Innovations in Soft Tissue Sarcoma Diagnosis and Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Causes, Screening and Diagnosis".

Deadline for manuscript submissions: 30 May 2024 | Viewed by 15030

Special Issue Editors


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Guest Editor
Sarcoma Oncology Research Center, Santa Monica, CA 90403, USA
Interests: sarcoma; gene therapy; natural killer cell therapy; immune and cell-cycle checkpoint inhibitors; tumor targeting

E-Mail Website
Guest Editor
Sarcoma Oncology Research Center, Santa Monica, CA 90403, USA
Interests: sarcoma; gene therapy; natural killer cell therapy; immune and cell-cycle checkpoint inhibitors; tumor targeting

E-Mail Website
Guest Editor
Sarcoma Oncology Research Center, Santa Monica, CA 90403, USA
Interests: cancer gene therapy; targeted gene delivery; cyclin G1; oncogenic drivers along the CCNG1 pathway; retroviral vector cloning; targeting pharmaceutical agents to injured tissues

Special Issue Information

Dear Colleagues,  

Recent advances in genetic screening, molecular profiling, targeted therapy, gene therapy and immunotherapy for soft tissue sarcomas (STS) have evoked increasing optimism in the medical and scientific community. Hence, it is time to reflect on the many faces of STS and current innovations in its diagnosis and treatment. STS is a rare cancer involving mesodermal tissues. Surgical resection is the standard of care for localized disease, but its recurrence rate is high and the prognosis for advanced STS is poor, with a median survival of 8–13 months.

This Special Issue entitled "Innovations in Soft Tissue Sarcoma Diagnosis and Treatment" will include review articles, original clinical and translational research articles that are hypothesis-generating toward the development of precision medicine for STS.

Dr. Erlinda M. Gordon
Dr. Sant P. Chawla
Dr. Frederick L. Hall
Guest Editors

Manuscript Submission Information

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Keywords

  • soft tissue sarcoma
  • gene therapy
  • natural killer cell therapy
  • immune and cell-cycle checkpoint inhibitors
  • targeted therapy
  • Genetics
  • Genomics
  • Surgery
  • Radiologic Imaging

Published Papers (7 papers)

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Research

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18 pages, 6493 KiB  
Article
PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma
by Kirsi Toivanen, Sami Kilpinen, Kalle Ojala, Nanna Merikoski, Sami Salmikangas, Mika Sampo, Tom Böhling and Harri Sihto
Cancers 2023, 15(22), 5308; https://doi.org/10.3390/cancers15225308 - 7 Nov 2023
Viewed by 1377
Abstract
Liposarcomas (LPSs) are a heterogeneous group of malignancies that arise from adipose tissue. Although LPSs are among the most common soft-tissue sarcoma subtypes, precision medicine treatments are not currently available. To discover LPS-subtype-specific therapy targets, we investigated RNA sequenced transcriptomes of 131 clinical [...] Read more.
Liposarcomas (LPSs) are a heterogeneous group of malignancies that arise from adipose tissue. Although LPSs are among the most common soft-tissue sarcoma subtypes, precision medicine treatments are not currently available. To discover LPS-subtype-specific therapy targets, we investigated RNA sequenced transcriptomes of 131 clinical LPS tissue samples and compared the data with a transcriptome database that contained 20,218 samples from 95 healthy tissues and 106 cancerous tissue types. The identified genes were referred to the NCATS BioPlanet library with Enrichr to analyze upregulated signaling pathways. PDE3A protein expression was investigated with immunohistochemistry in 181 LPS samples, and PDE3A and SLFN12 mRNA expression with RT-qPCR were investigated in 63 LPS samples. Immunoblotting and cell viability assays were used to study LPS cell lines and their sensitivity to PDE3A modulators. We identified 97, 247, and 37 subtype-specific, highly expressed genes in dedifferentiated, myxoid, and pleomorphic LPS subtypes, respectively. Signaling pathway analysis revealed a highly activated hedgehog signaling pathway in dedifferentiated LPS, phospholipase c mediated cascade and insulin signaling in myxoid LPS, and pathways associated with cell proliferation in pleomorphic LPS. We discovered a strong association between high PDE3A expression and myxoid LPS, particularly in high-grade tumors. Moreover, myxoid LPS samples showed elevated expression levels of SLFN12 mRNA. In addition, PDE3A- and SLFN12-coexpressing LPS cell lines SA4 and GOT3 were sensitive to PDE3A modulators. Our results indicate that PDE3A modulators are promising drugs to treat myxoid LPS. Further studies are required to develop these drugs for clinical use. Full article
(This article belongs to the Special Issue Innovations in Soft Tissue Sarcoma Diagnosis and Treatment)
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12 pages, 2168 KiB  
Article
Follow-Up after Curative Surgical Treatment of Soft-Tissue Sarcoma for Early Detection of Recurrence: Which Patients Have More or Fewer Visits than Advised in Guidelines?
by Anouk A. Kruiswijk, Laurien S. Kuhrij, Desiree M. J. Dorleijn, Michiel A. J. van de Sande, Leti van Bodegom-Vos and Perla J. Marang-van de Mheen
Cancers 2023, 15(18), 4617; https://doi.org/10.3390/cancers15184617 - 18 Sep 2023
Viewed by 694
Abstract
Introduction: Follow-up (FU) in soft-tissue sarcoma (STS) patients is designed for early detection of disease recurrence. Current guidelines are not evidenced-based and not tailored to patient or tumor characteristics, so they remain debated, particularly given concerns about cost, radiation frequency, and over-testing. This [...] Read more.
Introduction: Follow-up (FU) in soft-tissue sarcoma (STS) patients is designed for early detection of disease recurrence. Current guidelines are not evidenced-based and not tailored to patient or tumor characteristics, so they remain debated, particularly given concerns about cost, radiation frequency, and over-testing. This study assesses the extent to which STS patients received guideline-concordant FU and to characterize which type of patients received more or fewer visits than advised. Methods: All STS patients surgically treated at the Leiden University Medical Center between 2000–2020 were included. For each patient, along with individual characteristics, all radiological examinations from FU start up to 5 years were included and compared to guidelines. Recurrence was defined as local/regional recurrence or metastasis. Results: A total of 394 patients was included, of whom 250 patients had a high-grade tumor (63.5%). Only 24% of patients received the advised three FU visits in the first year. More FU visits were observed in younger patients and those diagnosed with a high-grade tumor. Among patients with a recurrence, 10% received fewer visits than advised, while 28% of patients without a recurrence received more visits than advised. Conclusions: A minority of STS patients received guideline-concordant FU visits, suggesting that clinicians seem to incorporate recurrence risk in decisions on FU frequency. Full article
(This article belongs to the Special Issue Innovations in Soft Tissue Sarcoma Diagnosis and Treatment)
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12 pages, 859 KiB  
Article
SAINT: A Phase I/Expanded Phase II Study Using Safe Amounts of Ipilimumab, Nivolumab and Trabectedin as First-Line Treatment of Advanced Soft Tissue Sarcoma
by Erlinda Maria Gordon, Sant P. Chawla, Walter Andree Tellez, Elan Younesi, Sonu Thomas, Victoria S. Chua-Alcala, Hripsime Chomoyan, Chrysler Valencia, Don Arlen Brigham, Ania Moradkhani, Doris Quon, Amornchit Srikureja, Steven G. Wong, William Tseng and Noah Federman
Cancers 2023, 15(3), 906; https://doi.org/10.3390/cancers15030906 - 31 Jan 2023
Cited by 8 | Viewed by 2266
Abstract
Background: This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma. Methods: Phase I endpoints—maximum tolerated dose in previously treated patients; Phase II [...] Read more.
Background: This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma. Methods: Phase I endpoints—maximum tolerated dose in previously treated patients; Phase II endpoints—best response, progression free survival and overall survival and incidence of adverse events in previously untreated patients; Phase I treatments—escalating doses of trabectedin (1.0, 1.2, 1.5 mg/m2) as continuous intravenous infusion over 24 h every 3 weeks, 1 mg/kg of ipilimumab given intravenously every 12 weeks, and 3 mg/kg of nivolumab given intravenously every 2 weeks; Phase II treatments—maximum tolerated dose of trabectedin and defined doses of ipilimumab and nivolumab. Results: Phase I (n = 9)—the maximum tolerated dose of trabectedin was 1.2 mg/m2; Phase II (n = 79)—6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median progression-free survival, 6.7 months (CI 95%: 4.4–7.9), median overall survival, 24.6 months (CI 95%: 17.0–.); Grade 3/4 therapy-related adverse events (n = 92)—increased ALT (25%), fatigue (8.7%), increased AST (8.7%), decreased neutrophil count (5.4%) and anemia (4.6%). Conclusion: SAINT is a safe and effective first-line treatment for advanced soft tissue sarcoma. Full article
(This article belongs to the Special Issue Innovations in Soft Tissue Sarcoma Diagnosis and Treatment)
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13 pages, 1910 KiB  
Article
Intraoperative Evaluation of Soft Tissue Sarcoma Surgical Margins with Indocyanine Green Fluorescence Imaging
by Matthew F. Gong, William T. Li, Sumail Bhogal, Brittany Royes, Tanya Heim, Maria Silvaggio, Marcus Malek, Rajeev Dhupar, Stella J. Lee, Richard L. McGough and Kurt R. Weiss
Cancers 2023, 15(3), 582; https://doi.org/10.3390/cancers15030582 - 18 Jan 2023
Cited by 6 | Viewed by 2082
Abstract
Soft tissue sarcomas (STS) are rare malignant tumors often associated with poor outcomes and high local recurrence rates. Current tools for intraoperative and definitive margin assessment include intraoperative frozen section and permanent pathology, respectively. Indocyanine green dye (ICG) is a historically safe fluorophore [...] Read more.
Soft tissue sarcomas (STS) are rare malignant tumors often associated with poor outcomes and high local recurrence rates. Current tools for intraoperative and definitive margin assessment include intraoperative frozen section and permanent pathology, respectively. Indocyanine green dye (ICG) is a historically safe fluorophore dye that has demonstrated efficacy for intraoperative margin assessment in the surgical management of both breast and gastrointestinal cancers. The utility of ICG in the surgical management of sarcoma surgery has primarily been studied in pre-clinical mouse models and warrants further investigation as a potential adjunct to achieving negative margins. This study is a prospective, non-randomized clinical study conducted on patients with confirmed or suspected STS. Patients younger than 18 years, with a prior adverse reaction to iodine or fluorescein, or with renal disease were excluded from the study. Intravenous ICG was infused approximately three hours prior to surgery at a dosage of 2.0–2.5 mg/kg, and following tumor resection, the excised tumor and tumor bed were imaged for fluorescence intensity. When scanning the tumor bed, a threshold of 77% calibrated to the region of maximum intensity in the resected tumor was defined as a positive ICG margin, according to published protocols from the breast cancer literature. ICG results were then compared with the surgeon’s clinical impression of margin status and permanent pathology results. Out of 26 subjects recruited for the original study, 18 soft tissue sarcomas (STS) were included for analysis. Three subjects were excluded for having bone sarcomas, and five subjects were excluded due to final pathology, which was ultimately inconsistent with sarcoma. The average age of patients was 64.1 years old (range: 28–83), with an average ICG dose of 201.8 mg. In 56% (10/18) of patients, ICG margins were consistent with the permanent pathology margins, with 89% specificity. The use of ICG as an intraoperative adjunct to obtaining negative margins in soft tissue sarcoma surgery is promising. However, studies with larger sample sizes are warranted to further delineate the accuracy, optimal dosage, timing, and types of sarcoma in which this diagnostic tool may be most useful. Full article
(This article belongs to the Special Issue Innovations in Soft Tissue Sarcoma Diagnosis and Treatment)
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Review

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24 pages, 14096 KiB  
Review
Targeting the Molecular and Immunologic Features of Leiomyosarcoma
by Brandon M. Cope, Raymond S. Traweek, Rossana Lazcano, Emily Z. Keung, Alexander J. Lazar, Christina L. Roland and Elise F. Nassif
Cancers 2023, 15(7), 2099; https://doi.org/10.3390/cancers15072099 - 31 Mar 2023
Cited by 5 | Viewed by 3643
Abstract
Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a [...] Read more.
Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies. Full article
(This article belongs to the Special Issue Innovations in Soft Tissue Sarcoma Diagnosis and Treatment)
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16 pages, 314 KiB  
Review
The Next Frontier in Sarcoma: Molecular Pathways and Associated Targeted Therapies
by Ted Kim and Nam Q. Bui
Cancers 2023, 15(6), 1692; https://doi.org/10.3390/cancers15061692 - 9 Mar 2023
Viewed by 1684
Abstract
Soft tissue sarcomas (STS) are a rare, complex, heterogeneous group of mesenchymal neoplasms with over 150 different histological subtypes. Treatments for this malignancy have been especially challenging due to the heterogeneity of the disease and the modest efficacy of conventional chemotherapy. The next [...] Read more.
Soft tissue sarcomas (STS) are a rare, complex, heterogeneous group of mesenchymal neoplasms with over 150 different histological subtypes. Treatments for this malignancy have been especially challenging due to the heterogeneity of the disease and the modest efficacy of conventional chemotherapy. The next frontier lies in discerning the molecular pathways in which these mesenchymal neoplasms arise, metastasize, and develop drug-resistance, thereby helping guide new therapeutic targets for the treatment of STS. This comprehensive review will discuss the current understanding of tumorigenesis of specific STS subtypes, including oncogenic pathway alterations involved in cell cycle regulation, angiogenesis, NOTCH signaling, and aberrant genetic rearrangements. It will then review current therapies that have been recently developed to target these pathways, including a review of ongoing clinical studies for targeted sarcoma treatment, as well as discuss new potential avenues for therapies against known molecular pathways of sarcomagenesis. Full article
(This article belongs to the Special Issue Innovations in Soft Tissue Sarcoma Diagnosis and Treatment)
16 pages, 1776 KiB  
Review
Imaging Hallmarks of Sarcoma Progression Via X-ray Computed Tomography: Beholding the Flower of Evil
by Elena Popova, Sergey Tkachev, Igor Reshetov, Peter Timashev and Ilya Ulasov
Cancers 2022, 14(20), 5112; https://doi.org/10.3390/cancers14205112 - 19 Oct 2022
Viewed by 2140
Abstract
Sarcomas are a leading cause of cancer death in individuals younger than 20 years of age and represent the largest group of rare solid tumors. To date, more than 100 morphological subtypes of sarcomas have been described, among which epidemiology, clinical features, management, [...] Read more.
Sarcomas are a leading cause of cancer death in individuals younger than 20 years of age and represent the largest group of rare solid tumors. To date, more than 100 morphological subtypes of sarcomas have been described, among which epidemiology, clinical features, management, and prognosis differ significantly. Delays and errors in the diagnosis of sarcomas limit the number of effective therapeutic modalities and catastrophically worsen the prognosis. Therefore, the development of an algorithm for the early accurate diagnosis of sarcomas seems to be as important as the development of novel therapeutic advances. This literature review aims to summarize the results of recent investigations regarding the imaging of sarcoma progression based on the use of X-ray computed tomography (CT) in preclinical studies and in current clinical practice through the lens of cancer hallmarks. We attempted to summarize the main CT imaging features of soft-tissue and bone sarcomas. We noted the development of new molecular markers with high specificity to antibodies and chemokines, which are expressed in particular sarcoma subtypes to reach tumor type-specific imaging. We demonstrate the possibility of the use of X-ray computed microtomography (micro-CT) for non-destructive 3D visualization of solid tumors by increasing the visibility of soft tissues with X-ray scattering agents. Based on the results of recent studies, we hypothesize that micro-CT enables the visualization of neovascularization and stroma formation in sarcomas at high-resolution in vivo and ex vivo, including the novel techniques of whole-block and whole-tissue imaging. Finding correlations between CT, PET/CT, and micro-CT imaging features, the results of the histopathological specimen examination and clinical outcomes may significantly increase the accuracy of soft-tissue and bone tumor diagnostics, which leads to the initiation of appropriate histotype-specific management in a timely manner and, consequently, to improved outcomes. Full article
(This article belongs to the Special Issue Innovations in Soft Tissue Sarcoma Diagnosis and Treatment)
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