Journal of Clinical Medicine

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10 pages, 848 KiB

Open AccessArticle

Does the Use of Peripheral Immune-Related Markers Indicate Whether to Administer Pazopanib, Trabectedin, or Eribulin to Advanced Soft Tissue Sarcoma Patients?

by Eijiro Shimada, Makoto Endo, Yoshihiro Matsumoto, Kenji Tsuchihashi, Mamoru Ito, Hitoshi Kusaba, Akira Nabeshima, Tomoya Nawata, Akira Maekawa, Tomoya Matsunobu, Nokitaka Setsu, Toshifumi Fujiwara, Keiichiro Iida, Makoto Nakagawa, Takeshi Hirose, Masaya Kanahori, Ryunosuke Oyama, Taichi Isobe, Hiroshi Ariyama, Kenichi Kohashi, Hidetaka Yamamoto, Yoshinao Oda, Yukihide Iwamoto, Koichi Akashi, Eishi Baba and Yasuharu Nakashima Show full author list Hide full author list

J. Clin. Med. 2021, 10(21), 4972; https://doi.org/10.3390/jcm10214972 - 26 Oct 2021

Cited by 6 | Viewed by 2242

Abstract

Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when [...] Read more.

Pazopanib, trabectedin, and eribulin are administered for the treatment of soft tissue sarcomas (STSs); however, there is little consensus on which agent should be preferentially used in a clinical setting. This study assessed whether peripheral immune-related markers served as a useful reference when selecting pazopanib, trabectedin, or eribulin. This study included 63 patients who were administered pazopanib, trabectedin, or eribulin for advanced STSs between March 2015 and December 2020. Patients were divided into three groups based on the first drug administered among these three drugs. Differences in overall survival (OS) or progression-free survival (PFS) among the three groups were analyzed. OS showed no significant differences among the drugs administered first. For patients with low neutrophil-to-lymphocyte ratio (NLR), the OS of patients administered pazopanib as the first choice was shorter than the others (hazard ratio [HR] = 9.53, 95% confidence interval [CI] = 1.94–18.13, p = 0.0018). In the low platelet-to-lymphocyte ratio (PLR) subgroup, the OS of the patients administered eribulin for the first choice was longer than that of the others (HR = 0.32, 95%CI = 0.10–0.98, p = 0.046). Therefore, NLR and PLR might be used as prognostic indicators to dictate whether STS patients receive pazopanib, trabectedin, or eribulin. Full article

(This article belongs to the Special Issue Novel Pathogenic Mechanisms and Therapeutic Approaches for Sarcomas)

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11 pages, 15501 KiB

Open AccessArticle

Efficacy of Sirolimus Treatment in PEComa–10 Years of Practice Perspective

by Tomasz Świtaj, Aleksandra Sobiborowicz, Paweł Teterycz, Anna Klimczak, Donata Makuła, Michał Wągrodzki, Anna Szumera-Ciećkiewicz, Piotr Rutkowski and Anna M. Czarnecka

J. Clin. Med. 2021, 10(16), 3705; https://doi.org/10.3390/jcm10163705 - 20 Aug 2021

Cited by 14 | Viewed by 2779

Abstract

Perivascular epithelioid cell tumors (PEComa) represent a family of rare mesenchymal tumors resultant from deregulation in mTOR pathway activity. The aim of this study is to evaluate the long-term efficacy of targeted PEComa treatment. We reviewed all consecutive patients with PEComa who started [...] Read more.

Perivascular epithelioid cell tumors (PEComa) represent a family of rare mesenchymal tumors resultant from deregulation in mTOR pathway activity. The aim of this study is to evaluate the long-term efficacy of targeted PEComa treatment. We reviewed all consecutive patients with PEComa who started systemic treatment with sirolimus in our reference sarcoma center between January 2011 and August 2020. Histopathology of PEComa was reviewed and confirmed in all cases by a designated sarcoma pathologist. Any surviving progression-free patients were censored at the last follow-up (31 March 2021). Survival curves were calculated according to Kaplan–Meier method and compared with the log-rank test or a Cox proportional hazard model. Fifteen (12 females and 3 males) consecutive PEComa patients were treated. The median age of patients treated systemically was 50 years. Median progression-free survival (PFS) was 4.9 months (95% CI: 3.8-NA) for first-line chemotherapy and was not reached (95% CI: 42.0-NA) for sirolimus as first-line therapy. There was one objective response (OR) in the chemotherapy group. The OR rate reached 73% (11/15 cases) for sirolimus regardless of the treatment line. All patients archived disease control. Three patients died due to disease progression after 55, 32, and 32 months since metastatic disease diagnosis. After a median follow-up of 55.7 (range: 3.2–220) months, the 5 yr OS was 65% (CI 95% 39–100). Our study is the largest single-institution report on PEComa systemic targeted therapy and fills the gap in the field of advanced PEComa care since the FDA/EMEA approval of sirolimus. Full article

(This article belongs to the Special Issue Novel Pathogenic Mechanisms and Therapeutic Approaches for Sarcomas)

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28 pages, 27174 KiB

Open AccessArticle

Complex Interplay of Genes Underlies Invasiveness in Fibrosarcoma Progression Model

by Michaela Kripnerová, Hamendra Singh Parmar, Jiří Šána, Alena Kopková, Lenka Radová, Sieghart Sopper, Krzysztof Biernacki, Jan Jedlička, Michaela Kohoutová, Jitka Kuncová, Jan Peychl, Emil Rudolf, Miroslav Červinka, Zbyněk Houdek, Pavel Dvořák, Kateřina Houfková, Martin Pešta, Zdeněk Tůma, Martina Dolejšová, Filip Tichánek, Václav Babuška, Martin Leba, Ondřej Slabý and Jiří Hatina Show full author list Hide full author list

J. Clin. Med. 2021, 10(11), 2297; https://doi.org/10.3390/jcm10112297 - 25 May 2021

Viewed by 3430

Abstract

Sarcomas are a heterogeneous group of mesenchymal tumours, with a great variability in their clinical behaviour. While our knowledge of sarcoma initiation has advanced rapidly in recent years, relatively little is known about mechanisms of sarcoma progression. JUN-murine fibrosarcoma progression series consists of [...] Read more.

Sarcomas are a heterogeneous group of mesenchymal tumours, with a great variability in their clinical behaviour. While our knowledge of sarcoma initiation has advanced rapidly in recent years, relatively little is known about mechanisms of sarcoma progression. JUN-murine fibrosarcoma progression series consists of four sarcoma cell lines, JUN-1, JUN-2, JUN-2fos-3, and JUN-3. JUN-1 and -2 were established from a single tumour initiated in a H2K/v-jun transgenic mouse, JUN-3 originates from a different tumour in the same animal, and JUN-2fos-3 results from a targeted in vitro transformation of the JUN-2 cell line. The JUN-1, -2, and -3 cell lines represent a linear progression from the least transformed JUN-2 to the most transformed JUN-3, with regard to all the transformation characteristics studied, while the JUN-2fos-3 cell line exhibits a unique transformation mode, with little deregulation of cell growth and proliferation, but pronounced motility and invasiveness. The invasive sarcoma sublines JUN-2fos-3 and JUN-3 show complex metabolic profiles, with activation of both mitochondrial oxidative phosphorylation and glycolysis and a significant increase in spared respiratory capacity. The specific transcriptomic profile of invasive sublines features very complex biological relationships across the identified genes and proteins, with accentuated autocrine control of motility and angiogenesis. Pharmacologic inhibition of one of the autocrine motility factors identified, Ccl8, significantly diminished both motility and invasiveness of the highly transformed fibrosarcoma cell. This progression series could be greatly valuable for deciphering crucial aspects of sarcoma progression and defining new prognostic markers and potential therapeutic targets. Full article

(This article belongs to the Special Issue Novel Pathogenic Mechanisms and Therapeutic Approaches for Sarcomas)

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14 pages, 14604 KiB

Open AccessArticle

Feasibility and Long-Term Efficacy of PEComa Treatment—20 Years of Experience

by Aleksandra Sobiborowicz, Tomasz Świtaj, Paweł Teterycz, Mateusz J. Spałek, Anna Szumera-Ciećkiewicz, Michał Wągrodzki, Marcin Zdzienicki, Anna M. Czarnecka and Piotr Rutkowski

J. Clin. Med. 2021, 10(10), 2200; https://doi.org/10.3390/jcm10102200 - 19 May 2021

Cited by 13 | Viewed by 3471

Abstract

Perivascular epithelioid cell tumors (PEComas) represent a family of rare mesenchymal neoplasms, some of which are malignant. There are no specific management guidelines for PEComas, and factors correlating with the disease course are not well defined. This analysis aimed to describe the outcomes [...] Read more.

Perivascular epithelioid cell tumors (PEComas) represent a family of rare mesenchymal neoplasms, some of which are malignant. There are no specific management guidelines for PEComas, and factors correlating with the disease course are not well defined. This analysis aimed to describe the outcomes of PEComa patients treated radically, including those treated exclusively in the national reference sarcoma center. The secondary aim of the study was to analyze factors associated with PEComa treatment efficacy. We performed an analysis of 27 patients subsequently treated radically for PEComa between 1999 and 2019 who were in follow-up in the national sarcoma reference center. The proportional-hazards model was used to compare the risk of death. The median age at diagnosis was 45 (21–67) years, and 67% of patients were female. The median follow-up period was 68 months (95% CI: 39–101). At the time of analysis, eleven patients (40.7%) experienced progression of the disease and four (14.8%) died. Surgery in the reference sarcoma center was associated with a longer disease control (log-rank p < 0.001). The 5-year-OS rate was 88% (95% CI: 74–100) for the whole analyzed group. We concluded that PEComa treatment should be managed in reference sarcoma centers by a multidisciplinary tumor board with an experienced surgical team. Microscopically radical resection is associated with a longer disease-free survival. Patients requiring long-term follow-ups as late recurrence may be expected. Full article

(This article belongs to the Special Issue Novel Pathogenic Mechanisms and Therapeutic Approaches for Sarcomas)

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15 pages, 3022 KiB

Open AccessArticle

Nano-Encapsulation of Mithramycin in Transfersomes and Polymeric Micelles for the Treatment of Sarcomas

by Óscar Estupiñán, Claudia Rendueles, Paula Suárez, Verónica Rey, Dzohara Murillo, Francisco Morís, Gemma Gutiérrez, María del Carmen Blanco-López, María Matos and René Rodríguez

J. Clin. Med. 2021, 10(7), 1358; https://doi.org/10.3390/jcm10071358 - 25 Mar 2021

Cited by 11 | Viewed by 3159

Abstract

Sarcomas are aggressive tumors which often show a poor response to current treatments. As a promising therapeutic alternative, we focused on mithramycin (MTM), a natural antibiotic with a promising anti-tumor activity but also a relevant systemic toxicity. Therefore, the encapsulation of MTM in [...] Read more.

Sarcomas are aggressive tumors which often show a poor response to current treatments. As a promising therapeutic alternative, we focused on mithramycin (MTM), a natural antibiotic with a promising anti-tumor activity but also a relevant systemic toxicity. Therefore, the encapsulation of MTM in nano-delivery systems may represent a way to increase its therapeutic window. Here, we designed novel transfersomes and PLGA polymeric micelles by combining different membrane components (phosphatidylcholine, Span 60, Tween 20 and cholesterol) to optimize the nanoparticle size, polydispersity index (PDI) and encapsulation efficiency (EE). Using both thin film hydration and the ethanol injection methods we obtained MTM-loaded transferosomes displaying an optimal hydrodynamic diameter of 100–130 nm and EE values higher than 50%. Additionally, we used the emulsion/solvent evaporation method to synthesize polymeric micelles with a mean size of 228 nm and a narrow PDI, capable of encapsulating MTM with EE values up to 87%. These MTM nano-delivery systems mimicked the potent anti-tumor activity of free MTM, both in adherent and cancer stem cell-enriched tumorsphere cultures of myxoid liposarcoma and chondrosarcoma models. Similarly to free MTM, nanocarrier-delivered MTM efficiently inhibits the signaling mediated by the pro-oncogenic factor SP1. In summary, we provide new formulations for the efficient encapsulation of MTM which may constitute a safer delivering alternative to be explored in future clinical uses. Full article

(This article belongs to the Special Issue Novel Pathogenic Mechanisms and Therapeutic Approaches for Sarcomas)

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Review

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19 pages, 2048 KiB

Open AccessReview

Cancer Stem Cells as a Source of Drug Resistance in Bone Sarcomas

by Sofía T. Menéndez, Borja Gallego, Dzohara Murillo, Aida Rodríguez and René Rodríguez

J. Clin. Med. 2021, 10(12), 2621; https://doi.org/10.3390/jcm10122621 - 14 Jun 2021

Cited by 28 | Viewed by 3902

Abstract

Bone sarcomas are commonly characterized by a high degree of intra-tumor heterogeneity, which in part is due to the presence of subpopulations of tumor cells presenting stem cell properties. Similar to normal stem cells, these cancer stem cells (CSCs) display a drug resistant [...] Read more.

Bone sarcomas are commonly characterized by a high degree of intra-tumor heterogeneity, which in part is due to the presence of subpopulations of tumor cells presenting stem cell properties. Similar to normal stem cells, these cancer stem cells (CSCs) display a drug resistant phenotype and therefore are responsible for relapses and tumor dissemination. Drug resistance in bone sarcomas could be enhanced/modulated during tumor evolution though the acquisition of (epi)-genetic alterations and the adaptation to changing microenvironments, including drug treatments. Here we summarize findings supporting the involvement of pro-stemness signaling in the development of drug resistance in bone sarcomas. This include the activation of well-known pro-stemness pathways (Wnt/β-Cat, NOTCH or JAT/STAT pathways), changes in the metabolic and autophagic activities, the alteration of epigenetic pathways, the upregulation of specific non-coding RNAs and the crosstalk with different microenvironmental factors. This altered signaling is expected to be translated to the clinic in the form of biomarkers of response and new therapies able to overcome drug resistance. Full article

(This article belongs to the Special Issue Novel Pathogenic Mechanisms and Therapeutic Approaches for Sarcomas)

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17 pages, 1163 KiB

Open AccessReview

Pathogenesis and Current Treatment of Osteosarcoma: Perspectives for Future Therapies

by Richa Rathore and Brian A. Van Tine

J. Clin. Med. 2021, 10(6), 1182; https://doi.org/10.3390/jcm10061182 - 12 Mar 2021

Cited by 62 | Viewed by 7409

Abstract

Osteosarcoma is the most common primary malignant bone tumor in children and young adults. The standard-of-care curative treatment for osteosarcoma utilizes doxorubicin, cisplatin, and high-dose methotrexate, a standard that has not changed in more than 40 years. The development of patient-specific therapies requires [...] Read more.

Osteosarcoma is the most common primary malignant bone tumor in children and young adults. The standard-of-care curative treatment for osteosarcoma utilizes doxorubicin, cisplatin, and high-dose methotrexate, a standard that has not changed in more than 40 years. The development of patient-specific therapies requires an in-depth understanding of the unique genetics and biology of the tumor. Here, we discuss the role of normal bone biology in osteosarcomagenesis, highlighting the factors that drive normal osteoblast production, as well as abnormal osteosarcoma development. We then describe the pathology and current standard of care of osteosarcoma. Given the complex heterogeneity of osteosarcoma tumors, we explore the development of novel therapeutics for osteosarcoma that encompass a series of molecular targets. This analysis of pathogenic mechanisms will shed light on promising avenues for future therapeutic research in osteosarcoma. Full article

(This article belongs to the Special Issue Novel Pathogenic Mechanisms and Therapeutic Approaches for Sarcomas)

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23 pages, 21860 KiB

Open AccessReview

Cold Atmospheric Plasma: A New Strategy Based Primarily on Oxidative Stress for Osteosarcoma Therapy

by Miguel Mateu-Sanz, Juan Tornín, Maria-Pau Ginebra and Cristina Canal

J. Clin. Med. 2021, 10(4), 893; https://doi.org/10.3390/jcm10040893 - 23 Feb 2021

Cited by 38 | Viewed by 6193

Abstract

Osteosarcoma is the most common primary bone tumor, and its first line of treatment presents a high failure rate. The 5-year survival for children and teenagers with osteosarcoma is 70% (if diagnosed before it has metastasized) or 20% (if spread at the time [...] Read more.

Osteosarcoma is the most common primary bone tumor, and its first line of treatment presents a high failure rate. The 5-year survival for children and teenagers with osteosarcoma is 70% (if diagnosed before it has metastasized) or 20% (if spread at the time of diagnosis), stressing the need for novel therapies. Recently, cold atmospheric plasmas (ionized gases consisting of UV–Vis radiation, electromagnetic fields and a great variety of reactive species) and plasma-treated liquids have been shown to have the potential to selectively eliminate cancer cells in different tumors through an oxidative stress-dependent mechanism. In this work, we review the current state of the art in cold plasma therapy for osteosarcoma. Specifically, we emphasize the mechanisms unveiled thus far regarding the action of plasmas on osteosarcoma. Finally, we review current and potential future approaches, emphasizing the most critical challenges for the development of osteosarcoma therapies based on this emerging technique. Full article

(This article belongs to the Special Issue Novel Pathogenic Mechanisms and Therapeutic Approaches for Sarcomas)

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