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Keywords = pleomorphic leiomyosarcoma

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30 pages, 400 KiB  
Review
Novel Therapeutics in Soft Tissue Sarcoma
by Leonidas Mavroeidis, Andrea Napolitano, Paul Huang and Robin L. Jones
Cancers 2025, 17(1), 10; https://doi.org/10.3390/cancers17010010 - 24 Dec 2024
Cited by 4 | Viewed by 2623
Abstract
There has been noteworthy progress in molecular characterisation and therapeutics in soft tissue sarcomas. Novel agents have gained regulatory approval by the FDA. Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab [...] Read more.
There has been noteworthy progress in molecular characterisation and therapeutics in soft tissue sarcomas. Novel agents have gained regulatory approval by the FDA. Examples are the tyrosine kinase inhibitors avapritinib and ripretinib in gastrointestinal stromal tumours (GIST), the immune check point inhibitor atezolizumab in alveolar soft part tissue sarcoma, the γ-secretase inhibitor nirogacestat in desmoid tumours, the NTRK inhibitors larotrectinib and entrectinib in tumours with NTRK fusions, the mTOR inhibitor nab-sirolimus in PEComa, and the EZH-2 inhibitor tazemetostat in epithelioid sarcoma. The FDA has also recently granted accelerated approval for autologous T-cell therapy with afami-cel in patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. There are other promising treatments that are still investigational, such as MDM2 and CDK4/6 inhibitors in well-/dedifferentiated liposarcoma, immune checkpoint inhibitors in the head and neck angiosarcoma and a subset of patients with undifferentiated pleomorphic sarcoma, and PARP inhibitors in leiomyosarcoma. The challenges in drug development in soft tissue sarcoma are due to the rarity and the molecular heterogeneity of the disease and the fact that many subtypes are associated with complex karyotypes or non-targetable molecular alterations. We believe that progress maybe possible with a better understanding of the complex biology, the development of novel compounds for difficult targets such as proteolysis targeting chimeras (Protacs), the utilisation of modern clinical trial designs, and enhanced collaboration of academia with industry to develop treatments with a strong biologic rationale. Full article
(This article belongs to the Special Issue Advances in Cancer Therapeutics)
21 pages, 811 KiB  
Review
Dysregulation of miRNAs in Soft Tissue Sarcomas
by Stefano Zoroddu, Angela Lucariello, Antonio De Luca and Luigi Bagella
Cells 2024, 13(22), 1853; https://doi.org/10.3390/cells13221853 - 8 Nov 2024
Cited by 5 | Viewed by 1785
Abstract
MicroRNAs (miRNAs) are pivotal regulators of gene expression, influencing key cellular processes such as proliferation, differentiation, apoptosis, and metastasis. In the realm of sarcomas—a diverse group of malignant tumors affecting soft tissues and bone sarcomas—miRNAs have emerged as crucial players in tumorigenesis and [...] Read more.
MicroRNAs (miRNAs) are pivotal regulators of gene expression, influencing key cellular processes such as proliferation, differentiation, apoptosis, and metastasis. In the realm of sarcomas—a diverse group of malignant tumors affecting soft tissues and bone sarcomas—miRNAs have emerged as crucial players in tumorigenesis and tumor progression. This review delves into the intricate roles of miRNAs across various soft tissue sarcoma subtypes, including rhabdomyosarcoma, liposarcoma, leiomyosarcoma, synovial sarcoma, fibrosarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma (UPS), and malignant peripheral nerve sheath tumor (MPNST). We explore how dysregulated miRNAs function as oncogenes or tumor suppressors, modulating critical pathways that define the aggressive nature of these cancers. Furthermore, we discuss the diagnostic and prognostic potential of specific miRNAs and highlight their promise as therapeutic targets. By understanding the miRNA-mediated regulatory networks, this review aims to provide a comprehensive overview of current research while pointing towards future directions for miRNA-based therapies. Our findings underscore the potential of miRNAs to transform the landscape of sarcoma treatment, offering hope for more precise, personalized, and effective therapeutic strategies. Full article
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12 pages, 1790 KiB  
Article
Brain Metastases in Sarcomas: A Multicenter Retrospective Cohort Study
by Ellen Zhang, Sheima Farag, Hilary Dietz, Daniel Wang, Angela Hirbe, Kristen Ganjoo, Brian Van Tine, Shane Zaid, Aisha Miah, Vicki Keedy, Elizabeth Davis and Nam Bui
Cancers 2024, 16(22), 3760; https://doi.org/10.3390/cancers16223760 - 7 Nov 2024
Cited by 3 | Viewed by 1365
Abstract
Purpose: Brain metastases (BM) in sarcomas occur rarely and are associated with poor prognosis. This study is a large retrospective cohort describing the demographic and clinical characteristics of these patients, treatment strategies, and survival outcomes. Methods: In total, 81 patients with BM from [...] Read more.
Purpose: Brain metastases (BM) in sarcomas occur rarely and are associated with poor prognosis. This study is a large retrospective cohort describing the demographic and clinical characteristics of these patients, treatment strategies, and survival outcomes. Methods: In total, 81 patients with BM from sarcomas were identified across five sarcoma centers. Demographic data, clinical presentation, and treatment modalities were analyzed. Results: The most common histologies were leiomyosarcoma (12.3%) and undifferentiated pleomorphic sarcoma (12.3%). The median time from sarcoma diagnosis to brain metastases was 1.9 years. Upon presentation, 88.9% of patients with BM from sarcomas were symptomatic with the most common presenting symptom being focal neurological deficits (37.9%) and headaches (22.1%). Higher-grade sarcomas were more likely to metastasize and were usually preceded by metastases to other sites, most commonly the lungs. One-year overall survival was 31% from initial sarcoma diagnosis, and the median time from diagnosis of BM until death was 6.0 months. For treatment, 60 (74.1%) patients had radiation, 39 (48.1%) patients had systemic therapy, and 29 (35.8%) patients had surgery. In a multivariate analysis, surgery (HR 0.30) and chemotherapy (HR 0.23) were found to be significantly correlated with improved survival outcomes. Although radiation as a whole was not found to significantly correlate with survival, improved outcomes were seen with stereotactic radiosurgery (SRS, mOS 11.6 mo) as opposed to whole-brain radiation therapy (WBRT, mOS 8.3 mo). Additionally, patients with leptomeningeal disease were significantly less likely to survive more than one year compared to patients with brain metastases only. Conclusions: Our findings identify that patients with metastatic sarcoma to the brain have poor prognoses, often have concurrent metastasis, and have a median survival of only 6 months. Additionally, our study found that leptomeningeal metastases is a rare presentation with poor survival outcomes. There are various treatment modalities for sarcomas with BM; however, there are no guidelines, unlike in other malignancies. Further research is necessary to evaluate the role of therapeutic measures in terms of type, timing, and outcomes. Full article
(This article belongs to the Section Cancer Metastasis)
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12 pages, 2945 KiB  
Article
Retrospective Single-Center Case Study of Clinical Variables and the Degree of Actinic Elastosis Associated with Rare Skin Cancers
by Konstantin Drexler, Lara Bollmann, Sigrid Karrer, Mark Berneburg, Sebastian Haferkamp and Dennis Niebel
Biology 2024, 13(7), 529; https://doi.org/10.3390/biology13070529 - 16 Jul 2024
Viewed by 1319
Abstract
(1) Background: Rare skin cancers include epithelial, neuroendocrine, and hematopoietic neoplasias as well as cutaneous sarcomas. Ultraviolet (UV) radiation and sunburns are important drivers for the incidence of certain cutaneous sarcomas; however, the pathogenetic role of UV light is less clear in rare [...] Read more.
(1) Background: Rare skin cancers include epithelial, neuroendocrine, and hematopoietic neoplasias as well as cutaneous sarcomas. Ultraviolet (UV) radiation and sunburns are important drivers for the incidence of certain cutaneous sarcomas; however, the pathogenetic role of UV light is less clear in rare skin cancers compared to keratinocyte cancer and melanoma. In this study, we compared the degree of actinic elastosis (AE) as a surrogate for lifetime UV exposure among selected rare skin cancers (atypical fibroxanthoma [AFX], pleomorphic dermal sarcoma [PDS], dermatofibrosarcoma protuberans [DFSP], Kaposi sarcoma [KS], Merkel cell carcinoma [MCC], and leiomyosarcoma [LMS]) while taking into account relevant clinical variables (age, sex, and body site). (2) Methods: We newly established a semi-quantitative score for the degree of AE ranging from 0 = none to 3 = total loss of elastic fibers (basophilic degeneration) and multiplied it by the perilesional vertical extent (depth), measured histometrically (tumor-associated elastosis grade (TEG)). We matched the TEG of n = 210 rare skin cancers from 210 patients with their clinical variables. (3) Results: TEG values were correlated with age and whether tumors arose on UV-exposed body sites. TEG values were significantly higher in AFX and PDS cases compared to all other analyzed rare skin cancer types. As expected, TEG values were low in DFSP and KS, while MCC cases exhibited intermediate TEG values. (4) Conclusions: High cumulative UV exposure is more strongly associated with AFX/PDS and MCC than with other rare skin cancers. These important results expand the available data associated with rare skin cancers while also offering insight into the value of differentiating among these tumor types based on their relationship with sun exposure, potentially informing preventative, diagnostic and/or therapeutic approaches. Full article
(This article belongs to the Special Issue Physiology and Pathophysiology of Skin)
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9 pages, 5621 KiB  
Article
TRPS1 Expression Is Frequently Seen in a Subset of Cutaneous Mesenchymal Neoplasms and Tumors of Uncertain Differentiation: A Potential Diagnostic Pitfall
by Moon Joo Kim, Yi A. Liu, Yunyi Wang, Jing Ning and Woo Cheal Cho
Dermatopathology 2024, 11(3), 200-208; https://doi.org/10.3390/dermatopathology11030021 - 15 Jul 2024
Cited by 4 | Viewed by 2195
Abstract
Although extensively studied in cutaneous epithelial neoplasms, the TRPS1 immunoreactivity in cutaneous mesenchymal neoplasms and tumors of uncertain differentiation (CMNTUDs), such as atypical fibroxanthoma (AFX), remains largely unexplored. We assessed TRPS1 immunoreactivity in 135 CMNTUDs, comprising 46 fibrohistiocytic/fibroblastic tumors, 28 vascular tumors, 24 [...] Read more.
Although extensively studied in cutaneous epithelial neoplasms, the TRPS1 immunoreactivity in cutaneous mesenchymal neoplasms and tumors of uncertain differentiation (CMNTUDs), such as atypical fibroxanthoma (AFX), remains largely unexplored. We assessed TRPS1 immunoreactivity in 135 CMNTUDs, comprising 46 fibrohistiocytic/fibroblastic tumors, 28 vascular tumors, 24 peripheral nerve sheath tumors (PNSTs), 21 tumors of uncertain differentiation, and 16 smooth muscle tumors. Additionally, we included selected cases of melanoma with spindled cell morphology or desmoplastic features (n = 9) and sarcomatoid squamous cell carcinoma (SSCC) (n = 5) to compare TRPS1 expression patterns with those of AFX. TRPS1 expression was prevalent in dermatofibromas (24/24), leiomyomas (8/8), AFXs/pleomorphic dermal sarcoma (PDS) (20/21), dermatofibrosarcomas protuberans (14/22), and leiomyosarcomas (6/8). It was uncommon in angiosarcomas (3/20), Kaposi sarcomas (2/8), and neurofibromas (5/17) and absent in perineuriomas (0/2). AFXs/PDS exhibited the highest median H-score of 240, contrasting with minimal TRPS1 immunoreactivity in vascular neoplasms and PNSTs, with median H-scores consistently below 10. Significant differences in H-score were observed between AFXs/PDS and angiosarcomas (p < 0.001), melanomas (p < 0.001), and leiomyosarcomas (p = 0.029). However, no significant difference was found compared to SSCCs, suggesting limited discriminatory power of TRPS1 in this context. This study sheds light on TRPS1 expression patterns in a subset of CMNTUDs, extending beyond prior studies primarily focused on epithelial tumors, while underscoring potential pitfalls associated with TRPS1 immunohistochemistry. Full article
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19 pages, 6312 KiB  
Article
Dedifferentiated Leiomyosarcoma of the Uterine Corpus with Heterologous Component: Clinicopathological Analysis of Five Consecutive Cases from a Single Institution and Comprehensive Literature Review
by Suyeon Kim, Hyunsik Bae and Hyun-Soo Kim
Diagnostics 2024, 14(2), 160; https://doi.org/10.3390/diagnostics14020160 - 10 Jan 2024
Cited by 5 | Viewed by 2436
Abstract
Dedifferentiation is a very rare phenomenon in uterine leiomyosarcoma (LMS). The aim of this study was to comprehensively analyze the clinicopathological characteristics of uterine dedifferentiated LMS (DDLMS). We reviewed electronic medical records and pathology slides from five patients with uterine DDLMS and performed [...] Read more.
Dedifferentiation is a very rare phenomenon in uterine leiomyosarcoma (LMS). The aim of this study was to comprehensively analyze the clinicopathological characteristics of uterine dedifferentiated LMS (DDLMS). We reviewed electronic medical records and pathology slides from five patients with uterine DDLMS and performed immunostaining. The mean age of the patients was 56 years. Two patients presented with abdominal discomfort, while in three cases the uterine tumors were detected on routine medical examination. The mean size of the tumors was 17.0 cm. Four patients underwent hysterectomy. The initial stages were distributed as IB (2/5), IIIC (2/5), and IVC (1/5). Post-operative concurrent chemoradiation therapy, radiation therapy, and chemotherapy were administered in one, one, and two patients, respectively. Despite post-operative treatment, three patients developed metastatic recurrences in the abdominal and pelvic organs. Recurrence-free survival time ranged between 4 and 30 months. Histologically, the differentiated areas demonstrated the classic morphology of malignant smooth muscle differentiation, whereas the dedifferentiated areas resembled undifferentiated pleomorphic sarcoma and were characterized by large pleomorphic tumor cells admixed with haphazardly arranged atypical cells with marked nuclear pleomorphism. All cases also exhibited heterologous components, including chondrosarcoma (CSA; 3/5) and rhabdomyosarcoma (2/5). In two cases, the heterologous components were initially detected in primary tumors. In three cases, the primary tumors did not exhibit any dedifferentiated or heterologous components. Instead, more than half of the recurrent tumors consisted of heterologous components. Three cases showed a sharp demarcation between the LMS and CSA components, while in two cases the dedifferentiated area imperceptibly merged with the differentiated component. Immunostaining revealed that the dedifferentiated components exhibited a lack of desmin immunoreactivity in three of the four examined cases. A subset of uterine LMS represents various amounts and types of dedifferentiation and heterologous components in both primary and recurrent tumors. Routine recognition of DDLMS and distinction from its mimickers are required for accurate diagnosis and further characterization of these rare tumors. Full article
(This article belongs to the Special Issue Pathology and Diagnosis of Gynecologic Diseases, 2nd Edition)
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6 pages, 7811 KiB  
Case Report
A Case of Pleomorphic Dermal Sarcoma: Giant Exophytic Tumor of the Medial Canthus
by Rylee Moody, Kavita Darji, Tricia A. Missall, Peter Chow and Ramona Behshad
Dermatopathology 2024, 11(1), 13-18; https://doi.org/10.3390/dermatopathology11010003 - 29 Dec 2023
Viewed by 2304
Abstract
We present the case of a 99-year-old Caucasian female who was referred for treatment of a painless, 8.0 cm × 7.8 cm exophytic, pedunculated, ulcerated tumor of the left medial canthus. Pathology showed spindled, oval, and polygonal cells with pleomorphic nuclei. Many multinuclear [...] Read more.
We present the case of a 99-year-old Caucasian female who was referred for treatment of a painless, 8.0 cm × 7.8 cm exophytic, pedunculated, ulcerated tumor of the left medial canthus. Pathology showed spindled, oval, and polygonal cells with pleomorphic nuclei. Many multinuclear giant cells and mitotic figures were also noted. The tumor was highlighted with CD10, showed focal positivity with actin, desmin, and CD68, and had increased Ki67 immunohistochemical staining. The tumor was negative for pancytokeratin, CK5/6, p63, MART-1/MelanA, S100, Sox10, p40, CD34, and CD23. Based on clinicopathologic correlation, the diagnosis of pleomorphic dermal sarcoma (PDS) was made. Pleomorphic dermal sarcoma (PDS) refers to a deep, histologically high-grade tumor that often resembles other tumors clinically and histologically. As PDS is frequently aggressive and related to adverse outcomes, it is important to recognize its distinguishing features in comparison to other similar entities, including atypical fibroxanthoma (AFX) and pleomorphic leiomyosarcoma (PLMS). To our knowledge, there is only one other reported case in the literature of PDS occurring on the eye. By reviewing and understanding characteristic etiologies, locations of presentation, histopathological features, and management techniques, pathologists can make a more accurate diagnosis and dermatologists can provide more effective patient care in a timely manner. Full article
(This article belongs to the Special Issue Educational Case Reports in Dermatopathology)
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20 pages, 1459 KiB  
Review
Practical Management of Adult Ultra-Rare Primary Retroperitoneal Soft Tissue Sarcoma: A Focus on Perivascular Epithelioid Tumours and Extraosseous Ewing Sarcoma
by Sameer S. Apte, Eyal Mor, Catherine Mitchell and David E. Gyorki
Curr. Oncol. 2023, 30(7), 5953-5972; https://doi.org/10.3390/curroncol30070445 - 21 Jun 2023
Cited by 4 | Viewed by 3246
Abstract
With the exception of well-differentiated liposarcoma, dedifferentiated liposarcoma, leiomyosarcoma, solitary fibrous tumour, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma, the majority of the ≈70 histologic subtypes of retroperitoneal sarcoma are defined as ‘ultra-rare’ sarcomas, with an incidence of ≤1–5/1,000,000 persons/year. For [...] Read more.
With the exception of well-differentiated liposarcoma, dedifferentiated liposarcoma, leiomyosarcoma, solitary fibrous tumour, malignant peripheral nerve sheath tumour, and undifferentiated pleomorphic sarcoma, the majority of the ≈70 histologic subtypes of retroperitoneal sarcoma are defined as ‘ultra-rare’ sarcomas, with an incidence of ≤1–5/1,000,000 persons/year. For most of these ultra-rare RPS subtypes, diagnosis and treatment follows international guidelines for the management of more common RPS histologies, with en bloc surgical resection as the mainstay of curative treatment, and enrolment in clinical trials where possible. Because the treatment of RPS is heavily driven by histology, the surgeon must be familiar with specific issues related to the diagnosis and management of ultra-rare sarcoma subtypes. Expert radiological and surgeon reviews are required to differentiate similarly presenting tumours where surgery can be avoided (e.g., angiomyolipoma), or where upfront systemic therapy is indicated (e.g., extraosseous Ewing’s sarcoma). Thus, the management of all retroperitoneal sarcomas should occur at a sarcoma referral centre, with a multidisciplinary team of experts dedicated to the surgical and medical management of these rare tumours. In this focused review, we highlight how diagnosis and management of the ultra-rare primary RPS histologies of malignant perivascular epithelioid cell tumour (PEComa), extraosseous Ewing sarcoma (EES), extraosseous osteosarcoma (EOS), and rhabdomyosarcoma (RMS) critically diverge from the management of more common RPS subtypes. Full article
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14 pages, 1781 KiB  
Review
Clinical and Dermoscopic Characteristics of Cutaneous Sarcomas: A Literature Review
by Zoe Apalla, Konstantinos Liopyris, Eirini Kyrmanidou, Christina Fotiadou, Dimitrios Sgouros, Aikaterini Patsatsi, Myrto-Georgia Trakatelli, Evangelia Kalloniati, Aimilios Lallas and Elizabeth Lazaridou
Diagnostics 2023, 13(10), 1822; https://doi.org/10.3390/diagnostics13101822 - 22 May 2023
Cited by 10 | Viewed by 4615
Abstract
Under the umbrella of cutaneous sarcomas (CS) we include a heterogeneous group of rare, malignant, mesenchymal neoplasia, such as dermatofibrosarcoma protuberans, atypical fibroxanthoma, cutaneous undifferentiated pleomorphic sarcoma, cutaneous angiosarcoma and leiomyosarcoma. Clinical presentation and histopathological examination are the cornerstone of CS diagnosis and [...] Read more.
Under the umbrella of cutaneous sarcomas (CS) we include a heterogeneous group of rare, malignant, mesenchymal neoplasia, such as dermatofibrosarcoma protuberans, atypical fibroxanthoma, cutaneous undifferentiated pleomorphic sarcoma, cutaneous angiosarcoma and leiomyosarcoma. Clinical presentation and histopathological examination are the cornerstone of CS diagnosis and classification. There are scarce data in the literature in regards to the clinical and dermatoscopic characteristics of CS and the role of dermatoscopy in their early identification. We performed a literature review, aiming to summarize current data on the clinical and dermatoscopic presentation of the most common types of cutaneous sarcomas that may facilitate early diagnosis and prompt management. Based on the available published data, CS are characterized by mostly unspecific dermatoscopic patterns. Dermatofibrosarcoma protuberans, Kaposi’s sarcoma, and in a lesser degree, cutaneous angiosarcoma, may display distinct dermatoscopic features, facilitating their early clinical recognition. In conclusion, dermatoscopy, in conjunction with the overall clinical context, may aid towards suspicion of CS. Full article
(This article belongs to the Special Issue Skin and Cutaneous Adnexal Tumors: Diagnosis and Management)
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12 pages, 1573 KiB  
Article
Individualized Mini-Panel Sequencing of ctDNA Allows Tumor Monitoring in Complex Karyotype Sarcomas
by David Braig, Alexander Runkel, Anja E. Eisenhardt, Adrian Schmid, Johannes Zeller, Thomas Pauli, Ute Lausch, Julius Wehrle, Peter Bronsert, Matthias Jung, Jurij Kiefer, Melanie Boerries and Steffen U. Eisenhardt
Int. J. Mol. Sci. 2022, 23(18), 10215; https://doi.org/10.3390/ijms231810215 - 6 Sep 2022
Cited by 4 | Viewed by 2263
Abstract
Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For [...] Read more.
Soft tissue sarcomas (STS) are rare tumors of mesenchymal origin with high mortality. After curative resection, about one third of patients suffer from distant metastases. Tumor follow-up only covers a portion of recurrences and is associated with high cost and radiation burden. For metastasized STS, only limited inferences can be drawn from imaging data regarding therapy response. To date there are no established and evidence-based diagnostic biomarkers for STS due to their rarity and diversity. In a proof-of-concept study, circulating tumor DNA (ctDNA) was quantified in (n = 25) plasma samples obtained from (n = 3) patients with complex karyotype STS collected over three years. Genotyping of tumor tissue was performed by exome sequencing. Patient-individual mini-panels for targeted next-generation sequencing were designed encompassing up to 30 mutated regions of interest. Circulating free DNA (cfDNA) was purified from plasma and ctDNA quantified therein. ctDNA values were correlated with clinical parameters. ctDNA concentrations correlated with the tumor burden. In case of full remission, no ctDNA was detectable. Patients with a recurrence at a later stage showed low levels of ctDNA during clinical remission, indicating minimal residual disease. In active disease (primary tumor or metastatic disease), ctDNA was highly elevated. We observed direct response to treatment, with a ctDNA decline after tumor resections, radiotherapy, and chemotherapy. Quantification of ctDNA allows for the early detection of recurrence or metastases and can be used to monitor treatment response in STS. Therapeutic decisions can be made earlier, such as the continuation of a targeted adjuvant therapy or the implementation of extended imaging to detect recurrences. In metastatic disease, therapy can be adjusted promptly in case of no response. These advantages may lead to a survival benefit for patients in the future. Full article
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19 pages, 9446 KiB  
Article
ERK5 Is a Major Determinant of Chemical Sarcomagenesis: Implications in Human Pathology
by Elena Arconada-Luque, Jaime Jiménez-Suarez, Raquel Pascual-Serra, Syong Hyun Nam-Cha, Teresa Moline, Francisco J. Cimas, Germán Fliquete, Marta Ortega-Muelas, Olga Roche, Diego M. Fernández-Aroca, Raúl Muñoz Velasco, Natalia García-Flores, Cristina Garnés-García, Adrián Sánchez-Fdez, Sofía Matilla-Almazán, Víctor J. Sánchez-Arévalo Lobo, Javier Hernández-Losa, Borja Belandia, Atanasio Pandiella, Azucena Esparís-Ogando, Santiago Ramón y Cajal, Luis del Peso, Ricardo Sánchez-Prieto and María José Ruiz-Hidalgoadd Show full author list remove Hide full author list
Cancers 2022, 14(14), 3509; https://doi.org/10.3390/cancers14143509 - 19 Jul 2022
Cited by 2 | Viewed by 4404
Abstract
Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with [...] Read more.
Sarcomas are a heterogeneous group of tumors in which the role of ERK5 is poorly studied. To clarify the role of this MAPK in sarcomatous pathology, we used a murine 3-methyl-cholanthrene (3MC)-induced sarcoma model. Our data show that 3MC induces pleomorphic sarcomas with muscle differentiation, showing an increased expression of ERK5. Indeed, this upregulation was also observed in human sarcomas of muscular origin, such as leiomyosarcoma or rhabdomyosarcoma. Moreover, in cell lines derived from these 3MC-induced tumors, abrogation of Mapk7 expression by using specific shRNAs decreased in vitro growth and colony-forming capacity and led to a marked loss of tumor growth in vivo. In fact, transcriptomic profiling in ERK5 abrogated cell lines by RNAseq showed a deregulated gene expression pattern for key biological processes such as angiogenesis, migration, motility, etc., correlating with a better prognostic in human pathology. Finally, among the various differentially expressed genes, Klf2 is a key mediator of the biological effects of ERK5 as indicated by its specific interference, demonstrating that the ERK5–KLF2 axis is an important determinant of sarcoma biology that should be further studied in human pathology. Full article
(This article belongs to the Special Issue Advances in Translational Research for Soft Tissue Sarcomas)
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18 pages, 2865 KiB  
Review
Clinical and Molecular Insights of Radiation-Induced Breast Sarcomas: Is There Hope on the Horizon for Effective Treatment of This Aggressive Disease?
by Stefania Kokkali, Jose Duran Moreno, Jerzy Klijanienko and Stamatios Theocharis
Int. J. Mol. Sci. 2022, 23(8), 4125; https://doi.org/10.3390/ijms23084125 - 8 Apr 2022
Cited by 16 | Viewed by 3649
Abstract
Radiation-induced breast sarcomas (RIBS) are rare entities representing <1% of all primary breast malignancies, limiting most reports to small retrospective case series. They constitute a heterogeneous group of neoplasms, with high-grade angiosarcoma being the most common subtype. Other sarcoma histotypes, such as undifferentiated [...] Read more.
Radiation-induced breast sarcomas (RIBS) are rare entities representing <1% of all primary breast malignancies, limiting most reports to small retrospective case series. They constitute a heterogeneous group of neoplasms, with high-grade angiosarcoma being the most common subtype. Other sarcoma histotypes, such as undifferentiated pleomorphic sarcoma and leiomyosarcoma, can also be identified. Radiation-induced breast angiosarcoma (RIBA) has an incidence of approximately 0.1% after breast-conserving therapy and arises mainly from the dermis of the irradiated breast. MYC gene amplification is highly indicative of secondary breast angiosarcomas. Their clinical presentation often mimics benign port-radiation lesions, leading to a delay in diagnosis and a lost window of opportunity for cure. Surgery with negative margins is the mainstay of treatment of localized RIBS. In the case of angiosarcoma, technical difficulties, including multifocality, infiltrative margins, and difficulty in assessing tumor margins, render surgical treatment quite challenging. A limited number of studies showed that adjuvant radiation therapy reduces local recurrences; therefore, it is proposed by many groups for large, high-grade tumors. Chemotherapy has been evaluated retrospectively in a small subset of patients, with some evidence supporting its use in angiosarcoma patients. Approximately half of patients with RIBA will show local recurrence. In the advanced setting, different therapeutic options are discussed in the review, including chemotherapy, antiangiogenic therapy, and immunotherapy, whereas the need for further research on molecular therapeutic targets is pointed out. Full article
(This article belongs to the Special Issue Molecular Advances in Cancer Therapy)
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14 pages, 3177 KiB  
Case Report
Characteristic of Uterine Rhabdomyosarcoma by Algorithm of Potential Biomarkers for Uterine Mesenchymal Tumor
by Saya Tamura, Takuma Hayashi, Tomoyuki Ichimura, Nobuo Yaegashi, Kaoru Abiko and Ikuo Konishi
Curr. Oncol. 2022, 29(4), 2350-2363; https://doi.org/10.3390/curroncol29040190 - 28 Mar 2022
Cited by 5 | Viewed by 3545
Abstract
Background/Aim: Patients with uterine sarcoma comprise 2–5% of all patients with uterine malignancies; however, the morbidity of uterine sarcoma is low compared with that of other gynecological cancers. For many cases, malignant uterine tumors are diagnosed during follow-up of benign uterine leiomyoma. Of [...] Read more.
Background/Aim: Patients with uterine sarcoma comprise 2–5% of all patients with uterine malignancies; however, the morbidity of uterine sarcoma is low compared with that of other gynecological cancers. For many cases, malignant uterine tumors are diagnosed during follow-up of benign uterine leiomyoma. Of the uterine sarcomas, rhabdomyosarcoma is considered a mixed tumor containing components of epithelial cells and mesenchymal cells. Therefore, the onset of primary uterine rhabdomyosarcoma during follow-up of uterine leiomyoma is extremely rare. Rhabdomyosarcoma is a relatively common malignant tumor in children, but rhabdomyosarcoma in adults is extremely rare, accounting for approximately 3% of all patients with soft tissue sarcoma. Rhabdomyosarcoma in children is highly sensitive to chemotherapy and radiation therapy; however, the response to chemotherapy and radiation therapy in adult rhabdomyosarcoma is low and survival in adult rhabdomyosarcoma with metastatic lesions to other organs is approximately 14 months. We experienced a case of pleomorphic rhabdomyosarcoma during the follow-up of a uterine leiomyoma. Materials and Methods: We examined the oncological properties of uterine rhabdomyosarcoma in adults using molecular pathological techniques on tissue excised from patients with uterine leiomyoma. Result: A differential diagnosis was made for this case by molecular pathology, which included candidate biomarkers for uterine smooth muscle tumors. The oncological nature of uterine rhabdomyosarcoma was found to be similar to the oncological properties of uterine leiomyosarcoma. However, in uterine rhabdomyosarcoma, LMP2/β1i-positive cells were clearly observed. Conclusion: It is expected that establishing a diagnostic and treatment method targeting characteristics of mesenchymal tumor cells will lead to the treatment of malignant tumors with a low risk of recurrence and metastasis. Full article
(This article belongs to the Topic Soft Tissue Sarcomas: Treatment and Management)
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14 pages, 2005 KiB  
Review
A Multidisciplinary Approach to Complex Dermal Sarcomas Ensures an Optimal Clinical Outcome
by Hannah Trøstrup, Amir K. Bigdeli, Christina Krogerus, Ulrich Kneser, Grethe Schmidt and Volker J. Schmidt
Cancers 2022, 14(7), 1693; https://doi.org/10.3390/cancers14071693 - 26 Mar 2022
Cited by 7 | Viewed by 6207
Abstract
Primary dermal sarcomas (PDS) belong to a highly clinically, genetically and pathologically heterogeneous group of rare malignant mesenchymal tumours primarily involving the dermis or the subcutaneous tissue. The tumours are classified according to the mesenchymal tissue from which they originate: dermal connective tissue, [...] Read more.
Primary dermal sarcomas (PDS) belong to a highly clinically, genetically and pathologically heterogeneous group of rare malignant mesenchymal tumours primarily involving the dermis or the subcutaneous tissue. The tumours are classified according to the mesenchymal tissue from which they originate: dermal connective tissue, smooth muscle or vessels. Clinically, PDS may mimic benign soft tissue lesions such as dermatofibromas, hypertrophic scarring, etc. This may cause substantial diagnostic delay. As a group, PDS most commonly comprises the following clinicopathological forms of dermal sarcomas: dermatofibrosarcoma protuberans (DFSP), atypical fibroxanthoma (AFX), dermal undifferentiated pleomorphic sarcoma (DUPS), leiomyosarcoma (LMS), and vascular sarcomas (Kaposi’s sarcoma, primary angiosarcoma, and radiation-induced angiosarcoma). This clinical entity has a broad spectrum regarding malignant potential; however, local aggressive behaviour in some forms causes surgical challenges. Preoperative, individualised surgical planning with complete free margins is pivotal along with a multidisciplinary approach and collaboration across highly specialised surgical and medical specialties. The present review gives a structured overview of the most common forms of dermal sarcomas including surgical recommendations and examples for advanced reconstructions as well as the current adjunctive medical treatment strategies. Optimal aesthetic and functional outcomes with low recurrence rates can be achieved by using a multidisciplinary approach to complex dermal sarcomas. In cases of extended local tumour invasion in dermal sarcomas, advanced reconstructive techniques can be applied, and the interdisciplinary microsurgeon should be an integral part of the sarcoma board. Full article
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17 pages, 4258 KiB  
Article
GPR64, Screened from Ewing Sarcoma Cells, Is a Potential Target for Antibody-Based Therapy for Various Sarcomas
by Koichi Nakamura, Kunihiro Asanuma, Takayuki Okamoto, Keisuke Yoshida, Yumi Matsuyama, Kouji Kita, Tomohito Hagi, Tomoki Nakamura and Akihiro Sudo
Cancers 2022, 14(3), 814; https://doi.org/10.3390/cancers14030814 - 5 Feb 2022
Cited by 8 | Viewed by 3338
Abstract
Ewing sarcoma is an aggressive and the second most common bone tumor in adolescent and young adult patients. The 5-year survival rate is 60–70% for localized disease but 30% for patients with metastases. Here, we aimed to identify a therapeutic target for Ewing [...] Read more.
Ewing sarcoma is an aggressive and the second most common bone tumor in adolescent and young adult patients. The 5-year survival rate is 60–70% for localized disease but 30% for patients with metastases. Here, we aimed to identify a therapeutic target for Ewing sarcoma and evaluate antibody-based therapeutic agents using in vitro and in vivo models. We identified G protein-coupled receptor 64 (GPR64) as a therapeutic target for Ewing sarcoma via next-generation RNA-sequencing. GPR64v205 mRNA was expressed in HTB166, A673, MG63, 143B, HS-Sy II, and HT1080 cell lines as well as in Ewing sarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, and synovial sarcoma tissues. GPR64 expression was observed in 62.5% of sarcoma cases and was overexpressed in 33.9% cases. GPR64-specific monoclonal antibodies were tested as near-infrared probes for in vivo imaging using subcutaneous tumor mouse xenografts. Fluorescence intensity was stronger for the AF700-labeled anti-GPR64 antibody than that for the AF700-labeled isotype control antibody. GPR64 was detected in engrafted tumors of A673, 143B, HT1080, and the epididymis but not in other resected tissues. The anti-GPR64 antibody showed excellent binding to GPR64-positive tumors but not to healthy tissues. This antibody has potential for drug delivery in the antibody-based treatment of sarcomas. Full article
(This article belongs to the Special Issue Immunotherapy for Solid Tumors)
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