Cancers

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12 pages, 757 KiB

Open AccessArticle

Rapid Classification of Sarcomas Using Methylation Fingerprint: A Pilot Study

by Aviel Iluz, Myriam Maoz, Nir Lavi, Hanna Charbit, Omer Or, Noam Olshinka, Jonathan Abraham Demma, Mohammad Adileh, Marc Wygoda, Philip Blumenfeld, Masha Gliner-Ron, Yusef Azraq, Joshua Moss, Tamar Peretz, Amir Eden, Aviad Zick and Iris Lavon

Cancers 2023, 15(16), 4168; https://doi.org/10.3390/cancers15164168 - 18 Aug 2023

Cited by 2 | Viewed by 1502

Abstract

Sarcoma classification is challenging and can lead to treatment delays. Previous studies used DNA aberrations and machine-learning classifiers based on methylation profiles for diagnosis. We aimed to classify sarcomas by analyzing methylation signatures obtained from low-coverage whole-genome sequencing, which also identifies copy-number alterations. [...] Read more.

Sarcoma classification is challenging and can lead to treatment delays. Previous studies used DNA aberrations and machine-learning classifiers based on methylation profiles for diagnosis. We aimed to classify sarcomas by analyzing methylation signatures obtained from low-coverage whole-genome sequencing, which also identifies copy-number alterations. DNA was extracted from 23 suspected sarcoma samples and sequenced on an Oxford Nanopore sequencer. The methylation-based classifier, applied in the nanoDx pipeline, was customized using a reference set based on processed Illumina-based methylation data. Classification analysis utilized the Random Forest algorithm and t-distributed stochastic neighbor embedding, while copy-number alterations were detected using a designated R package. Out of the 23 samples encompassing a restricted range of sarcoma types, 20 were successfully sequenced, but two did not contain tumor tissue, according to the pathologist. Among the 18 tumor samples, 14 were classified as reported in the pathology results. Four classifications were discordant with the pathological report, with one compatible and three showing discrepancies. Improving tissue handling, DNA extraction methods, and detecting point mutations and translocations could enhance accuracy. We envision that rapid, accurate, point-of-care sarcoma classification using nanopore sequencing could be achieved through additional validation in a diverse tumor cohort and the integration of methylation-based classification and other DNA aberrations. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

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12 pages, 1289 KiB

Open AccessArticle

What Is the Significance of Indeterminate Pulmonary Nodules in High-Grade Soft Tissue Sarcomas? A Retrospective Cohort Study

by Marcus J. Brookes, Corey D. Chan, Timothy P. Crowley, Maniram Ragbir, Thomas Beckingsale, Kanishka M. Ghosh and Kenneth S. Rankin

Cancers 2023, 15(13), 3531; https://doi.org/10.3390/cancers15133531 - 07 Jul 2023

Cited by 1 | Viewed by 1085

Abstract

Background: Sarcomas are rare, aggressive cancers which frequently metastasise to the lungs. Following diagnosis, patients typically undergo staging by means of a CT scan of their chest. This often identifies indeterminate pulmonary nodules (IPNs), but the significance of these in high-grade soft tissue [...] Read more.

Background: Sarcomas are rare, aggressive cancers which frequently metastasise to the lungs. Following diagnosis, patients typically undergo staging by means of a CT scan of their chest. This often identifies indeterminate pulmonary nodules (IPNs), but the significance of these in high-grade soft tissue sarcoma (STS) is unclear. Identifying whether these are benign or malignant is important for clinical decision making. This study analyses the clinical relevance of IPNs in high-grade STS. Methods: All patients treated at our centre for high-grade soft tissue sarcoma between 2010 and 2020 were identified from a prospective database. CT scans and their reports were reviewed, and survival data were collected from patient records. Results: 389 suitable patients were identified; 34.4% had IPNs on their CT staging scan and 20.1% progressed into lung metastases. Progression was more likely with IPNs ≥ 5 mm in diameter (p = 0.006), multiple IPNs (p = 0.013) or bilateral IPNs (p = 0.022), as well as in patients with primaries ≥ 5 cm (p = 0.014), grade 3 primaries (p = 0.009) or primaries arising deep to the fascia (p = 0.041). The median time to progression was 143 days. IPNs at diagnosis were associated with an increased risk of developing lung metastases and decreased OS in patients with grade 3 STS (p = 0.0019 and p = 0.0016, respectively); this was not observed in grade 2 patients. Conclusions: IPNs at diagnosis are associated with significantly worse OS in patients with grade 3 STS. It is crucial to consider the primary tumour as well as the IPNs when considering the risk of progression. Surveillance CT scans should be carried out within 6 months. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

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17 pages, 3203 KiB

Open AccessArticle

The First-In-Class Anti-AXL×CD3ε Pronectin™-Based Bispecific T-Cell Engager Is Active in Preclinical Models of Human Soft Tissue and Bone Sarcomas

by Nicoletta Polerà, Antonia Mancuso, Caterina Riillo, Daniele Caracciolo, Stefania Signorelli, Katia Grillone, Serena Ascrizzi, Craig A. Hokanson, Francesco Conforti, Nicoletta Staropoli, Luigia Gervasi, Maria Teresa Di Martino, Mariamena Arbitrio, Giuseppe Nisticò, Roberto Crea, Pierosandro Tagliaferri, Giada Juli and Pierfrancesco Tassone

Cancers 2023, 15(6), 1647; https://doi.org/10.3390/cancers15061647 - 08 Mar 2023

Cited by 1 | Viewed by 2172

Abstract

Sarcomas are heterogeneous malignancies with limited therapeutic options and a poor prognosis. We developed an innovative immunotherapeutic agent, a first-in-class Pronectin™-based Bispecific T-Cell Engager (pAXL×CD3ε), for the targeting of AXL, a TAM family tyrosine kinase receptor highly expressed in sarcomas. AXL expression was [...] Read more.

Sarcomas are heterogeneous malignancies with limited therapeutic options and a poor prognosis. We developed an innovative immunotherapeutic agent, a first-in-class Pronectin™-based Bispecific T-Cell Engager (pAXL×CD3ε), for the targeting of AXL, a TAM family tyrosine kinase receptor highly expressed in sarcomas. AXL expression was first analyzed by flow cytometry, qRT-PCR, and Western blot on a panel of sarcoma cell lines. The T-cell-mediated pAXL×CD3ε cytotoxicity against sarcoma cells was investigated by flow cytometry, luminescence assay, and fluorescent microscopy imaging. The activation and degranulation of T cells induced by pAXL×CD3ε were evaluated by flow cytometry. The antitumor activity induced by pAXL×CD3ε in combination with trabectedin was also investigated. In vivo activity studies of pAXL×CD3ε were performed in immunocompromised mice (NSG), engrafted with human sarcoma cells and reconstituted with human peripheral blood mononuclear cells from healthy donors. Most sarcoma cells showed high expression of AXL. pAXL×CD3ε triggered T-lymphocyte activation and induced dose-dependent T-cell-mediated cytotoxicity. The combination of pAXL×CD3ε with trabectedin increased cytotoxicity. pAXL×CD3ε inhibited the in vivo growth of human sarcoma xenografts, increasing the survival of treated mice. Our data demonstrate the antitumor efficacy of pAXL×CD3ε against sarcoma cells, providing a translational framework for the clinical development of pAXL×CD3ε in the treatment of human sarcomas, aggressive and still-incurable malignancies. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

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13 pages, 2172 KiB

Open AccessArticle

Treatment Pathways and Prognosis in Advanced Sarcoma with Peritoneal Sarcomatosis

by Fabian Klingler, Hany Ashmawy, Lena Häberle, Irene Esposito, Lars Schimmöller, Wolfram Trudo Knoefel and Andreas Krieg

Cancers 2023, 15(4), 1340; https://doi.org/10.3390/cancers15041340 - 20 Feb 2023

Cited by 2 | Viewed by 1611

Abstract

Sarcomas represent a heterogeneous group of mesenchymal malignancies that most commonly occur in the extremities, retroperitoneum, and head and neck. Intra-abdominal manifestations are rare and prove particularly difficult to treat when peritoneal sarcomatosis is present. Because of the overall poor prognosis of the [...] Read more.

Sarcomas represent a heterogeneous group of mesenchymal malignancies that most commonly occur in the extremities, retroperitoneum, and head and neck. Intra-abdominal manifestations are rare and prove particularly difficult to treat when peritoneal sarcomatosis is present. Because of the overall poor prognosis of the disease, a tailored approach to surgical management is essential to achieve satisfactory outcomes with limited morbidity. We present the perioperative and long-term outcomes of 19 cases of sarcoma with peritoneal sarcomatosis treated surgically at our hospital. Treatment pathways were reviewed and clinical follow-up was performed. Patient characteristics, medical history, tumor subtype, surgical approach, hospital stay, complications, follow-up, and overall survival (OS) were assessed. Our patients were 9 women and 10 men with a median age of 45.9 years (18–88) and a median survival of 30 months (0–200). In most cases, peritoneal sarcomatosis was either discovered during surgery or the procedure was performed with palliative intent from the beginning. The surgical approach in these cases is very heterogeneous and should consider a variety of factors to tailor an approach for each patient. Sharing our experiences will help to increase knowledge about this rare disease and provide insight into the management of future cases. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

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Review

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20 pages, 367 KiB

Open AccessReview

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

by Ekaterina A. Lesovaya, Timur I. Fetisov, Beniamin Yu. Bokhyan, Varvara P. Maksimova, Evgeny P. Kulikov, Gennady A. Belitsky, Kirill I. Kirsanov and Marianna G. Yakubovskaya

Cancers 2024, 16(2), 271; https://doi.org/10.3390/cancers16020271 - 08 Jan 2024

Cited by 1 | Viewed by 1048

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

17 pages, 754 KiB

Open AccessReview

Gender Differences in Soft Tissue and Bone Sarcoma: A Narrative Review

by Ilaria Cosci, Paolo Del Fiore, Simone Mocellin and Alberto Ferlin

Cancers 2024, 16(1), 201; https://doi.org/10.3390/cancers16010201 - 31 Dec 2023

Cited by 1 | Viewed by 1254

Abstract

Sarcomas, uncommon malignancies, stem from mesenchymal tissues, distinct from epithelial tissues, originating in the embryonic mesodermal layer. These sarcomas have been categorized as either bone or soft tissue sarcomas, depending on their originating tissue. The majority of sarcomas occur sporadically with their etiology [...] Read more.

Sarcomas, uncommon malignancies, stem from mesenchymal tissues, distinct from epithelial tissues, originating in the embryonic mesodermal layer. These sarcomas have been categorized as either bone or soft tissue sarcomas, depending on their originating tissue. The majority of sarcomas occur sporadically with their etiology being unknown, but there are several, well-established genetic predisposition syndromes and some environmental exposures associated with specific sarcomas. Recently, many studies have shown that sarcomas, in analogy with colorectal, skin, head and neck, esophageal, lung, and liver carcinomas, also have a male sex predilection. Significant gender differences have already been observed in childhood sarcomas. Among the tumors strongly associated with the male sex, childhood sarcomas have been identified as being particularly sensitive to the biological differences between the sexes, with special regard to soft tissue sarcomas. As the biological mechanisms underlying the sex differences in the incidence of soft tissue sarcomas remain largely unexplored, this review aims to highlight the factors underlying these differences to inform prevention and treatment. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

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28 pages, 986 KiB

Open AccessReview

Current Landscape of Immunotherapy for Advanced Sarcoma

by Víctor Albarrán, María Luisa Villamayor, Javier Pozas, Jesús Chamorro, Diana Isabel Rosero, María San Román, Patricia Guerrero, Patricia Pérez de Aguado, Juan Carlos Calvo, Coral García de Quevedo, Carlos González and María Ángeles Vaz

Cancers 2023, 15(8), 2287; https://doi.org/10.3390/cancers15082287 - 13 Apr 2023

Cited by 5 | Viewed by 2988

Abstract

There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy [...] Read more.

There is substantial heterogeneity between different subtypes of sarcoma regarding their biological behavior and microenvironment, which impacts their responsiveness to immunotherapy. Alveolar soft-part sarcoma, synovial sarcoma and undifferentiated pleomorphic sarcoma show higher immunogenicity and better responses to checkpoint inhibitors. Combination strategies adding immunotherapy to chemotherapy and/or tyrosine–kinase inhibitors globally seem superior to single-agent schemes. Therapeutic vaccines and different forms of adoptive cell therapy, mainly engineered TCRs, CAR-T cells and TIL therapy, are emerging as new forms of immunotherapy for advanced solid tumors. Tumor lymphocytic infiltration and other prognostic and predictive biomarkers are under research. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

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24 pages, 6645 KiB

Open AccessReview

Classification of Chondrosarcoma: From Characteristic to Challenging Imaging Findings

by Jun-Ho Kim and Seul Ki Lee

Cancers 2023, 15(6), 1703; https://doi.org/10.3390/cancers15061703 - 10 Mar 2023

Cited by 13 | Viewed by 8968

Abstract

Chondrosarcomas can be classified into various forms according to the presence or absence of a precursor lesion, location, and histological subtype. The new 2020 World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone classifies chondrogenic bone tumors as benign, intermediate [...] Read more.

Chondrosarcomas can be classified into various forms according to the presence or absence of a precursor lesion, location, and histological subtype. The new 2020 World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone classifies chondrogenic bone tumors as benign, intermediate (locally aggressive), or malignant, and separates atypical cartilaginous tumors (ACTs) and chondrosarcoma grade 1 (CS1) as intermediate and malignant tumors. respectively. Furthermore, the classification categorizes chondrosarcomas (including ACT) into eight subtypes: central conventional (grade 1 vs. 2–3), secondary peripheral (grade 1 vs. 2–3), periosteal, dedifferentiated, mesenchymal, and clear cell chondrosarcoma. Most chondrosarcomas are the low-grade, primary central conventional type. The rarer subtypes include clear cell, mesenchymal, and dedifferentiated chondrosarcomas. Comprehensive analysis of the characteristic imaging findings can help differentiate various forms of chondrosarcomas. However, distinguishing low-grade chondrosarcomas from enchondromas or high-grade chondrosarcomas is radiologically and histopathologically challenging, even for experienced radiologists and pathologists. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

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9 pages, 268 KiB

Open AccessReview

Predictors of Symptomatic Venous Thromboembolism in Patients with Soft Tissue Sarcoma in the Lower Extremity

by Pramod N. Kamalapathy, Adam Kline, Hannah Hollow, Kevin Raskin, Joseph H. Schwab and Santiago Lozano-Calderón

Cancers 2023, 15(1), 315; https://doi.org/10.3390/cancers15010315 - 03 Jan 2023

Cited by 1 | Viewed by 1563

Abstract

Orthopedic surgery and soft-tissue sarcoma (STS) both independently increase the risk of developing symptomatic venous thromboembolic events (SVTE), but there are no established risk factors or guidelines for how to prophylactically treat patients with STS undergoing surgery. The objectives of this study were [...] Read more.

Orthopedic surgery and soft-tissue sarcoma (STS) both independently increase the risk of developing symptomatic venous thromboembolic events (SVTE), but there are no established risk factors or guidelines for how to prophylactically treat patients with STS undergoing surgery. The objectives of this study were to (1) identify the prevalence of SVTE in patients undergoing STS surgery, (2) identify risk factors for SVTE, and (3) determine the risk of wound complications associated with VTE prophylaxis. This retrospective study was conducted in a tertiary level, academic hospital. A total of 642 patients were treated for soft-tissue sarcoma in the lower extremity with follow up for at least 90 days for the development of SVTE such as deep venous thrombosis and pulmonary embolism. Multivariate logistic regression was used to identify predictors for these events by controlling for patient characteristics, surgical characteristics, and treatment variables, with significance held at p < 0.05. Twenty eight patients (4.36%) were diagnosed with SVTE. Multivariate analysis found six significant predictors ordered based on standardized coefficients: pre-operative (PTT) partial thromboplastin time (p < 0.001), post-operative PTT (p = 0.010), post-op chemotherapy (p = 0.013), metastasis at diagnosis (p = 0.025), additional surgery for metastasis or local recurrence (p = 0.004), and tumor size larger than 10 cm (p < 0.001). The risk of wound complications (p = 0.04) and infection (p = 0.017) increased significantly in patients who received chemical prophylaxis. Our study identifies risk factors for patients at increased risk of developing VTE. Further prospective research is necessary to identify which protocols would be beneficial in preventing SVTE in high-risk patients with a low profile of wound complications. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

Other

Jump to: Research, Review

15 pages, 898 KiB

Open AccessSystematic Review

Soft Tissue Sarcoma Mimicking Melanoma: A Systematic Review

by Fortunato Cassalia, Francesco Cavallin, Andrea Danese, Paolo Del Fiore, Claudia Di Prata, Marco Rastrelli, Anna Belloni Fortina and Simone Mocellin

Cancers 2023, 15(14), 3584; https://doi.org/10.3390/cancers15143584 - 12 Jul 2023

Cited by 1 | Viewed by 1667

Abstract

Background: Sarcoma may show similarities to malignant melanoma in terms of morphologic and immunohistochemical aspects, making it difficult to differentiate between these two neoplasms during the diagnostic process. This systematic review aims to summarize available evidence on cases of sarcoma that were initially [...] Read more.

Background: Sarcoma may show similarities to malignant melanoma in terms of morphologic and immunohistochemical aspects, making it difficult to differentiate between these two neoplasms during the diagnostic process. This systematic review aims to summarize available evidence on cases of sarcoma that were initially diagnosed as melanoma. Methods: A comprehensive search of the MEDLINE/Pubmed, EMBASE, and SCOPUS databases was conducted through March 2023. We included case series and case reports of sarcoma patients that were initially diagnosed as malignant melanoma. PRISMA guidelines were followed. Results: Twenty-three case reports and four case series with a total of 34 patients were included. The clinical presentation was heterogeneous, and the most involved anatomical regions were lower limbs (24%), head/neck (24%), and upper limbs (21%). IHC positivity was reported for S100 (69%), HMB45 (63%), MelanA (31%), and MiTF (3%). The main reasons for a second assessment were unusual presentation (48%) and uncertain diagnosis (28%). EWSR1 translocation was investigated in 17/34 patients (50%) and found to be positive in 16/17 (94%). The final diagnosis was clear cell sarcoma (50%) or other soft tissue sarcomas (50%). Conclusions: Melanoma and some histotypes of sarcoma share many similarities. In cases of atypical lesions, a second diagnosis should be considered, and ESWR1 translocation should be investigated. Full article

(This article belongs to the Special Issue Advances in Soft Tissue and Bone Sarcoma)

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