resistance, associated with polarization of a subset of CD4- CD8- unconventional αß T cells (UTCαß). Bulk and single-cell RNA sequencing (scRNA-seq) analyses unveiled the innate-like features and diversity of UTCαß associated with neutrophil-dependent anti-sarcoma immunity. In selected human tumors, including undifferentiated pleomorphic sarcoma, CSF3R expression, a neutrophil signature and neutrophil infiltration were associated with a type 1 immune response and better clinical outcome. Thus, neutrophils driving UTCαß polarization and type 1 immunity are essential for resistance against murine sarcomas and selected human tumors.

Habitat escalated adaptive therapy (HEAT): a phase 2 trial utilizing radiomic habitat-directed and genomic-adjusted radiation dose (GARD) optimization for high-grade soft tissue sarcoma.

BACKGROUND: Soft tissue sarcomas (STS), have significant inter- and intra-tumoral heterogeneity, with poor response to standard neoadjuvant radiotherapy (RT). Achieving a favorable pathologic response (FPR ≥ 95%) from RT is associated with improved patient outcome. Genomic adjusted radiation dose (GARD), a radiation-specific metric that quantifies the expected RT treatment effect as a function of tumor dose and genomics, proposed that STS is significantly underdosed. STS have significant radiomic heterogeneity, where radiomic habitats can delineate regions of intra-tumoral hypoxia and radioresistance. We designed a novel clinical trial, Habitat Escalated Adaptive Therapy (HEAT), utilizing radiomic habitats to identify areas of radioresistance within the tumor and targeting them with GARD-optimized doses, to improve FPR in high-grade STS. METHODS: Phase 2 non-randomized single-arm clinical trial includes non-metastatic, resectable high-grade STS patients. Pre-treatment multiparametric MRIs (mpMRI) delineate three distinct intra-tumoral habitats based on apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) sequences. GARD estimates that simultaneous integrated boost (SIB) doses of 70 and 60 Gy in 25 fractions to the highest and intermediate radioresistant habitats, while the remaining volume receives standard 50 Gy, would lead to a > 3 fold FPR increase to 24%. Pre-treatment CT guided biopsies of each habitat along with clip placement will be performed for pathologic evaluation, future genomic studies, and response assessment. An mpMRI taken between weeks two and three of treatment will be used for biological plan adaptation to account for tumor response, in addition to an mpMRI after the completion of radiotherapy in addition to pathologic response, toxicity, radiomic response, disease control, and survival will be evaluated as secondary endpoints. Furthermore, liquid biopsy will be performed with mpMRI for future ancillary studies. DISCUSSION: This is the first clinical trial to test a novel genomic-based RT dose optimization (GARD) and to utilize radiomic habitats to identify and target radioresistance regions, as a strategy to improve the outcome of RT-treated STS patients. Its success could usher in a new phase in radiation oncology, integrating genomic and radiomic insights into clinical practice and trial designs, and may reveal new radiomic and genomic biomarkers, refining personalized treatment strategies for STS. TRIAL REGISTRATION: NCT05301283. TRIAL STATUS: The trial started recruitment on March 17, 2022.

Local treatment in initially unresected non-rhabdomyosarcoma soft-tissue sarcomas of children and adolescents: A retrospective single-center experience.

BACKGROUND: Pediatric non-rhabdomyosarcoma soft-tissue sarcomas (NRSTS) are a heterogeneous group of aggressive tumors. Patients with locally advanced/initially unresected disease represent a subset of patients with unsatisfactory outcome: limited data are available on the best treatment approach, in particular regarding local therapy. METHODS: This retrospective analysis concerned 71 patients < 21 years old with nonmetastatic, initially unresected adult-type NRSTS, treated at a referral center for pediatric sarcomas from 1990 to 2021. Patients were treated using a multimodal approach, based on the protocols adopted at the time of their diagnosis. RESULTS: The series included a selected group of patients with unfavorable clinical characteristics, i.e., most cases had high-grade and large tumors, arising from axial sites in 61% of cases. All patients received neoadjuvant chemotherapy, 58 (82%) had delayed surgery (R0 in 45 cases), and 50 (70%) had radiotherapy. Partial response to chemotherapy was observed in 46% of cases. With a median follow-up of 152 months (range, 18-233), 5-year event-free survival (EFS) and overall survival (OS) were 39.9% and 56.5%, respectively. Survival was significantly better for patients who responded to chemotherapy, and those who had a delayed R0 resection. Local relapse at 5 years was 7.7% for patients who did not undergo delayed surgery. CONCLUSIONS: Our series underscores the unsatisfactory outcome of initially unresected NRSTS patients. Improving the outcome of this patient category requires therapeutic strategies able to combine novel effective systemic therapies with a better-defined local treatment approach to offer patients the best chances to have R0 surgery.

Opportunities and Challenges in Soft Tissue Sarcoma Risk Stratification in the Era of Personalised Medicine.

OPINION STATEMENT: Soft tissue sarcomas (STS) are a rare and heterogeneous group of cancers. Treatment options have changed little in the past thirty years, and the role of neoadjuvant chemotherapy is controversial. Accurate risk stratification is crucial in STS in order to facilitate clinical discussions around peri-operative treatment. Current risk stratification tools used in clinic, such as Sarculator, use clinicopathological characteristics and may be specific to anatomical site or to histology. More recently, risk stratification tools have been developed using molecular or immunological data. Combining Sarculator with other risk stratification tools may identify novel patient groups with differential clinical outcomes. There are several considerations when translating risk stratification tools into widespread clinical use, including establishing clinical utility, health economic value, being applicable to existing clinical pathways, having strong real-world performance, and being supported by investment into infrastructure. Future work may include incorporation of novel modalities and data integration techniques.

Impact of resection margin on outcome in soft-tissue sarcomas of the extremities treated with limb-sparing surgery and postoperative radiotherapy.

BACKGROUND: The standard curative treatments for extremity soft tissue sarcoma (ESTS) include surgical resection with negative margins and perioperative radiotherapy. However, the optimal resection margin remains controversial. This study aimed to evaluate the outcomes in ESTS between microscopically positive margin (R1) and microscopically negative margin (R0) according to the Union for International Cancer Control (UICC) (R + 1 mm) classification. METHODS: Medical records of patients with localized ESTS who underwent primary limb-sparing surgery and postoperative radiotherapy between 2004 and 2015 were retrospectively reviewed. Patients were followed for at least 5 years or till local or distant recurrence was diagnosed during follow-up. Outcomes were local and distal recurrences and survival. RESULTS: A total of 52 patients were included in this study, in which 17 underwent R0 resection and 35 underwent R1 resection. No significant differences were observed in rates of local recurrence (11.4% vs. 35.3%, p = 0.062) or distant recurrence (40.0% vs. 41.18%, p = 0.935) between R0 and R1 groups. Multivariate analysis showed that distant recurrences was associated with a Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade (Grade III vs. I, adjusted hazard ratio (aHR): 12.53, 95% confidence interval (CI): 2.67-58.88, p = 0.001) and tumor location (lower vs. upper extremity, aHR: 0.23, 95% CI: 0.07-0.7, p = 0.01). Kaplan-Meier plots showed no significant differences in local (p = 0.444) or distant recurrent-free survival (p = 0.161) between R0 and R1 groups. CONCLUSIONS: R1 margins, when complemented by radiotherapy, did not significantly alter outcomes of ESTS as R0 margins. Further studies with more histopathological types and larger cohorts are necessary to highlight the path forward.

Metastatic adult-type non-rhabdomyosarcoma soft tissue sarcomas in children and adolescents: A cohort study from the European paediatric Soft tissue sarcoma Study Group.

BACKGROUND: Limited data exist on the clinical behavior of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined. METHODS: This cohort study reports on pediatric adult-type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the randomized BERNIE study and the single-arm MTS 2008 study developed by the European paediatric Soft tissue sarcoma Study Group. Treatment programs were originally designed for patients with metastatic rhabdomyosarcoma, i.e., nine courses of multidrug chemotherapy (with or without bevacizumab in the BERNIE study), followed by 12 cycles of maintenance therapy, whereas radiotherapy and/or surgery (on primary tumor and/or metastases) were delayed until after seven courses of chemotherapy had been administered. RESULTS: The study included 61 patients <21 years old treated from July 2008 to December 2016. The lung was the site of metastases in 75% of the cases. All patients received multi-agent chemotherapy, 44% had local therapy to primary tumor, and 18% had treatment of metastases. Median time to progression/relapse was 6 months. A high rate of tumor progression was observed during the initial part of the chemotherapy program. With a median follow-up of 41.5 months (range, 2-111 months), 3-year event-free survival and overall survival were 15.4% (95% confidence interval [CI], 7.6-25.7) and 34.9% (95% CI, 22.7-47.5), respectively. There were no statistically significant differences in outcome depending on the type of treatment administered. CONCLUSIONS: The study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge. PLAIN LANGUAGE SUMMARY: Pediatric non-rhabdomyosarcoma soft tissue sarcomas form a heterogeneous group of rare tumors. Although recent international studies have defined the standard of care for patients with localized disease, limited data are available on the clinical behavior of patients with distant metastases. This study on 61 metastatic cases treated on two prospective European protocols confirms that the chances of survival of such patients are often dismal and a standard treatment is still lacking.

Clinical markers of immunotherapy outcomes in advanced sarcoma.

BACKGROUND: Despite immunotherapy's promise in oncology, its use for sarcoma remains challenging. There are no sarcoma-specific biomarkers for immune checkpoint inhibitors (ICI). Previously, we reported our institutional experience highlighting ICI activity in 29 patients with sarcoma. In this study, we explore responses to ICI based on ICI regimen and other covariates to identify significant clinical factors in advanced sarcoma outcomes. METHODS: Patients in The Ohio State University Sarcoma Clinics were enrolled in the Sarcoma Retrospective ICI database from January 1, 2015 through November 1, 2021. Data included treatment regimen (single-agent ICI or ICI + combination) along with clinical covariates. ICI + combination was further categorized into ICI + medication, ICI + radiation, ICI + surgery, or ICI + multiple (more than 2 modalities). Statistical analysis included log-rank tests and proportional hazard regression. The primary objective was to evaluate overall survival (OS) and progression-free survival (PFS). RESULTS: Of the patients in the database, 135 met inclusion criteria. We demonstrated improved OS in patients treated with ICI + combination (p = 0.014, median 64 weeks), but no effect on PFS (p = 0.471, median 31 weeks). Patients with a documented immune-related adverse event (irAE) of dermatitis had improved OS, but only in the ICI + combination cohort (p = 0.021). Patients who received single-agent ICI and whose change in the neutrophil-to-lymphocyte ratio (NLR) was less than 5 had an improved OS (p = 0.002); this was not seen in patients who received ICI + combination therapy (p = 0.441). There were no differences in OS based on age, gender, histology, or subcategories of ICI + combination. This was not the case for PFS; patients who received any ICI regimen and were younger than 70 had a worse PFS (p = 0.036) compared with their older counterparts in this dataset. Patients who developed an irAE, specifically colitis (p = 0.009), hepatitis (p = 0.048), or dermatitis (p = 0.003), had an improved PFS. There were no differences in PFS based on ICI regimen (or subcategories of ICI + combination), gender, histology, change in NLR, or grade of irAE. CONCLUSIONS: This retrospective study demonstrates that ICI + combination therapy can improve OS in some patients with advanced sarcoma. This is consistent with our prior results of ICI in sarcoma.

Oncostatin M and Nivolumab Affect the Cytotoxic T-Cell Proportions and the Susceptibility to TRAIL-Induced Death in Non-Leukocyte Cell Subpopulations in Soft Tissue Sarcomas.

INTRODUCTION: Soft tissue sarcomas (STSs) are malignant tumors arising from mesenchymal tissues. Patients with advanced and metastatic STSs have low overall survival rates and relatively limited treatment options. Oncostatin M (OSM) is a pleiotropic cytokine that was shown to carry both pro- and anti-tumorigenic properties in various cancer types. However, the role of OSM in STSs has not yet been elucidated. Moreover, the potential additive effects of combining OSM and anti-PD-1 therapy have not been carried out so far. METHODS: The aim of this study was to determine the effects of in vitro OSM administration on liposarcoma, leiomyosarcoma, and myxofibrosarcoma immune cells isolated from peripheral blood and tumor tissues and the potential cooperative nature of OSM and nivolumab in treating these STSs. We designed a cohort study to explore novel histology-driven therapies in our target STSs. The immune cells were isolated from the peripheral blood and tumors of patients with STS, and the proportions and phenotypes of immune cells were evaluated with flow cytometry after cultivation with therapeutic monoclonal antibodies. RESULTS: The proportion of peripheral CD45+ cells was not affected by OSM but was significantly increased by nivolumab, whereas both treatments had an effect on CD8+ T cells. In tumor tissues, CD8+ T cell and CD45‒ TRAIL+ cell cultures were boosted by nivolumab and significantly enriched by OSM. Our data suggest that OSM may play a role in the treatment of leiomyosarcoma, myxofibrosarcoma, and liposarcoma. CONCLUSION: In conclusion, the biological efficacy of OSM is reflected in the tumor microenvironment rather than in the peripheral blood of the patients in our cohort, and nivolumab could potentiate its mechanism of action in selected cases. Nevertheless, more histotype-tailored studies are needed to fully understand the functions of OSM in STSs.

Radiomics model based on intravoxel incoherent motion and diffusion kurtosis imaging for predicting histopathological grade and Ki-67 expression level of soft tissue sarcomas.

BACKGROUND: Accurate identification of the histopathological grade and the Ki-67 expression level is important in clinical cases of soft tissue sarcomas (STSs). PURPOSE: To explore the feasibility of a radiomics model based on intravoxel incoherent motion (IVIM) magnetic resonance imaging (MRI) and diffusion kurtosis imaging (DKI) MRI parameter maps in predicting the histopathological grade and Ki-67 expression level of STSs. MATERIAL AND METHODS: In total, 42 patients diagnosed with STSs between May 2018 and January 2020 were selected. The MADC software in Functool of GE ADW 4.7 workstation was used to obtain standard apparent diffusion coefficient (ADC), D, D*, f, mean diffusivity, and mean kurtosis (MK). The histopathological grade and Ki-67 expression level of STSs were identified. The radiomics features of IVIM and DKI parameter maps were used as the dataset. The area under the receiver operating characteristic curve (AUC) and F1-score were calculated. RESULTS: D-SVM achieved the best diagnostic performance for histopathological grade. The AUC in the validation cohort was 0.88 (sensitivity: 0.75 [low level] and 0.83 [high level]; specificity: 0.83 [low level] and 0.75 [high level]; F1-score: 0.75 [low level] and 0.83 [high level]). MK-SVM achieved the best diagnostic performance for Ki-67 expression level. The AUC in the validation cohort was 0.83 (sensitivity: 0.83 [low level] and 0.50 [high level; specificity: 0.50 [low level] and 0.83 [high level]; F1-score: 0.77 [low level] and 0.57 [high level]). CONCLUSION: The proposed radiomics classifier could predict the pathological grade of STSs and the Ki-67 expression level in STSs.

Epidemiology and survival factors for sarcoma patients in minority populations: a SEER-retrospective study.

Background: Epidemiologic studies have demonstrated race as a predictor of worse oncological outcomes. To better understand the effect of race on oncological outcomes, we utilized the Surveillance, Epidemiology, and End Results (SEER) database to determine what treatment courses are provided to minority patients and how this impacts survival. Materials and methods: A retrospective review of bone and soft tissue sarcoma cases was performed using the SEER database for a minimum 5-year survival rate (SR) using Kaplan-Meier curves. Categorical variables were compared using Pearson's χ2 test and Cramer V. Kaplan-Meier curves were used to determine survival rates (SR) and Cox regression analysis was used to determine hazard ratios (HRs). Results: Races that had an increased risk of death included Native American/Alaska Native (NA/AN) [hazard ratio (HR): 1.36, 95% confidence interval (CI): 1.049-1.761, p = 0.020) and Black (HR = 1.17, 95% CI: 1.091-1.256, p < 0.001). NA/AN individuals had the lowest SR (5-year SR = 70.9%, 95% CI: 63.8-78.0%, p < 0.001). The rate of metastasis at diagnosis for each race was 13.07% - Hispanic, 10.62% - NA/AN, 12.77% - Black, 10.61% - Asian/Pacific Islander (A/PI), and 9.02% - White individuals (p < 0.001). There were increases in the rate of metastasis at diagnosis and decreases in rates of surgical excision for Hispanic and Black patients (p < 0.001). Conclusion: Race is determined to be an independent risk factor for death in NA/AN and Black patients with sarcomas of the extremities. Access to healthcare and delay in seeking treatment may contribute to higher rates of metastasis upon diagnosis for minority patients, and decreased rates of surgical excision could be associated with poor follow up and lack of resources.

Critical impact of radiotherapy protocol compliance and quality in the treatment of retroperitoneal sarcomas: Results from the EORTC 62092-22092 STRASS trial.

BACKGROUND: The European Organization for Research and Treatment of Cancer 22092-62092 STRASS trial failed to demonstrate the superiority of neoadjuvant radiotherapy (RT) over surgery alone in patients with retroperitoneal sarcoma. Therefore, an RT quality-assurance program was added to the study protocol to detect and correct RT deviations. The authors report results from the trial RT quality-assurance program and its potential effect on patient outcomes. METHODS: To evaluate the effect of RT compliance on survival outcomes, a composite end point was created. It combined the information related to planning target volume coverage, target delineation, total dose received, and overall treatment time into 2 groups: non-RT-compliant (NRC) for patients who had unacceptable deviation(s) in any of the previous categories and RT-compliant (RC) otherwise. Abdominal recurrence-free survival (ARFS) and overall survival were compared between the 2 groups using a Cox proportional hazard model adjusted for known prognostic factors. RESULTS: Thirty-six of 125 patients (28.8%) were classified as NRC, and the remaining 89 patients (71.2%) were classified as RC. The 3-year ARFS rate was 66.8% (95% confidence interval [CI], 55.8%-75.7%) and 49.8% (95% CI, 32.7%-64.8%) for the RC and NRC groups, respectively (adjusted hazard ratio, 2.32; 95% CI, 1.25-4.32; P = .008). Local recurrence after macroscopic complete resection occurred in 13 of 89 patients (14.6%) versus 2 of 36 patients (5.6%) in the RC and NRC groups, respectively. CONCLUSIONS: The current analysis suggests a significant benefit in terms of ARFS in favor of the RC group. This association did not translate into less local relapses after complete resection in the RC group. Multidisciplinary collaboration and review of cases are critical to avoid geographic misses, especially for rare tumors like retroperitoneal sarcoma.

CSPG4 expression in soft tissue sarcomas is associated with poor prognosis and low cytotoxic immune response.

BACKGROUND: Soft tissue sarcomas (STS) are heterogeneous and pro-metastatic tumors. Identification of accurate prognostic factors and novel therapeutic targets are crucial. CSPG4 is a cell surface proteoglycan with oncogenic functions. It recently emerged as a potential target for immunotherapy, including cell therapy based on CSPG4-specific chimeric antigen receptor (CAR)-redirected cytokine-induced killer lymphocytes (CSPG4-CAR.CIKs) in STS. However, expression of CSPG4 is poorly known in STS so far. METHODS: We analyzed CSPG4 gene expression in 1378 localized STS clinical samples, and searched for correlations with clinicopathological data, including disease-free survival (DFS), and with tumor immune features. RESULTS: CSPG4 expression was heterogeneous across samples. High expression was associated with younger patients' age, more frequent undifferentiated pleomorphic sarcoma and myxofibrosarcoma pathological subtypes, more frequent internal trunk tumor site, and more CINSARC high-risk samples. No correlation existed with pathological tumor size and grade, and tumor depth. Patients with high CSPG4 expression displayed 49% (95% CI 42-57) 5-year DFS versus 61% (95% CI 56-68) in patients with low expression (p = 3.17E-03), representing a 49% increased risk of event in the "CSPG4-high" group (HR = 1.49, 95% CI 1.14-1.94). This unfavorable prognostic value persisted in multivariate analysis, independently from other variables. There were significant differences in immune variables between "CSPG4-high" and "CSPG4-low" tumors. The "CSPG4-low" tumors displayed profiles suggesting higher anti-tumor cytotoxic immune response and higher potential vulnerability to immune checkpoint inhibitors (ICI). By contrast, the "CSPG4-high" tumors displayed profiles implying an immune-excluded tumor microenvironment, potentially induced by hypoxia, resulting from an immature chaotic microvasculature, and/or the presence of contractile myofibroblasts. CONCLUSIONS: Patients with "CSPG4-high" STS, theoretically candidate for CAR.CIKs, display shorter DFS and an immune environment unfavorable to vulnerability to CAR.CIKs, which could be improved by combining anti-angiogenic drugs able to normalize the tumor vasculature. By contrast, "CSPG4-low" STS are better candidates for immune therapy involving ICI.

An Update in Imaging Evaluation of Histopathological Grade of Soft Tissue Sarcomas Using Structural and Quantitative Imaging and Radiomics.

Over the past two decades, considerable efforts have been made to develop non-invasive methods for determining tumor grade or surrogates for predicting the biological behavior, aiding early treatment decisions, and providing prognostic information. The development of new imaging tools, such as diffusion-weighted imaging, diffusion kurtosis imaging, perfusion imaging, and magnetic resonance spectroscopy have provided leverage in the diagnosis of soft tissue sarcomas. Artificial intelligence is a new technology used to study and simulate human thinking and abilities, which can extract and analyze advanced and quantitative image features from medical images with high throughput for an in-depth characterization of the spatial heterogeneity of tumor tissues. This article reviews the current imaging modalities used to predict the histopathological grade of soft tissue sarcomas and highlights the advantages and limitations of each modality. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

Deep learning radiomic nomogram to predict recurrence in soft tissue sarcoma: a multi-institutional study.

OBJECTIVES: To evaluate the performance of a deep learning radiomic nomogram (DLRN) model at predicting tumor relapse in patients with soft tissue sarcomas (STS) who underwent surgical resection. METHODS: In total, 282 patients who underwent MRI and resection for STS at three independent centers were retrospectively enrolled. In addition, 113 of the 282 patients received additional contrast-enhanced MRI scans. We separated the participants into a development cohort and an external test cohort. The development cohort consisted of patients from one center and the external test cohort consisted of patients from two other centers. Two MRI-based DLRNs for prediction of tumor relapse after resection of STS were established. We universally tested the DLRNs and compared them with other prediction models constructed by using widespread adopted predictors (i.e., staging systems and Ki67) instead of radiomics features. RESULTS: The DLRN1 model incorporated plain MRI-based radiomics signature into the clinical data, and the DLRN2 model integrated radiomics signature extracted from plain and contrast-enhanced MRI with the clinical predictors. Across both study sets, the two MRI-based DLRNs had relatively better prognostic capability (C index ≥ 0.721 and median AUC ≥ 0.746; p < 0.05 compared with most other models and predictors) and less opportunity for prediction error (integrated Brier score ≤ 0.159). The decision curve analysis indicates that the DLRNs have greater benefits than staging systems, Ki67, and other models. We selected appropriate cutoff values for the DLRNs to divide STS recurrence into three risk strata (low, medium, and high) and calculated those groups' cumulative risk rates. CONCLUSION: The DLRNs were shown to be a reliable and externally validated tool for predicting STS recurrence by comparing with other prediction models. KEY POINTS: • The prediction of a high recurrence rate of STS before emergence of local recurrence can help to determine whether more active treatment should be implemented. • Two MRI-based DLRNs for prediction of tumor relapse were shown to be a reliable and externally validated tool for predicting STS recurrence. • We used the DLRNs to divide STS recurrence into three risk strata (low, medium, and high) to facilitate more targeted postoperative management in the clinic.

Driving forward: beneficial treatment strategies for leiomyosarcoma patients.

Tweetable abstract "Leiomyosarcomas, as a group, represent one of the most common subtypes of soft tissue sarcoma, accounting for 10-20% of all cases."

Current molecular and therapeutic advances in liposarcoma, rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma, and angiosarcoma.

Sarcomas probably develop after malignant transformation of embryonic mesenchymal cells and have broad spectrum histopathologically since they can develop from striated skeletal muscle and smooth muscle, fat and fibrous tissue, bone, cartilage and other mesenchymal tissues. The most common histological subtypes of soft tissue sarcoma in adults are: liposarcoma, leiomyosarcoma, poorly differentiated pleomorphic sarcoma, and gastrointestinal stromal tumor. Molecular and genetic studies of soft tissue sarcomas, which are considered as heterogeneous groups in terms of their molecular and clinical characteristics, are still an important area of ​​interest The heterogeneity of the molecular and genetic alterations of these malignancies, which are mostly treated with surgery and chemotherapy, also offers hope to the researchers in terms of treatment targets. In this article, molecular biologic features of the soft tissue sarcomas including liposarcoma, rhabdomyosarcoma, leiomyosarcoma, synovial sarcoma, and angiosarcoma are discussed in the light of recent developments in molecular biology, targeted therapies and immunotherapy.

Radiological and histopathological assessment of bone infiltration in soft tissue sarcomas.

BACKGROUND: Deep soft tissue sarcomas are frequently in contact with bone. The therapeutic decision of a composite resection strategy may be challenging, which is usually based on clinical and radiological criteria. The aims of the study were to evaluate the overall frequency of bone and periosteal infiltration in these patients in whom composite resection was indicated, and evaluate the role of magnetic resonance imaging and bone scintigraphy in this scenario. METHODS: Forty-nine patients with a composite surgical resection (soft tissue sarcoma and bone), treated at a single institution between 2006 and 2018, were retrospectively included. Presurgical planning of the resection limits was based on clinical and imaging findings (magnetic resonance imaging and bone scintigraphy). Magnetic resonance imaging was performed in all patients (100%) and bone scintigraphy in 41 (83.7% of the cases). According to magnetic resonance imaging results, patients were divided into two groups: Group A, in which the tumor is adjacent to the bone without evidence of infiltration (n = 24, 48,9%), and Group B, patients with evidence of bone involvement by magnetic resonance imaging (n = 25, 51,1%). BS showed a pathological deposit in 28 patients (68.3%). Histological analysis of the resection specimen was preceded to identify bone and periosteal infiltration. For the analysis of the diagnostic validity of imaging tests, histological diagnosis was considered as the gold standard in the evaluation of STS bone infiltration. RESULTS: Histological bone infiltration was identified in 49% of patients and isolated periosteal infiltration in 14.3%. In terms of diagnostic accuracy, magnetic resonance imaging and bone scintigraphy sensitivity values were 92% and 90%, and their specificity values were 91.7% and 52.4%, respectively. CONCLUSIONS: The incidence of bone and periosteal infiltration of soft tissue sarcomas in contact with bone is high. Presurgical bone assessment by MRI has proven to be a sensitive and specific tool in the diagnosis of bone infiltration. Due to its high negative predictive value, BS is a useful test to rule out it. In those cases, in which there is suspicion of bone infiltration not confirmed by MRI, new diagnostic protocols should be established in order to avoid inappropriate resections.

Current Reality of Treating Advanced Soft Tissue Sarcoma as Illustrated by Case Studies.

In the first-line setting of advanced soft tissue sarcomas (STS), the treatment aim generally drives decision-making. Anthracycline combinations with ifosfamide or dacarbazine are more appropriate when the aim is tumour shrinkage, and doxorubicin monotherapy is suitable for tumour control. In patients who progress on anthracycline-based regimens, scope exists for tumour shrinkage with trabectedin and concurrent low-dose radiotherapy. Selecting systemic treatment for patients with advanced STS unsuited to receive standard anthracycline-based therapy often involves complex decision-making as clinical trial evidence comparing alternative options is lacking. Key factors to consider are patient characteristics (e.g., age, medical history, performance status), disease characteristics (e.g., stage, histology), and treatment requirements such as the drug's safety profile, evidence of efficacy by subtype, and approved indication as an alternative first-line treatment option. Real-world data for elderly STS patients derived from retrospective studies and post hoc analyses of clinical trials have particular value in guiding treatment selection and improving the management of this populous but undertreated segment of the STS population.

Molecular profiling of advanced soft-tissue sarcomas: the MULTISARC randomized trial.

BACKGROUND: Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant's outcome. METHODS: This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm "NGS" and the standard "No NGS". NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in "No NGS" arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator. DISCUSSION: The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale. TRIAL REGISTRATION: clinicaltrial.gov NCT03784014 .

Magnetic Resonance Imaging-Based Radiomics Nomogram for Prediction of the Histopathological Grade of Soft Tissue Sarcomas: A Two-Center Study.

BACKGROUND: Preoperative prediction of soft tissue sarcoma (STS) grade is important for treatment decisions. Therefore, formulation an STS grade model is strongly needed. PURPOSE: To develop and test an magnetic resonance imaging (MRI)-based radiomics nomogram for predicting the grade of STS (low-grade vs. high grade). STUDY TYPE: Retrospective POPULATION: One hundred and eighty patients with STS confirmed by pathologic results at two independent institutions were enrolled (training set, N = 109; external validation set, N = 71). FIELD STRENGTH/SEQUENCE: Unenhanced T1-weighted (T1WI) and fat-suppressed T2-weighted images (FS-T2WI) were acquired at 1.5 T and 3.0 T. ASSESSMENT: Clinical-MRI characteristics included age, gender, tumor-node-metastasis (TNM) stage, American Joint Committee on Cancer (AJCC) stage, progression-free survival (PFS), and MRI morphological features (ie, margin). Radiomics feature extraction were performed on T1WI and FS-T2WI images by minimum redundancy maximum relevance (MRMR) method and least absolute shrinkage and selection operator (LASSO) algorithm. The selected features constructed three radiomics signatures models (RS-T1， RS-FST2, and RS-Combined). Univariate and multivariate logistic regression analysis were applied for screening significant risk factors. Radiomics nomogram was constructed by incorporating the radiomics signature and risk factors. STATISTICAL TESTS: Clinical-MRI characteristics were performed by a univariate analysis. Model performances (discrimination, calibration, and clinical usefulness) were validated in the external validation set. The RS-T1 model, RS-FST2 model, and RS-Combined model had an area under curves (AUCs) of 0.645, 0.641, and 0.829, respectively, in the external validation set. The radiomics nomogram, incorporating significant risk factors and the RS-Combined model had AUCs of 0.916 (95%CI, 0.866-0.966, training set) and 0.879 (95%CI, 0.791-0.967, external validation set), and demonstrated good calibration and good clinical utility. DATA CONCLUSION: The proposed noninvasive MRI-based radiomics models showed good performance in differentiating low-grade from high-grade STSs. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.