Epithelioid sarcoma: Difference between revisions

Epithelioid sarcoma
Epithelioid sarcoma
	Micrograph of an epithelioid sarcoma. H&E stain.
Specialty	Oncology

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Epithelioid sarcoma is a rare soft tissue sarcoma arising from mesenchymal tissue and characterized by epithelioid-like features. It accounts for less than 1% of all soft tissue sarcomas. It was first definitively characterized by F.M. Enzinger in 1970.^[1] It commonly presents itself in the distal limbs (fingers, hands, forearms, or feet) of young adults as a small, soft mass or a cluster of bumps. A proximal version has also been described, frequently occurring in the upper extremities.^[2] Less commonly, cases are reported in the pelvis, vulva, penis, and spine.

Histologically, epithelioid sarcoma forms nodules with central necrosis surrounded by bland, polygonal cells with eosinophilic cytoplasm and peripheral spindling.^[3] Epithelioid sarcomas typically express vimentin, cytokeratins, epithelial membrane antigen, and CD34, whereas they are usually negative for S100, desmin, and FLI1 (FLI-1).^[3] They characteristically lack the protein INI1 (see below). Epithelioid sarcomas typically stain positive for CA125.^[4]

Epithelioid sarcoma most commonly strikes young adults, yet no age group is immune. The disease has a tendency to develop local recurrences and metastasis thereafter to regional lymph nodes, lung, bone, brain, and other locations.^[3] Generally speaking, epithelioid sarcoma has a high rate of relapse after initial treatment and tends to recur locally or regionally (at or near the original tumor site). Epithelioid sarcoma also demonstrates lymphatic spread (in 22-48% of cases), and metastasis (in 21-63% of cases).^[5] These events, as well as advanced stage (progression) and grade (aggressiveness), are predictive of an overall worse outcome. Associated with a more positive outcome are younger age, female vs. male sex, distal vs. proximal location, smaller tumor size, and negative margins upon tumor resection.^[1]^[6]^[7]

Signs and symptoms

Epithelioid sarcoma is a slow-growing and relatively painless tumor, often resulting in a lengthy period of time between presentation and diagnosis.^[8] Due to the difficulty of discerning this cancer as different from more common cancers, such as cancers of the skin (squamous cell carcinoma or basal cell carcinoma), it is often misdiagnosed, mistaken as a persistent wart or cyst. It most commonly presents itself in the distal limbs (fingers, hands, forearms, or feet) as a small, soft mass or a cluster of nodules. It is most often described as a firm-to-hard palpable mass, either in the deep soft tissue or in the dermis. These cancers can form a crater or ulcer, leading to a mistaken diagnosis of a poorly healing traumatic wound or wart. About 13% of patients present with multifocal tumors, and about 13% of patients present with metastatic disease.^[9]

Genetics

The most common genetic mutation (found in 80-90% of epithelioid sarcomas) is the inactivation of the SMARCB1 gene, or the loss of protein INI1 function,.^[10]^[11] Epithelioid sarcoma typically contains chromosome 22q11.2 mutations or deletions and 8q gains. Aberrations of 18q as well as recurrent gains at 11q13, have also been observed.^[12]^[13]^[14]

The SMARCB1 gene (whose protein product is termed BAF47, INI1, or hSNF5) is located on chromosome 22q11.2.^[10] It codes for a member of the SWI/SNF chromatin remodeling complex. Loss of SMARCB1 function is the most common genetic mutation observed in epithelioid sarcoma, and this dysfunction is likely a major driver of disease progression. SMARCB1 is a core protein subunit of the 15 subunit SWI/SNF (or BAF) complex involved in regulating the packaging of DNA in the cell nucleus.^[10] It has been shown to be a potent tumor suppressor gene,^[11]^[15] meaning that its primary role is to control cell division. Since this tumor suppressor is commonly inactivated in epithelioid sarcoma, cell division can fail to appropriately stop, resulting in uncontrolled cancer growth. Research teams are trying to develop ways to reverse this loss of genetic function characteristic of epithelioid sarcoma.^[8]

Molecular biology

A number of important proteins appear to be active in epithelioid sarcoma. Some of these are described below.

VEGF

VEGF (vascular endothelial growth factor) is often over-expressed in epithelioid sarcoma.^[16] This is a critical pathway in angiogenesis, a process that cancer cells use to form new blood vessels, which provide necessary elements to the tumor for tumor survival. Anti-VEGF agents such as pazopanib are approved for use in carcinomas and in soft tissue sarcomas such as epithelioid sarcoma, though access to these medications varies from country to country.^[17]

MET

MET (mesenchymal to epithelial transition) is a biological pathway that appears to be important for the development and progression of epithelioid sarcoma.^[18]^[19] MET is a tyrosine kinase oncogene, and its signaling pathway has been implicated in a variety of malignancies, including many cancers.^[20]

Sonic hedgehog and Notch

The Sonic hedgehog (SHH) and Notch signaling pathways appear to be active in epithelioid sarcoma. These cell signaling pathways control cellular proliferation and differentiation. They are also involved in cancer stem cell coordination and disease invasiveness and metastasis. Hhat inhibitors (such as RU-SKI 43) block the SHH pathway by inhibiting hedgehog palmitoyl acytl-transferase. Trials have investigated Notch inhibitors in sarcomas such as epithelioid sarcoma.^[21]

mTOR

The frequent overactivation of mTOR (mammalian target of rapamycin) signaling has also been observed in epithelioid sarcoma.^[19]^[22] The mTOR pathway has been described as a “master switch” for cellular catabolism and anabolism, and it can enhance cell cycle progression, cell survival, and block normal cell death (apoptosis).^[17] It has been demonstrated that simply blocking mTOR signaling can result in the reactivation of the AKT pathway, negating much of mTOR blockade.^[19] Reactivation of AKT has been shown to be MET-dependent,^[19] resulting in the rationale that blocking both mTOR and MET concurrently should be a useful approach to treat epithelioid sarcoma.

EGFR

The over-expression of epidermal growth factor receptor (EGFR) has been reported in a majority of epithelioid sarcomas.^[22]^[23] EGFR is a member of the HER receptor family. Upon ligand binding, EGFR phosphorylation triggers the activation of downstream signaling pathways involved in critical cellular functions such as proliferation, survival, and angiogenesis.^[24] In-vitro and in-vivo laboratory experiments have demonstrated that the blockade of EGFR in epithelioid sarcoma results in decreased cell proliferation, increased apoptosis, and abrogated invasion and migration capacities.^[22] While the blockade of EGFR with a medication has shown limited results in the clinical setting, when used as part of a combination with another drugs, such as an mTOR inhibitor, synergy has been observed, and superior tumor growth inhibition has been demonstrated.^[22]

CD109

CD109, usually found on lymphocytes, is also expressed in epithelioid sarcoma, and is thought to mark the cancer stem cell (or cancer initiating cell) of the disease.^[25] Its expression has also been shown to be predictive of outcome. Cancer stem cells are a small population of tumor cells characterized by general chemo-resistance, the ability to self-renew, multi-differentiation potential, dormancy capabilities, and tumorigenesis. In this way, cancer stem cells are thought to play key roles in the progression and relapse of cancer.

Cyclin D1

Cyclin D1 is a protein requisite for cell cycle progression and has been shown to be up-regulated in epithelioid sarcoma.^[14] Cyclin D1 is a regulator of cyclin-dependent kinases (specifically, CDK4 and CDK6). It has been shown to interact with the retinoblastoma protein (a tumor suppressor gene), CDK4 and CDK6, thyroid hormone receptor beta, and nuclear receptor coactivator 1, among others.^[14] Cyclin D and CDKs promote cell cycle progression by releasing transcription factors that are important for the initiation of DNA replication. Abnormal levels of cyclin D1 may be associated with more rapid cell division in epithelioid sarcoma.

Diagnosis

Tissue biopsy is the diagnostic modality of choice. Due to a high incidence of lymph node involvement, a sentinel lymph node biopsy may be performed. A common characteristic of epithelioid sarcoma (observed in 80% of all cases) is the loss of function of the SMARCB1 gene (whose protein product is termed BAF47, INI1, or hSNF5). Immunohistochemical staining of INI1 is available and helps to diagnose of epithelioid sarcoma. MRI is the diagnostic modality of choice for imaging prior to biopsy and pathologic diagnosis for most patients.

Staging

The staging for epithelioid sarcoma takes into account size and location of the primary tumor, lymph node involvement, presence and location of metastasis, and histologic grade (a measure of disease aggressiveness)^[26]

Treatment

Surgery, radiation, and systemic therapy such as chemotherapy are all used at various times in the treatment of patients who have epitheloid sarcoma. Since sarcomas are considered very rare, it is not surprising that outcomes for patients with this type of cancer are better when patients are evaluated in expert centers, and when possible, treated there.^[27]

Surgical resection of epithelioid sarcoma with wide margins remains the preferred method of treatment,^[28] and as of 2023, remains the only curative approach for the cancer, sometimes in concert with radiation or chemotherapy.^[28]^[29]^[30] Limb-sparing surgery is the standard of care for treating all sarcomas, and is used wherever possible for treatment of epithelioid sarcoma as well.^[31]

In cases of advanced, recurrent, or metastasized disease, or if the tumor is inoperable, chemotherapy and radiation are the standard of care.^[32] The benefit for standard medications such as doxorubicin, ifosfamide, and combinations involving gemcitabine is generally measured in months, not years.^[33]

In January 2020, The U.S. Food and Drug Administration approved the oral medication tazemetostat (trade name Tazverik), a drug that blocks the EZH2 methyltransferase, for the treatment of epithelioid sarcoma in patients aged 16 years and older with either metastatic or locally advanced (unable to be completely removed surgically) disease.^[34] The data that led to the drug's authorization have been supported by post-marketing studies. As with standard chemotherapy, the effectiveness of tazemetostat is generally measured in months, though some patients will fare better for a longer period of time.

Prognosis

The 5-year survival rate for epithelioid sarcoma patients is usually quoted as 50-70%, with the 10-year survival rate is 42-55%. Children with epithelioid sarcoma may have somewhat better outcomes than adults, with 5 year survival rates around 65%.^[6] Pediatric patients also less often demonstrate lymphatic spread and metastasis than adults with this diagnosis.^[6] In addition to stage and grade of the tumor, gender, site, age at diagnosis, tumor size and microscopic pathology all have been shown to affect prognosis.^[9]^[35] Unsurprisingly, advanced stage and grade are associated with worse outcomes. Females tend to have more favorable outcomes than males, proximal cases show worse outcomes than distal cases. Tumors more than 2 cm in diameter and tumors with necrosis and vascular invasion also have been correlated with a worse outcome.^[35]

Radiation therapy is also a treatment option when tumors are deemed inoperable or wide surgical margins are not achievable. Radiation therapy in combination with chemotherapy has so far resulted in only minimal improvements to response rates. Trials with brachytherapy (an internal radiation treatment that delivers a high dose of radiation directly to the tumor and is thought to have fewer long-term side effects) have produced some positive results.^{[citation needed]}

Forschung

Epithelioid sarcoma (especially advanced stage, recurrent, or metastasized disease) has been shown to become resistant to traditional cancer therapies, necessitating further exploration of novel treatment methods and techniques. Because of the relatively poor duration of the benefit of treatment of epithelioid sarcoma using traditional cancer treatments (such as chemotherapy and radiation), new treatment strategies are being examined.

Chemotherapy

New chemotherapies are being explored in current clinical trials for epithelioid sarcoma, although, thus far, none has shown significant improvement over the efficacy of doxorubicin and/or ifosfamide. Newer agents include gemcitabine, taxanes, vinorelbine and pazopanib.^[32]

Aldoxorubicin is a newer pro-drug version of doxorubicin that has been studied. Doxorubicin is the standard of care for advanced or metastatic epithelioid sarcoma, but it has dose-limiting toxicities, namely acute and chronic cardiac toxicity.^[36]^[37] Aldoxorubicin was designed to safely deliver a higher dose of the drug directly to the tumor, resulting in less toxicity. Phase I and II studies of aldoxorubicin were undertaken and little cardiac toxicity was observed. While usefulness was seen in some patients, the place of aldoxorubicin in treatment of patients with epithelioid sarcoma or other sarcomas, in particular compared to doxorubicin, has not been defined.

TH-302 was another research drug studied in sarcomas such as epithelioid sarcoma. It targets tumor hypoxia, a common event in tumorigenesis where the tumor microenvironment is depleted of oxygen and becomes hypoxic.^[38] Phase I, II, and III trials with TH-302 alone and in combination were undertaken,^[39] but two phase 3 trials failed in 2015, such that the drug is no longer actively being studied.

Immunotherapies

Immunotherapy is the strategy of using the body's own immune system to fight cancer. It usually involves “training” or “tweaking” the immune system so that it can better recognize and reject cancer cells. Different immunotherapies can include manipulation of the body's T-cells, NK cells, or Dendritic cells so they are more effective against cancer cells. They can also include the administration of laboratory-produced antibodies specific to tumor antigens to create or boost an immune response.^{[citation needed]}

Vaccine therapy is perhaps the simplest immunotherapeutic strategy,^[40] although, thus far, little to no evidence has emerged indicating that vaccination with any compound leads to shrinking of epithelioid sarcoma or other sarcomas.^[41] Multiple techniques and treatment strategies are currently being studied in many cancers in an effort to improve the usefulness of vaccine therapy.^[40] Vaccines can deliver various tumor-associated factors (tumor antigens) to the immune system, resulting in a natural antibody and T-cell response to the tumor. Unforunately, no such molecules that are specific to epithelioid sarcoma have been identified for testing such an approach.^[40]^[42]

Adoptive immunotherapy seeks to expand a population of the body's T cells that will recognize a specific tumor antigen. T-cells can be harvested and then expanded and genetically manipulated to recognize certain tumor markers.^[40]^[42] In one case, a patient with advanced epithelioid sarcoma who had failed multiple therapies showed a strong response to expanded lymphocytes and natural killer cells.^[43] However, as of 2023, no specific clinical trials are examining cellular therapy for epithelioid sarcoma specifically.

Immune checkpoint inhibitors are approved for use in many types of cancer, though there are no FDA approvals for such agents for patients with epithelioid sarcoma. Some cancers are known to deter recognition by the immune system and allow the tumor to escape immune surveillance.^[41] By targeting these inhibitory proteins, a pathway is opened for the immune system to recognize the tumor. Two of these inhibitory proteins are CTLA-4 and PD1,^[41] and medications targeting these immune system blockers are being examined in patients with sarcomas, such as epithelioid sarcoma.

Anti-angiogenic therapies

Several anti-angiogenic agents are being explored in epithelioid sarcoma,^{[citation needed]} a cancer that likely relies on angiogenesis for survival and progression. These agents interfere with various pro-angiogenic factors, several of which are known to be over-expressed in epithelioid sarcoma^[16]^[23] (VEGF and EGFR for example).^[44]^[45] Tumors require a blood supply to provide them with oxygen and nutrients necessary for their survival. As tumors expand and grow, they send out various signals (such as HIF1) that encourage new blood vessel development to the tumor.^[46] The antiangioenic agent pazopanib is approved in many countries for use in sarcomas such as epithelioid sarcoma.

"Targeted" therapies

Given the multiple genetic abnormalities and disrupted biological pathways observed in epithelioid sarcoma, drugs targeting unique tumor characteristics are being examine for more effective treatments.

Tyrosine kinase inhibitors

Tyrosine kinase inhibitors (such as sunitinib, pazopanib, and dasatinib) have shown some effect against several cancer types, one example among sarcomas being Imatinib in gastrointestinal stromal tumors (GISTs).^[47] Tyrosine kinase (a subclass of protein kinases) is an enzyme that transfers a phosphate group from an ATP molecule to a protein in a cell.^[48] It functions as an “on” or “off” switch for many cellular functions, including signaling within the cell, and cell division.

Tyrosine kinases can contain mutations that cause them to become constitutively active,^[49] or stuck in the “on” position, resulting in unregulated cell division (a hallmark of cancer). Tyrosine kinase Inhibitors block the action of these enzymes. Tyrosine kinase inhibitors have been shown to inhibit the VEGF, EGFR, and MET,^[48] pathways that are frequently over-expressed in epithelioid sarcoma. They also can be used against the KIT and JAK-STAT signaling pathways,^[48] which are involved in many cancers and may be involved in epithelioid sarcoma. Temsirolimus is a tyrosine kinase inhibitor that blocks the effects of the mTOR protein and inhibits the mTOR pathway. Because of crosstalk between cell signaling pathways, it has been shown that, while interfering with the mTOR pathway alone produces only limited results in halting tumorigenesis, inhibiting both the mTOR and the EGFR pathways concurrently shows an increased effect.^[22]

SINE

Selective inhibitors of nuclear export (SINE) compounds, such as selinexor and CBS9106, are being investigated in several sarcomas and have shown promising results in both hematological malignancies and solid tumors.^[50]^[51] However, a randomized trial of selinexor in liposarcoma, a distant cousin of epithelioid sarcoma, was negative. Selinexor does have approval for other cancer diagnoses.

HDAC inhibitors

Histone deacetylase (HDAC) inhibitors, such as vorinostat, have shown some promise in epithelioid sarcoma. Researchers in Texas are investigating whether or not HDAC inhibitors can reverse the loss of INI1 function that is characteristic of epithelioid sarcoma.^[8] HDAC inhibitors work by blocking events involved in DNA replication and, therefore, in cell division.^[52] Blocking HDAC has been shown to encourage cancer cells to enter apoptosis.^[8] Several dietary phytochemicals have been shown to be effective HDAC inhibitors.^[53] These include sulphorphane, indole-3-carbinol, and phenethyl isothiocyanates, found in broccoli, kale, and watercress, and epigallocatecehin-3-gallate, found in green tea.^{[citation needed]}

CDK inhibitors

Because of the association (see above) with cyclin D1 CDK inhibitors are being studied in a variety of cancers. Palbociclib is a CDK inhibitor (approved for some breast cancer by virtue of its blockade of CDK4 and CDK6). Other experimental CDK4/6 inhibitors include abemaciclib and ribociclib.

Targeting the cancer stem cell

Cancer stem cells (or cancer-initiating cells) are thought to be a small population of cells within the tumor that are directly responsible for tumor formation. They are thought to be resistant to treatment and to have the ability to form all the cells needed for tumor development. They are suspected to be a contributing factor in cancer progression and relapse after treatment. Certain “stem-like” cells have been found in epithelioid sarcoma that are marked by CD109 (cluster of differentiation 109),^[25] providing a theoretically druggable target for epithelioid sarcoma. However, CD109 is expressed in many normal cells of the body, such as T cells and endothelial cells lining every blood vessel, making CD109 a poor target for immunotherapy.

Oncolytic viral therapy

Oncolytic viral therapy is an emerging cancer therapy that attempts to infect cancer cells with a genetically engineered virus that can penetrate the DNA of the cell. The virus then (1) cann do direct damage to the cancer cell, (2) is passed on throughout the cells of the tumor via viral reproduction, and (3) provides a target for an immune response from the patient.^[17]^[54]

It has been noted that the therapeutic potential of oncolytic virotherapy is not a simple consequence of the cytopathic effect but strongly relies on the activation of the body's own immune response against infected cells.^[54]^[55] Superior anticancer effects have been observed when oncolytic viruses are engineered to express (or be co-administered with) immunostimulatory molecules such as GM-CSF.^[55]

Telomelysin (OBP-301) is an adenovirus that targets telomerase,^[56] an enzyme that is expressed in practically all cancer cells but not in normal cells. OBP-301 is not approved for use in cancer patients, but it has been studied in epithelioid sarcoma and shown to promote apoptosis and cell death in the laboratory.^[56]

CGTG-102 (developed by Oncos Therapeutics) is an adenovirus currently in orphan drug status for soft tissue sarcomas. It is modified to selectively replicate in p16/Rb-defective cells, which include most human cancer cells. In addition, CGTG-102 codes for the granulocyte–macrophage colony-stimulating factor (GM-CSF),^[55]^[57] a potent immunostimulatory molecule. While CGTG-102 has shown efficacy as a single agent against several soft tissue sarcomas in the laboratory, as of 2023, clinical research on it appears to have come to a halt.^[58]

Additional images

Intermed. mag.
High mag.
High mag. (SMARCB1)

References

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^ Chawla, S. P.; Cranmer, L. D.; Van Tine, B. A.; Reed, D. R.; Okuno, S. H.; Butrynski, J. E.; Adkins, D. R.; Hendifar, A. E.; Kroll, S.; Ganjoo, K. N. (2014). "Phase II Study of the Safety and Antitumor Activity of the Hypoxia-Activated Prodrug TH-302 in Combination With Doxorubicin in Patients With Advanced Soft Tissue Sarcoma". Journal of Clinical Oncology. 32 (29): 3299–306. doi:10.1200/JCO.2013.54.3660. PMC 4588714. PMID 25185097.
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^ Demicco, Elizabeth G.; Maki, Robert G.; Lev, Dina C.; Lazar, Alexander J. (2012). "New Therapeutic Targets in Soft Tissue Sarcoma". Advances in Anatomic Pathology. 19 (3): 170–80. doi:10.1097/PAP.0b013e318253462f. PMC 3353406. PMID 22498582.
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External links

[pmid5476785-1] Enzinger, F. M. (1970). "Epithelioid sarcoma.A sarcoma simulating a granuloma or a carcinoma". Cancer. 26 (5): 1029–41. doi:10.1002/1097-0142(197011)26:5<1029::AID-CNCR2820260510>3.0.CO;2-R. PMID 5476785.

[2] Guillou, L; Wadden, C; Coindre, JM; Krausz, T; Fletcher, CD (1997). "'Proximal-type' epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series". The American Journal of Surgical Pathology. 21 (2): 130–46. doi:10.1097/00000478-199702000-00002. PMID 9042279.

[pmid19415960-3] Armah, Henry B. Armah; Parwani, Anil V. (2009). "Epithelioid sarcoma". Archives of Pathology & Laboratory Medicine. 133 (5): 814–9. doi:10.5858/133.5.814. PMID 19415960.

[4] Kato, Hiroshi; Hatori, Masahito; Kokubun, Shoichi; Watanabe, Mika; Smith, Richard A; Hotta, Tetsuo; Ogose, Akira; Morita, Tetsuro; Murakami, Takashi; Aiba, Setsuya (2004). "CA125 expression in epithelioid sarcoma". Japanese Journal of Clinical Oncology. 34 (3): 149–54. doi:10.1093/jjco/hyh027. PMID 15078911.

[pmid24046109-5] Levy, Antonin; Le Péchoux, Cécile; Terrier, Philippe; Bouaita, Ryan; Domont, Julien; Mir, Olivier; Coppola, Sarah; Honoré, Charles; Le Cesne, Axel; Bonvalot, Sylvie (2014). "Epithelioid Sarcoma: Need for a Multimodal Approach to Maximize the Chances of Curative Conservative Treatment". Annals of Surgical Oncology. 21 (1): 269–76. doi:10.1245/s10434-013-3247-4. PMID 24046109. S2CID 21163484.

[pmid16353216-6] Casanova, Michela; Ferrari, Andrea; Collini, Paola; Bisogno, Gianni; Alaggio, Rita; Cecchetto, Giovanni; Gronchi, Alessandro; Meazza, Cristina; Garaventa, Alberto; Di Cataldo, Andrea; Carli, Modesto (2006). "Epithelioid sarcoma in children and adolescents". Cancer. 106 (3): 708–17. doi:10.1002/cncr.21630. PMID 16353216. S2CID 25321347.

[7] Jawad, Muhammad Umar; Extein, Jason; Min, Elijah S.; Scully, Sean P. (2009). "Prognostic Factors for Survival in Patients with Epithelioid Sarcoma: 441 Cases from the SEER Database". Clinical Orthopaedics and Related Research. 467 (11): 2939–48. doi:10.1007/s11999-009-0749-2. PMC 2758965. PMID 19224301.

[LevDina-8] Lev, Dina. "Epigenetic reprogramming of epitheliold sarcoma: a role for INI1-HDAC crosstalk". Archived from the original on 2015-04-22.

[pmid3392084-9] Bos, GD; Pritchard, DJ; Reiman, HM; Dobyns, JH; lstrup, DM; Landon, GC (1988). "Epithelioid sarcoma. An analysis of fifty-one cases". The Journal of Bone and Joint Surgery. American Volume. 70 (6): 862–70. doi:10.2106/00004623-198870060-00011. PMID 3392084. Archived from the original on 2020-03-28. Retrieved 2015-10-06.

[pmid19033866-10] Hornick, Jason L.; Dal Cin, Paola; Fletcher, Christopher D.M. (2009). "Loss of INI1 Expression is Characteristic of Both Conventional and Proximal-type Epithelioid Sarcoma". The American Journal of Surgical Pathology. 33 (4): 542–50. doi:10.1097/PAS.0b013e3181882c54. PMID 19033866. S2CID 5167769.

[pmid15899790-11] Modena, Piergiorgio; Lualdi, Elena; Facchinetti, Federica; Galli, Lisa; Teixeira, Manuel R.; Pilotti, Silvana; Sozzi, Gabriella (2005). "SMARCB1/INI1 Tumor Suppressor Gene Is Frequently Inactivated in Epithelioid Sarcomas". Cancer Research. 65 (10): 4012–9. doi:10.1158/0008-5472.CAN-04-3050. PMID 15899790.

[12] Lushnikova, Tamara; Knuutila, Sakari; Miettinen, Markku (2000). "DNA Copy Number Changes in Epithelioid Sarcoma and Its Variants: A Comparative Genomic Hybridization Study". Modern Pathology. 13 (10): 1092–6. doi:10.1038/modpathol.3880203. PMID 11048803. S2CID 23521276.

[13] Nishio, Jun; Iwasaki, Hiroshi; Nabeshima, Kazuki; Ishiguro, Masako; Naumann, Sabine; Isayama, Teruto; Naito, Masatoshi; Kaneko, Yasuhiko; Kikuchi, Masahiro; Bridge, Julia (2005). "Establishment of a new human epithelioid sarcoma cell line, FU-EPS-1: Molecular cytogenetic characterization by use of spectral karyotyping and comparative genomic hybridization". International Journal of Oncology. 27 (2): 361–9. doi:10.3892/ijo.27.2.361. PMID 16010416.

[pmid15578074-14] Lin, Lin; Hicks, David; Xu, Bo; Sigel, Jessica E; Bergfeld, Wilma F; Montgomery, Elizabeth; Fisher, Cyril; Hartke, Marybeth; Tubbs, Raymond; Goldblum, John R (2005). "Expression profile and molecular genetic regulation of cyclin D1 expression in epithelioid sarcoma". Modern Pathology. 18 (5): 705–9. doi:10.1038/modpathol.3800349. PMID 15578074. S2CID 24821026.

[15] Kahali, Bhaskar; Yu, Jinlong; Marquez, Stefanie B.; Thompson, Kenneth W.; Liang, Shermi Y.; Lu, Li; Reisman, David (2014). "The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors". Oncotarget. 5 (10): 3316–32. doi:10.18632/oncotarget.1945. PMC 4102812. PMID 24913006.

[pmid10782895-16] Kuhnen, Cornelius; Lehnhardt, Marcus; Tolnay, Edina; Muehlberger, Thomas; Vogt, Peter M.; Müller, Klaus-Michael (2000). "Patterns of expression and secretion of vascular endothelial growth factor in malignant soft-tissue tumours". Journal of Cancer Research and Clinical Oncology. 126 (4): 219–25. doi:10.1007/s004320050036. PMID 10782895. S2CID 21613610.

[pmid22701332-17] Martín Liberal, Juan; Lagares-Tena, Laura; Sáinz-Jaspeado, Miguel; Mateo-Lozano, Silvia; García del Muro, Xavier; Tirado, Oscar M. (2012). "Targeted Therapies in Sarcomas: Challenging the Challenge". Sarcoma. 2012: 1–13. doi:10.1155/2012/626094. PMC 3372278. PMID 22701332.

[18] Kuhnen, C.; Tolnay, Edina; Steinau, Hans Ulrich; Voss, Bruno; Müller, Klaus-Michael (1998). "Expression of c-Met receptor and hepatocyte growth factor/scatter factor in synovial sarcoma and epithelioid sarcoma". Virchows Archiv. 432 (4): 337–42. doi:10.1007/s004280050175. PMID 9565343. S2CID 30726514.

[pmid25098767-19] Imura, Yoshinori; Yasui, Hirohiko; Outani, Hidetatsu; Wakamatsu, Toru; Hamada, Kenichiro; Nakai, Takaaki; Yamada, Shutaro; Myoui, Akira; Araki, Nobuhito; Ueda, Takafumi; Itoh, Kazuyuki; Yoshikawa, Hideki; Naka, Norifumi (2014). "Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma". Molecular Cancer. 13: 185. doi:10.1186/1476-4598-13-185. PMC 4249599. PMID 25098767.

[20] Imura, Yoshinori; Yasui, Hirohiko; Outani, Hidetatsu; Wakamatsu, Toru; Hamada, Kenichiro; Nakai, Takaaki; Yamada, Shutaro; Myoui, Akira; Araki, Nobuhito; Ueda, Takafumi; Itoh, Kazuyuki; Yoshikawa, Hideki; Naka, Norifumi (2014-08-07). "Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma". Molecular Cancer. 13: 185. doi:10.1186/1476-4598-13-185. ISSN 1476-4598. PMC 4249599. PMID 25098767.

[21] Clinical trial number NCT01154452 for "Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma" at ClinicalTrials.gov

[pmid21821699-22] Xie, X.; Ghadimi, M. P. H.; Young, E. D.; Belousov, R.; Zhu, Q.-s.; Liu, J.; Lopez, G.; Colombo, C.; Peng, T.; Reynoso, D.; Hornick, J. L.; Lazar, A. J.; Lev, D. (2011). "Combining EGFR and mTOR Blockade for the Treatment of Epithelioid Sarcoma". Clinical Cancer Research. 17 (18): 5901–12. doi:10.1158/1078-0432.CCR-11-0660. PMC 3176924. PMID 21821699.

[pmid20118913-23] Cascio, Michael J; O'Donnell, Richard J; Horvai, Andrew E (2010). "Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare". Modern Pathology. 23 (4): 574–80. doi:10.1038/modpathol.2010.2. PMID 20118913. S2CID 11592703.

[24] Yang, J.-L.; Hannan, M.T.; Russell, P.J.; Crowe, P.J. (2006). "Expression of HER1/EGFR protein in human soft tissue sarcomas". European Journal of Surgical Oncology. 32 (4): 466–8. doi:10.1016/j.ejso.2006.01.012. PMID 16524687.

[pmid24376795-25] Ahmad, Aamir; Emori, Makoto; Tsukahara, Tomohide; Murase, Masaki; Kano, Masanobu; Murata, Kenji; Takahashi, Akari; Kubo, Terufumi; Asanuma, Hiroko; Yasuda, Kazuyo; Kochin, Vitaly; Kaya, Mitsunori; Nagoya, Satoshi; Nishio, Jun; Iwasaki, Hiroshi; Sonoda, Tomoko; Hasegawa, Tadashi; Torigoe, Toshihiko; Wada, Takuro; Yamashita, Toshihiko; Sato, Noriyuki (2013). "High Expression of CD109 Antigen Regulates the Phenotype of Cancer Stem-Like Cells/Cancer-Initiating Cells in the Novel Epithelioid Sarcoma Cell Line ESX and Is Related to Poor Prognosis of Soft Tissue Sarcoma". PLOS ONE. 8 (12): e84187. Bibcode:2013PLoSO...884187E. doi:10.1371/journal.pone.0084187. PMC 3869840. PMID 24376795.

[26] Soft Tissue Sarcoma Staging at eMedicine

[27] Blay, J.-Y.; Honoré, C.; Stoeckle, E.; Meeus, P.; Jafari, M.; Gouin, F.; Anract, P.; Ferron, G.; Rochwerger, A.; Ropars, M.; Carrere, S.; Marchal, F.; Sirveaux, F.; Di Marco, A.; Le Nail, L. R. (2019-07-01). "Surgery in reference centers improves survival of sarcoma patients: a nationwide study". Annals of Oncology. 30 (7): 1143–1153. doi:10.1093/annonc/mdz124. ISSN 1569-8041. PMC 6637376. PMID 31081028.

[pmid16804932-28] Visscher, Sebastiaan A. H. J.; van Ginkel, Robbert J.; Wobbes, Theo; Veth, René P. H.; ten Heuvel, Suzanne E.; Suurmeijer, Albert J. H.; Hoekstra, Harad J. (2006). "Epithelioid sarcoma: Still an only surgically curable disease". Cancer. 107 (3): 606–12. doi:10.1002/cncr.22037. PMID 16804932. S2CID 25833518.

[29] Rao, Bhaskar N.; Rodriguez-Galindo, Carlos (2003). "Local control in childhood extremity sarcomas: Salvaging limbs and sparing function". Medical and Pediatric Oncology. 41 (6): 584–7. doi:10.1002/mpo.10405. PMID 14595726.

[30] Ferrari, Andrea; Miceli, Rosalba; Rey, Annie; Oberlin, Odile; Orbach, Daniel; Brennan, Bernadette; Mariani, Luigi; Carli, Modesto; Bisogno, Gianni; Cecchetto, Giovanni; Salvo, Gian Luca De; Casanova, Michela; Vannoesel, Max M.; Kelsey, Anna; Stevens, Michael C.; Devidas, Meenakshi; Pappo, Alberto S.; Spunt, Sheri L. (2011). "Non-metastatic unresected paediatric non-rhabdomyosarcoma soft tissue sarcomas: Results of a pooled analysis from United States and European groups". European Journal of Cancer. 47 (5): 724–31. doi:10.1016/j.ejca.2010.11.013. PMC 3539303. PMID 21145727.

[31] DeGroot, Henry; Ellison, Bruce. "Limb Salvage Surgery for Extremity Sarcomas". Archived from the original on 2015-02-08. Retrieved 2015-04-23.^{[unreliable medical source?]}

[NCCN_Soft_Tissue_Sarcoma-32] Soft Tissue Sarcoma. Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Archived from the original on 2018-08-05. Retrieved 2015-10-06.^{[page needed]}

[33] Wolf, Patrick S.; Flum, David R.; Tanas, Munir R.; Rubin, Brian P.; Mann, Gary N. (2008). "Epithelioid sarcoma: the University of Washington experience". The American Journal of Surgery. 196 (3): 407–12. doi:10.1016/j.amjsurg.2007.07.029. PMID 18436180.

[34] "FDA approves first treatment option specifically for patients with epithelioid sarcoma, a rare soft tissue cancer" (Press release). FDA. January 23, 2020. Retrieved 2020-03-03.

[pmid4014539-35] Chase, DR; Enzinger, FM (1985). "Epithelioid sarcoma. Diagnosis, prognostic indicators, and treatment". The American Journal of Surgical Pathology. 9 (4): 241–63. doi:10.1097/00000478-198504000-00001. PMID 4014539. S2CID 36504524.

[36] Lefrak, Edward A.; Piťha, Jan; Rosenheim, Sidney; Gottlieb, Jeffrey A. (1973). "A clinicopathologic analysis of adriamycin cardiotoxicity". Cancer. 32 (2): 302–14. doi:10.1002/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2. PMID 4353012. S2CID 41537913.

[37] Lipshultz, Steven E.; Colan, Steven D.; Gelber, Richard D.; Perez-Atayde, Antonio R.; Sallan, Stephen E.; Sanders, Stephen P. (1991). "Late Cardiac Effects of Doxorubicin Therapy for Acute Lymphoblastic Leukemia in Childhood". New England Journal of Medicine. 324 (12): 808–15. doi:10.1056/NEJM199103213241205. PMID 1997853.

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 }}
-'''Epithelioid sarcoma''' is a rare [[soft tissue sarcoma]] arising from [[mesenchymal]] tissue and characterized by [[Epithelioid cell|epithelioid]]-like features. It accounts for less than 1% of all [[soft tissue sarcomas]]. It was first clearly characterized by F.M. Enzinger in 1970.<ref name=pmid5476785>{{cite journal |last1=Enzinger |first1=F. M. |title=Epithelioid sarcoma.A sarcoma simulating a granuloma or a carcinoma |journal=Cancer |volume=26 |issue=5 |pages=1029–41 |year=1970 |pmid=5476785 |doi=10.1002/1097-0142(197011)26:5<1029::AID-CNCR2820260510>3.0.CO;2-R }}</ref> It commonly presents itself in the [[distal]] limbs (fingers, hands, forearms, or feet) of young adults as a small, soft mass or a series of bumps. A [[proximal]] version has also been described, frequently occurring in the upper extremities.<ref>{{cite journal |last1=Guillou |first1=L |last2=Wadden |first2=C |last3=Coindre |first3=JM |last4=Krausz |first4=T |last5=Fletcher |first5=CD |title='Proximal-type' epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series |journal=The American Journal of Surgical Pathology |volume=21 |issue=2 |pages=130–46 |year=1997 |pmid=9042279 |doi=10.1097/00000478-199702000-00002}}</ref> Rare cases have been reported in the pelvis, vulva, penis, and spine.
+'''Epithelioid sarcoma''' is a rare [[soft tissue sarcoma]] arising from [[mesenchymal]] tissue and characterized by [[Epithelioid cell|epithelioid]]-like features. It accounts for less than 1% of all [[soft tissue sarcomas]]. It was first definitively characterized by F.M. Enzinger in 1970.<ref name=pmid5476785>{{cite journal |last1=Enzinger |first1=F. M. |title=Epithelioid sarcoma.A sarcoma simulating a granuloma or a carcinoma |journal=Cancer |volume=26 |issue=5 |pages=1029–41 |year=1970 |pmid=5476785 |doi=10.1002/1097-0142(197011)26:5<1029::AID-CNCR2820260510>3.0.CO;2-R |doi-access=free }}</ref> It commonly presents itself in the [[distal]] limbs (fingers, hands, forearms, or feet) of young adults as a small, soft mass or a cluster of bumps. A [[proximal]] version has also been described, frequently occurring in the upper extremities.<ref>{{cite journal |last1=Guillou |first1=L |last2=Wadden |first2=C |last3=Coindre |first3=JM |last4=Krausz |first4=T |last5=Fletcher |first5=CD |title='Proximal-type' epithelioid sarcoma, a distinctive aggressive neoplasm showing rhabdoid features. Clinicopathologic, immunohistochemical, and ultrastructural study of a series |journal=The American Journal of Surgical Pathology |volume=21 |issue=2 |pages=130–46 |year=1997 |pmid=9042279 |doi=10.1097/00000478-199702000-00002}}</ref> Less commonly, cases are reported in the pelvis, vulva, penis, and spine.
-Histologically, epithelioid sarcoma forms nodules with central necrosis surrounded by bland, polygonal cells with eosinophilic cytoplasm and peripheral spindling.<ref name=pmid19415960>{{cite journal |last1=Armah |first1=Henry B. Armah |last2=Parwani |first2=Anil V. |title=Epithelioid sarcoma |journal=Archives of Pathology & Laboratory Medicine |volume=133 |issue=5 |pages=814–9 |year=2009 |pmid=19415960 |doi=10.1043/1543-2165-133.5.814 |url=http://www.archivesofpathology.org/doi/10.1043/1543-2165-133.5.814?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed |doi-broken-date=2020-01-22 }}</ref> Epithelioid sarcomas typically express [[vimentin]], [[cytokeratins]], [[epithelial membrane antigen]], and [[CD34]], whereas they are usually negative for [[S100 protein|S100]], [[desmin]], and FLI-1.<ref name=pmid19415960/> They typically stain positive for [[CA125]].<ref>{{cite journal |last1=Kato |first1=Hiroshi |last2=Hatori |first2=Masahito |last3=Kokubun |first3=Shoichi |last4=Watanabe |first4=Mika |last5=Smith |first5=Richard A |last6=Hotta |first6=Tetsuo |last7=Ogose |first7=Akira |last8=Morita |first8=Tetsuro |last9=Murakami |first9=Takashi |last10=Aiba |first10=Setsuya |title=CA125 expression in epithelioid sarcoma |journal=Japanese Journal of Clinical Oncology |volume=34 |issue=3 |pages=149–54 |year=2004 |pmid=15078911 |doi=10.1093/jjco/hyh027 }}</ref>
+Histologically, epithelioid sarcoma forms nodules with central necrosis surrounded by bland, polygonal cells with eosinophilic cytoplasm and peripheral spindling.<ref name=pmid19415960>{{cite journal |last1=Armah |first1=Henry B. Armah |last2=Parwani |first2=Anil V. |title=Epithelioid sarcoma |journal=Archives of Pathology & Laboratory Medicine |volume=133 |issue=5 |pages=814–9 |year=2009 |pmid=19415960 |doi=10.5858/133.5.814 |url=http://www.archivesofpathology.org/doi/10.1043/1543-2165-133.5.814?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed }}</ref> Epithelioid sarcomas typically express [[vimentin]], [[cytokeratins]], [[epithelial membrane antigen]], and [[CD34]], whereas they are usually negative for [[S100 protein|S100]], [[desmin]], and [[FLI1]] (FLI-1).<ref name=pmid19415960/> They characteristically lack the protein INI1 (see below). Epithelioid sarcomas typically stain positive for [[CA125]].<ref>{{cite journal |last1=Kato |first1=Hiroshi |last2=Hatori |first2=Masahito |last3=Kokubun |first3=Shoichi |last4=Watanabe |first4=Mika |last5=Smith |first5=Richard A |last6=Hotta |first6=Tetsuo |last7=Ogose |first7=Akira |last8=Morita |first8=Tetsuro |last9=Murakami |first9=Takashi |last10=Aiba |first10=Setsuya |title=CA125 expression in epithelioid sarcoma |journal=Japanese Journal of Clinical Oncology |volume=34 |issue=3 |pages=149–54 |year=2004 |pmid=15078911 |doi=10.1093/jjco/hyh027 |doi-access= }}</ref>
-Epithelioid sarcoma most commonly strikes young adults, yet no age group is immune. The disease has a tendency to develop local recurrences and [[metastasis]] thereafter to regional lymph nodes, lung, bone, brain, and other locations, including the scalp.<ref name=pmid19415960/> Generally speaking, epithelioid sarcoma has a high rate of relapse after initial treatment and tends to recur locally (at or near the original tumor site). Epithelioid sarcoma also demonstrates lymphatic spread (in 22-48% of cases), and metastasis (in 21-63% of cases).<ref name=pmid24046109>{{cite journal |last1=Levy |first1=Antonin |last2=Le Péchoux |first2=Cécile |last3=Terrier |first3=Philippe |last4=Bouaita |first4=Ryan |last5=Domont |first5=Julien |last6=Mir |first6=Olivier |last7=Coppola |first7=Sarah |last8=Honoré |first8=Charles |last9=Le Cesne |first9=Axel |last10=Bonvalot |first10=Sylvie |title=Epithelioid Sarcoma: Need for a Multimodal Approach to Maximize the Chances of Curative Conservative Treatment |journal=Annals of Surgical Oncology |volume=21 |issue=1 |pages=269–76 |year=2014 |pmid=24046109 |doi=10.1245/s10434-013-3247-4 }}</ref> These events, as well as advanced stage (progression) and grade (aggressiveness), are predictive of an overall worse outcome. The overall five-year survival rate for epithelioid sarcoma is anywhere from 25 to 78%.<ref name=pmid24046109/> Importantly, the 10-year and 15-year survival rate drops off significantly.<ref name=LevDina>{{cite web |last1=Lev |first1=Dina |title=Epigenetic reprogramming of epitheliold sarcoma: a role for INI1-HDAC crosstalk |url=https://ofur.rice.edu/content.aspx?id=4294967475 |url-status=dead |archiveurl=https://archive.is/20150422160244/https://ofur.rice.edu/content.aspx?id=4294967475 |archivedate=2015-04-22 }}</ref><ref name=pmid16353216>{{cite journal |last1=Casanova |first1=Michela |last2=Ferrari |first2=Andrea |last3=Collini |first3=Paola |last4=Bisogno |first4=Gianni |last5=Alaggio |first5=Rita |last6=Cecchetto |first6=Giovanni |last7=Gronchi |first7=Alessandro |last8=Meazza |first8=Cristina |last9=Garaventa |first9=Alberto |last10=Di Cataldo |first10=Andrea |last11=Carli |first11=Modesto |title=Epithelioid sarcoma in children and adolescents |journal=Cancer |volume=106 |issue=3 |pages=708–17 |year=2006 |pmid=16353216 |doi=10.1002/cncr.21630 }}</ref> Associated with a more positive outcome are younger age, female vs. male sex, distal vs. proximal location, smaller tumor size, and negative margins upon tumor resection.<ref name=pmid5476785/><ref name=pmid16353216/><ref>{{cite journal |last1=Jawad |first1=Muhammad Umar |last2=Extein |first2=Jason |last3=Min |first3=Elijah S. |last4=Scully |first4=Sean P. |title=Prognostic Factors for Survival in Patients with Epithelioid Sarcoma: 441 Cases from the SEER Database |journal=Clinical Orthopaedics and Related Research |volume=467 |issue=11 |pages=2939–48 |year=2009 |pmid=19224301 |pmc=2758965 |doi=10.1007/s11999-009-0749-2 }}</ref>
+Epithelioid sarcoma most commonly strikes young adults, yet no age group is immune. The disease has a tendency to develop local recurrences and [[metastasis]] thereafter to regional lymph nodes, lung, bone, brain, and other locations.<ref name=pmid19415960/> Generally speaking, epithelioid sarcoma has a high rate of relapse after initial treatment and tends to recur locally or regionally (at or near the original tumor site). Epithelioid sarcoma also demonstrates lymphatic spread (in 22-48% of cases), and metastasis (in 21-63% of cases).<ref name=pmid24046109>{{cite journal |last1=Levy |first1=Antonin |last2=Le Péchoux |first2=Cécile |last3=Terrier |first3=Philippe |last4=Bouaita |first4=Ryan |last5=Domont |first5=Julien |last6=Mir |first6=Olivier |last7=Coppola |first7=Sarah |last8=Honoré |first8=Charles |last9=Le Cesne |first9=Axel |last10=Bonvalot |first10=Sylvie |title=Epithelioid Sarcoma: Need for a Multimodal Approach to Maximize the Chances of Curative Conservative Treatment |journal=Annals of Surgical Oncology |volume=21 |issue=1 |pages=269–76 |year=2014 |pmid=24046109 |doi=10.1245/s10434-013-3247-4 |s2cid=21163484 }}</ref> These events, as well as advanced stage (progression) and grade (aggressiveness), are predictive of an overall worse outcome. Associated with a more positive outcome are younger age, female vs. male sex, distal vs. proximal location, smaller tumor size, and negative margins upon tumor resection.<ref name=pmid5476785/><ref name="pmid16353216">{{cite journal |last1=Casanova |first1=Michela |last2=Ferrari |first2=Andrea |last3=Collini |first3=Paola |last4=Bisogno |first4=Gianni |last5=Alaggio |first5=Rita |last6=Cecchetto |first6=Giovanni |last7=Gronchi |first7=Alessandro |last8=Meazza |first8=Cristina |last9=Garaventa |first9=Alberto |last10=Di Cataldo |first10=Andrea |last11=Carli |first11=Modesto |year=2006 |title=Epithelioid sarcoma in children and adolescents |journal=Cancer |volume=106 |issue=3 |pages=708–17 |doi=10.1002/cncr.21630 |pmid=16353216 |s2cid=25321347 |doi-access=}}</ref><ref>{{cite journal |last1=Jawad |first1=Muhammad Umar |last2=Extein |first2=Jason |last3=Min |first3=Elijah S. |last4=Scully |first4=Sean P. |title=Prognostic Factors for Survival in Patients with Epithelioid Sarcoma: 441 Cases from the SEER Database |journal=Clinical Orthopaedics and Related Research |volume=467 |issue=11 |pages=2939–48 |year=2009 |pmid=19224301 |pmc=2758965 |doi=10.1007/s11999-009-0749-2 }}</ref>
 ==Signs and symptoms==
-In general, epithelioid sarcoma is a slow-growing and relatively painless tumor, often resulting in a lengthy period of time between presentation and diagnosis.<ref name=LevDina/> Due to its ambiguity, it is often misdiagnosed, mistaken as a persistent wart or cyst. It most commonly presents itself in the [[distal]] limbs (fingers, hands, forearms, or feet) as a small, soft mass or a series of bumps. It is most often described as a firm-to-hard palpable mass, either in the deep soft tissue or in the dermis. Often, superficial lesions will ulcerate causing a mistaken diagnosis of a poorly healing traumatic wound or wart. About 13% of patients will present with multifocal tumors, and about 13% of patients will present with metastatic disease.<ref name=pmid3392084>{{cite journal |last1=Bos |first1=GD |last2=Pritchard |first2=DJ |last3=Reiman |first3=HM |last4=Dobyns |first4=JH |last5=lstrup |first5=DM |last6=Landon |first6=GC |title=Epithelioid sarcoma. An analysis of fifty-one cases |journal=The Journal of Bone and Joint Surgery. American Volume |volume=70 |issue=6 |pages=862–70 |year=1988 |pmid=3392084 |url=http://www.jbjs.org/cgi/pmidlookup?view=long&pmid=3392084 |doi=10.2106/00004623-198870060-00011 }}</ref>
+Epithelioid sarcoma is a slow-growing and relatively painless tumor, often resulting in a lengthy period of time between presentation and diagnosis.<ref name="LevDina">{{cite web |last1=Lev |first1=Dina |title=Epigenetic reprogramming of epitheliold sarcoma: a role for INI1-HDAC crosstalk |url=https://ofur.rice.edu/content.aspx?id=4294967475 |url-status=dead |archive-url=https://archive.today/20150422160244/https://ofur.rice.edu/content.aspx?id=4294967475 |archive-date=2015-04-22}}</ref> Due to the difficulty of discerning this cancer as different from more common cancers, such as cancers of the skin (squamous cell carcinoma or basal cell carcinoma), it is often misdiagnosed, mistaken as a persistent wart or cyst. It most commonly presents itself in the [[distal]] limbs (fingers, hands, forearms, or feet) as a small, soft mass or a cluster of nodules. It is most often described as a firm-to-hard palpable mass, either in the deep soft tissue or in the dermis. These cancers can form a crater or ulcer, leading to a mistaken diagnosis of a poorly healing traumatic wound or wart. About 13% of patients  present with multifocal tumors, and about 13% of patients present with metastatic disease.<ref name=pmid3392084>{{cite journal |last1=Bos |first1=GD |last2=Pritchard |first2=DJ |last3=Reiman |first3=HM |last4=Dobyns |first4=JH |last5=lstrup |first5=DM |last6=Landon |first6=GC |title=Epithelioid sarcoma. An analysis of fifty-one cases |journal=The Journal of Bone and Joint Surgery. American Volume |volume=70 |issue=6 |pages=862–70 |year=1988 |pmid=3392084 |url=http://www.jbjs.org/cgi/pmidlookup?view=long&pmid=3392084 |doi=10.2106/00004623-198870060-00011 |access-date=2015-10-06 |archive-date=2020-03-28 |archive-url=https://web.archive.org/web/20200328202229/http://www.jbjs.org/cgi/pmidlookup?view=long&pmid=3392084 |url-status=dead }}</ref>
 ==Genetics==
-The most common genetic mutation (found in 80-90% of epithelioid sarcomas) is the inactivation of the [[SMARCB1]] gene, or the loss of INI-1 function,<ref name=pmid19033866>{{cite journal |last1=Hornick |first1=Jason L. |authorlink1=Jason Hornick|last2=Dal Cin |first2=Paola |last3=Fletcher |first3=Christopher D.M. |title=Loss of INI1 Expression is Characteristic of Both Conventional and Proximal-type Epithelioid Sarcoma |journal=The American Journal of Surgical Pathology |volume=33 |issue=4 |pages=542–50 |year=2009 |pmid=19033866 |doi=10.1097/PAS.0b013e3181882c54 }}</ref><ref name=pmid15899790>{{cite journal |last1=Modena |first1=Piergiorgio |last2=Lualdi |first2=Elena |last3=Facchinetti |first3=Federica |last4=Galli |first4=Lisa |last5=Teixeira |first5=Manuel R. |last6=Pilotti |first6=Silvana |last7=Sozzi |first7=Gabriella |title=''SMARCB1/INI1'' Tumor Suppressor Gene Is Frequently Inactivated in Epithelioid Sarcomas |journal=Cancer Research |volume=65 |issue=10 |pages=4012–9 |year=2005 |pmid=15899790 |doi=10.1158/0008-5472.CAN-04-3050 }}</ref> which is thought to be a major contributor to disease progression. Epithelioid sarcoma typically contains chromosome 22q11.2 mutations or deletions and 8q gains, particularly i(8) (>q10). Aberrations of 18q and 8q, as well as recurrent gains at 11q13, have also been observed.<ref>{{cite journal |last1=Lushnikova |first1=Tamara |last2=Knuutila |first2=Sakari |last3=Miettinen |first3=Markku |title=DNA Copy Number Changes in Epithelioid Sarcoma and Its Variants: A Comparative Genomic Hybridization Study |journal=Modern Pathology |volume=13 |issue=10 |pages=1092–6 |year=2000 |pmid=11048803 |doi=10.1038/modpathol.3880203 }}</ref><ref>{{cite journal |last1=Nishio |first1=Jun |last2=Iwasaki |first2=Hiroshi |last3=Nabeshima |first3=Kazuki |last4=Ishiguro |first4=Masako |last5=Naumann |first5=Sabine |last6=Isayama |first6=Teruto |last7=Naito |first7=Masatoshi |last8=Kaneko |first8=Yasuhiko |last9=Kikuchi |first9=Masahiro |last10=Bridge |first10=Julia |title=Establishment of a new human epithelioid sarcoma cell line, FU-EPS-1: Molecular cytogenetic characterization by use of spectral karyotyping and comparative genomic hybridization |journal=International Journal of Oncology |volume=27 |issue=2 |pages=361–9 |year=2005 |pmid=16010416 |doi=10.3892/ijo.27.2.361 }}</ref><ref name=pmid15578074>{{cite journal |last1=Lin |first1=Lin |last2=Hicks |first2=David |last3=Xu |first3=Bo |last4=Sigel |first4=Jessica E |last5=Bergfeld |first5=Wilma F |last6=Montgomery |first6=Elizabeth |last7=Fisher |first7=Cyril |last8=Hartke |first8=Marybeth |last9=Tubbs |first9=Raymond |last10=Goldblum |first10=John R |title=Expression profile and molecular genetic regulation of cyclin D1 expression in epithelioid sarcoma |journal=Modern Pathology |volume=18 |issue=5 |pages=705–9 |year=2005 |pmid=15578074 |doi=10.1038/modpathol.3800349 }}</ref>
+The most common genetic mutation (found in 80-90% of epithelioid sarcomas) is the inactivation of the ''[[SMARCB1]]'' gene, or the loss of protein INI1 function,.<ref name=pmid19033866>{{cite journal |last1=Hornick |first1=Jason L. |author-link1=Jason Hornick|last2=Dal Cin |first2=Paola |last3=Fletcher |first3=Christopher D.M. |title=Loss of INI1 Expression is Characteristic of Both Conventional and Proximal-type Epithelioid Sarcoma |journal=The American Journal of Surgical Pathology |volume=33 |issue=4 |pages=542–50 |year=2009 |pmid=19033866 |doi=10.1097/PAS.0b013e3181882c54 |s2cid=5167769 }}</ref><ref name=pmid15899790>{{cite journal |last1=Modena |first1=Piergiorgio |last2=Lualdi |first2=Elena |last3=Facchinetti |first3=Federica |last4=Galli |first4=Lisa |last5=Teixeira |first5=Manuel R. |last6=Pilotti |first6=Silvana |last7=Sozzi |first7=Gabriella |title=''SMARCB1/INI1'' Tumor Suppressor Gene Is Frequently Inactivated in Epithelioid Sarcomas |journal=Cancer Research |volume=65 |issue=10 |pages=4012–9 |year=2005 |pmid=15899790 |doi=10.1158/0008-5472.CAN-04-3050 |doi-access=free }}</ref> Epithelioid sarcoma typically contains chromosome 22q11.2 mutations or deletions and 8q gains. Aberrations of 18q as well as recurrent gains at 11q13, have also been observed.<ref>{{cite journal |last1=Lushnikova |first1=Tamara |last2=Knuutila |first2=Sakari |last3=Miettinen |first3=Markku |title=DNA Copy Number Changes in Epithelioid Sarcoma and Its Variants: A Comparative Genomic Hybridization Study |journal=Modern Pathology |volume=13 |issue=10 |pages=1092–6 |year=2000 |pmid=11048803 |doi=10.1038/modpathol.3880203 |s2cid=23521276 |doi-access=free }}</ref><ref>{{cite journal |last1=Nishio |first1=Jun |last2=Iwasaki |first2=Hiroshi |last3=Nabeshima |first3=Kazuki |last4=Ishiguro |first4=Masako |last5=Naumann |first5=Sabine |last6=Isayama |first6=Teruto |last7=Naito |first7=Masatoshi |last8=Kaneko |first8=Yasuhiko |last9=Kikuchi |first9=Masahiro |last10=Bridge |first10=Julia |title=Establishment of a new human epithelioid sarcoma cell line, FU-EPS-1: Molecular cytogenetic characterization by use of spectral karyotyping and comparative genomic hybridization |journal=International Journal of Oncology |volume=27 |issue=2 |pages=361–9 |year=2005 |pmid=16010416 |doi=10.3892/ijo.27.2.361 }}</ref><ref name=pmid15578074>{{cite journal |last1=Lin |first1=Lin |last2=Hicks |first2=David |last3=Xu |first3=Bo |last4=Sigel |first4=Jessica E |last5=Bergfeld |first5=Wilma F |last6=Montgomery |first6=Elizabeth |last7=Fisher |first7=Cyril |last8=Hartke |first8=Marybeth |last9=Tubbs |first9=Raymond |last10=Goldblum |first10=John R |title=Expression profile and molecular genetic regulation of cyclin D1 expression in epithelioid sarcoma |journal=Modern Pathology |volume=18 |issue=5 |pages=705–9 |year=2005 |pmid=15578074 |doi=10.1038/modpathol.3800349 |s2cid=24821026 |doi-access= }}</ref>
-The SMARCB1 gene (also termed BAF47, INI1, or hSNF5) is located on chromosome [[22q11.2]]<ref name=pmid19033866/> and codes for a member of the [[SWI/SNF]] chromatin remodeling complex. Loss of SMARCB1 function is the most common genetic mutation observed in epithelioid sarcoma, and this dysfunction is likely a major driver of disease progression. SMARCB1 is a core protein subunit of the 15 subunit SWI/SNF (or BAF) complex involved in regulating the nucleosome architecture of our genome<ref name=pmid19033866/> and has been shown to be a potent [[tumor suppressor gene]],<ref name=pmid15899790/><ref>{{cite journal |last1=Kahali |first1=Bhaskar |last2=Yu |first2=Jinlong |last3=Marquez |first3=Stefanie B. |last4=Thompson |first4=Kenneth W. |last5=Liang |first5=Shermi Y. |last6=Lu |first6=Li |last7=Reisman |first7=David |title=The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors |journal=Oncotarget |volume=5 |issue=10 |pages=3316–32 |year=2014 |pmid=24913006 |pmc=4102812 |doi=10.18632/oncotarget.1945 }}</ref> meaning that its primary role is to control cell division and to even halt division under appropriate circumstances (i.e. signals to over-replicate). As this tumor suppressor is commonly inactivated in epithelioid sarcoma, cell division can fail to appropriately halt, resulting in unregulated cellular growth and the formation of cancer tumors. Several research teams are currently developing techniques to reverse this loss of genetic function characteristic of epithelioid sarcoma.<ref name=LevDina/>
+The ''SMARCB1'' gene (whose protein product is termed BAF47, INI1, or hSNF5) is located on chromosome [[22q11.2]].<ref name=pmid19033866/> It codes for a member of the [[SWI/SNF]] chromatin remodeling complex. Loss of SMARCB1 function is the most common genetic mutation observed in epithelioid sarcoma, and this dysfunction is likely a major driver of disease progression. SMARCB1 is a core protein subunit of the 15 subunit SWI/SNF (or BAF) complex involved in regulating the packaging of DNA in the cell nucleus.<ref name=pmid19033866/> It has been shown to be a potent [[tumor suppressor gene]],<ref name=pmid15899790/><ref>{{cite journal |last1=Kahali |first1=Bhaskar |last2=Yu |first2=Jinlong |last3=Marquez |first3=Stefanie B. |last4=Thompson |first4=Kenneth W. |last5=Liang |first5=Shermi Y. |last6=Lu |first6=Li |last7=Reisman |first7=David |title=The silencing of the SWI/SNF subunit and anticancer gene BRM in Rhabdoid tumors |journal=Oncotarget |volume=5 |issue=10 |pages=3316–32 |year=2014 |pmid=24913006 |pmc=4102812 |doi=10.18632/oncotarget.1945 }}</ref> meaning that its primary role is to control cell division. Since this tumor suppressor is commonly inactivated in epithelioid sarcoma, cell division can fail to appropriately stop, resulting in uncontrolled cancer growth. Research teams are trying to develop ways to reverse this loss of genetic function characteristic of epithelioid sarcoma.<ref name=LevDina/>
 ==Molecular biology==
+A number of important proteins appear to be active in epithelioid sarcoma. Some of these are described below.
 ===VEGF===
-[[VEGF]] (vascular endothelial growth factor) is often over-expressed in epithelioid sarcoma.<ref name=pmid10782895>{{cite journal |last1=Kuhnen |first1=Cornelius |last2=Lehnhardt |first2=Marcus |last3=Tolnay |first3=Edina |last4=Muehlberger |first4=Thomas |last5=Vogt |first5=Peter M. |last6=Müller |first6=Klaus-Michael |title=Patterns of expression and secretion of vascular endothelial growth factor in malignant soft-tissue tumours |journal=Journal of Cancer Research and Clinical Oncology |volume=126 |issue=4 |pages=219–25 |year=2000 |pmid=10782895 |doi=10.1007/s004320050036 }}</ref> This is a critical pathway in [[angiogenesis]], a process that cancer cells use to form new blood vessels, which provide necessary elements to the [[tumor]] for tumor survival. Anti-VEGF agents such as [[pazopanib]] have shown promise across several different carcinomas and in soft tissue sarcomas.<ref name=pmid22701332>{{cite journal |last1=Martín Liberal |first1=Juan |last2=Lagares-Tena |first2=Laura |last3=Sáinz-Jaspeado |first3=Miguel |last4=Mateo-Lozano |first4=Silvia |last5=García del Muro |first5=Xavier |last6=Tirado |first6=Oscar M. |title=Targeted Therapies in Sarcomas: Challenging the Challenge |journal=Sarcoma |volume=2012 |issue= |pages=1–13 |year=2012 |pmid=22701332 |pmc=3372278 |doi=10.1155/2012/626094 }}</ref> In one case study, a patient with advanced metastatic vulvar epithelioid sarcoma showed a partial resolution of both lung and pleural metastases when pazopanib was administered, whereas all other therapies had failed<ref>{{cite journal |last1=Chung |first1=Hye Won |title=The treatment of pazopanib on vulvar epithelioid sarcoma: A case report and review of literature |journal=대한산부인과학회 학술발표논문집 |volume=100 |pages=373 |url=http://www.papersearch.net/view/detail.asp?detail_key=40327863 |year=2014 }}{{MEDRS|date=October 2015}}</ref>
+[[VEGF]] (vascular endothelial growth factor) is often over-expressed in epithelioid sarcoma.<ref name="pmid10782895">{{cite journal |last1=Kuhnen |first1=Cornelius |last2=Lehnhardt |first2=Marcus |last3=Tolnay |first3=Edina |last4=Muehlberger |first4=Thomas |last5=Vogt |first5=Peter M. |last6=Müller |first6=Klaus-Michael |year=2000 |title=Patterns of expression and secretion of vascular endothelial growth factor in malignant soft-tissue tumours |journal=Journal of Cancer Research and Clinical Oncology |volume=126 |issue=4 |pages=219–25 |doi=10.1007/s004320050036 |pmid=10782895 |s2cid=21613610}}</ref> This is a critical pathway in [[angiogenesis]], a process that cancer cells use to form new blood vessels, which provide necessary elements to the [[tumor]] for tumor survival. Anti-VEGF agents such as [[pazopanib]] are approved for use in carcinomas and in soft tissue sarcomas such as epithelioid sarcoma, though access to these medications varies from country to country.<ref name="pmid22701332">{{cite journal |last1=Martín Liberal |first1=Juan |last2=Lagares-Tena |first2=Laura |last3=Sáinz-Jaspeado |first3=Miguel |last4=Mateo-Lozano |first4=Silvia |last5=García del Muro |first5=Xavier |last6=Tirado |first6=Oscar M. |year=2012 |title=Targeted Therapies in Sarcomas: Challenging the Challenge |journal=Sarcoma |volume=2012 |pages=1–13 |doi=10.1155/2012/626094 |pmc=3372278 |pmid=22701332 |doi-access=free}}</ref>
 ===MET===
-[[Mesenchymal–epithelial transition|MET]] (mesenchymal to epithelial transition) is another biological pathway that is likely involved in the development and progression of epithelioid sarcoma.<ref>{{cite journal |last1=Kuhnen |first1=C. |last2=Tolnay |first2=Edina |last3=Steinau |first3=Hans Ulrich |last4=Voss |first4=Bruno |last5=Müller |first5=Klaus-Michael |title=Expression of c-Met receptor and hepatocyte growth factor/scatter factor in synovial sarcoma and epithelioid sarcoma |journal=Virchows Archiv |volume=432 |issue=4 |pages=337–42 |year=1998 |pmid=9565343 |doi=10.1007/s004280050175 }}</ref><ref name=pmid25098767>{{cite journal |last1=Imura |first1=Yoshinori |last2=Yasui |first2=Hirohiko |last3=Outani |first3=Hidetatsu |last4=Wakamatsu |first4=Toru |last5=Hamada |first5=Kenichiro |last6=Nakai |first6=Takaaki |last7=Yamada |first7=Shutaro |last8=Myoui |first8=Akira |last9=Araki |first9=Nobuhito |last10=Ueda |first10=Takafumi |last11=Itoh |first11=Kazuyuki |last12=Yoshikawa |first12=Hideki |last13=Naka |first13=Norifumi |title=Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma |journal=Molecular Cancer |volume=13 |issue= |pages=185 |year=2014 |pmid=25098767 |pmc=4249599 |doi=10.1186/1476-4598-13-185 }}</ref> c-MET is a [[tyrosine kinase]] [[oncogene]], and its signaling pathway has been implicated in a variety of malignancies, including many cancers.{{citation needed|date=November 2018}}
+[[Mesenchymal–epithelial transition|MET]] (mesenchymal to epithelial transition) is a biological pathway that appears to be important for the development and progression of epithelioid sarcoma.<ref>{{cite journal |last1=Kuhnen |first1=C. |last2=Tolnay |first2=Edina |last3=Steinau |first3=Hans Ulrich |last4=Voss |first4=Bruno |last5=Müller |first5=Klaus-Michael |title=Expression of c-Met receptor and hepatocyte growth factor/scatter factor in synovial sarcoma and epithelioid sarcoma |journal=Virchows Archiv |volume=432 |issue=4 |pages=337–42 |year=1998 |pmid=9565343 |doi=10.1007/s004280050175 |s2cid=30726514 }}</ref><ref name=pmid25098767>{{cite journal |last1=Imura |first1=Yoshinori |last2=Yasui |first2=Hirohiko |last3=Outani |first3=Hidetatsu |last4=Wakamatsu |first4=Toru |last5=Hamada |first5=Kenichiro |last6=Nakai |first6=Takaaki |last7=Yamada |first7=Shutaro |last8=Myoui |first8=Akira |last9=Araki |first9=Nobuhito |last10=Ueda |first10=Takafumi |last11=Itoh |first11=Kazuyuki |last12=Yoshikawa |first12=Hideki |last13=Naka |first13=Norifumi |title=Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma |journal=Molecular Cancer |volume=13 |pages=185 |year=2014 |pmid=25098767 |pmc=4249599 |doi=10.1186/1476-4598-13-185 |doi-access=free }}</ref> MET is a [[tyrosine kinase]] [[oncogene]], and its signaling pathway has been implicated in a variety of malignancies, including many cancers.<ref>{{Cite journal |last1=Imura |first1=Yoshinori |last2=Yasui |first2=Hirohiko |last3=Outani |first3=Hidetatsu |last4=Wakamatsu |first4=Toru |last5=Hamada |first5=Kenichiro |last6=Nakai |first6=Takaaki |last7=Yamada |first7=Shutaro |last8=Myoui |first8=Akira |last9=Araki |first9=Nobuhito |last10=Ueda |first10=Takafumi |last11=Itoh |first11=Kazuyuki |last12=Yoshikawa |first12=Hideki |last13=Naka |first13=Norifumi |date=2014-08-07 |title=Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma |journal=Molecular Cancer |volume=13 |pages=185 |doi=10.1186/1476-4598-13-185 |issn=1476-4598 |pmc=4249599 |pmid=25098767 |doi-access=free }}</ref>
 ===Sonic hedgehog and Notch===
-The [[Sonic hedgehog]] and [[Notch signaling pathway]]s are also suspected to be up-regulated in epithelioid sarcoma. These cell signaling pathways control cellular proliferation and differentiation. They are also involved in [[cancer stem cell]] coordination and disease invasiveness and metastasis. Hhat inhibitors (such as RU-SKI 43) block the Sonic hedgehog signaling pathway by inhibiting hedgehog palmitoyl acytl-transferase. Current trials are investigating Notch inhibitors against epithelioid sarcoma.<ref>{{ClinicalTrialsGov|NCT01154452|Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma}}</ref>
+The [[Sonic hedgehog]] (SHH) and [[Notch signaling pathway]]s appear to be active in epithelioid sarcoma. These cell signaling pathways control cellular proliferation and differentiation. They are also involved in [[cancer stem cell]] coordination and disease invasiveness and metastasis. Hhat inhibitors (such as RU-SKI 43) block the SHH pathway by inhibiting hedgehog palmitoyl acytl-transferase. Trials have investigated Notch inhibitors in sarcomas such as epithelioid sarcoma.<ref>{{ClinicalTrialsGov|NCT01154452|Vismodegib and Gamma-Secretase/Notch Signalling Pathway Inhibitor RO4929097 in Treating Patients With Advanced or Metastatic Sarcoma}}</ref>
 ===mTOR===
-The frequent hyperactivation of [[mTOR]] (mammalian target of rapamycin) signaling has also been observed in epithelioid sarcoma.<ref name=pmid25098767/><ref name=pmid21821699>{{cite journal |last1=Xie |first1=X. |last2=Ghadimi |first2=M. P. H. |last3=Young |first3=E. D. |last4=Belousov |first4=R. |last5=Zhu |first5=Q.-s. |last6=Liu |first6=J. |last7=Lopez |first7=G. |last8=Colombo |first8=C. |last9=Peng |first9=T. |last10=Reynoso |first10=D. |last11=Hornick |first11=J. L. |last12=Lazar |first12=A. J. |last13=Lev |first13=D. |title=Combining EGFR and mTOR Blockade for the Treatment of Epithelioid Sarcoma |journal=Clinical Cancer Research |volume=17 |issue=18 |pages=5901–12 |year=2011 |pmid=21821699 |pmc=3176924 |doi=10.1158/1078-0432.CCR-11-0660 }}</ref> The mTOR pathway has been described as a “master switch” for cellular [[catabolism]] and [[anabolism]], and it can enhance [[cell cycle progression]], cell survival, and block normal cell death ([[apoptosis]]).<ref name=pmid22701332/> It has been demonstrated that simply blocking mTOR signaling can result in the reactivation of the [[AKT]] pathway, negating much of the anti-mTOR's efficacy.<ref name=pmid25098767/> This reactivation of AKT has been shown to be c-MET-dependent,<ref name=pmid25098767/> resulting in the rationale that blocking both mTOR and c-MET concurrently would show increased efficacy.
+The frequent overactivation of [[mTOR]] (mammalian target of rapamycin) signaling has also been observed in epithelioid sarcoma.<ref name=pmid25098767/><ref name=pmid21821699>{{cite journal |last1=Xie |first1=X. |last2=Ghadimi |first2=M. P. H. |last3=Young |first3=E. D. |last4=Belousov |first4=R. |last5=Zhu |first5=Q.-s. |last6=Liu |first6=J. |last7=Lopez |first7=G. |last8=Colombo |first8=C. |last9=Peng |first9=T. |last10=Reynoso |first10=D. |last11=Hornick |first11=J. L. |last12=Lazar |first12=A. J. |last13=Lev |first13=D. |title=Combining EGFR and mTOR Blockade for the Treatment of Epithelioid Sarcoma |journal=Clinical Cancer Research |volume=17 |issue=18 |pages=5901–12 |year=2011 |pmid=21821699 |pmc=3176924 |doi=10.1158/1078-0432.CCR-11-0660 }}</ref> The mTOR pathway has been described as a “master switch” for cellular [[catabolism]] and [[anabolism]], and it can enhance [[cell cycle progression]], cell survival, and block normal cell death ([[apoptosis]]).<ref name=pmid22701332/> It has been demonstrated that simply blocking mTOR signaling can result in the reactivation of the [[AKT]] pathway, negating much of mTOR blockade.<ref name=pmid25098767/> Reactivation of AKT has been shown to be MET-dependent,<ref name=pmid25098767/> resulting in the rationale that blocking both mTOR and MET concurrently should be a useful approach to treat epithelioid sarcoma.
 ===EGFR===
-The over-expression of [[epidermal growth factor receptor]] (EGFR) has been reported in a majority of epithelioid sarcomas.<ref name=pmid21821699/><ref name=pmid20118913>{{cite journal |last1=Cascio |first1=Michael J |last2=O'Donnell |first2=Richard J |last3=Horvai |first3=Andrew E |title=Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare |journal=Modern Pathology |volume=23 |issue=4 |pages=574–80 |year=2010 |pmid=20118913 |doi=10.1038/modpathol.2010.2 }}</ref> EGFR is a member of the [[ErbB|HER receptor family]]. Upon [[ligand binding]], EGFR phosphorylation triggers the activation of downstream signaling pathways involved in critical cellular functions such as [[Cell growth|proliferation]], survival, and [[angiogenesis]].<ref>{{cite journal |last1=Yang |first1=J.-L. |last2=Hannan |first2=M.T. |last3=Russell |first3=P.J. |last4=Crowe |first4=P.J. |title=Expression of HER1/EGFR protein in human soft tissue sarcomas |journal=European Journal of Surgical Oncology |volume=32 |issue=4 |pages=466–8 |year=2006 |pmid=16524687 |doi=10.1016/j.ejso.2006.01.012 }}</ref> [[In-vitro]] and [[in-vivo]] laboratory experiments have demonstrated that the blockade of EGFR in epithelioid sarcoma results in decreased cell proliferation, increased apoptosis, and abrogated invasion and migration capacities.<ref name=pmid21821699/> While the simple blockade of EGFR with a single agent has shown limited results in the clinical setting, when used as part of a combination regime (where an EGFR inhibitor is combined with an mTOR inhibitor), a [[Synergy|synergism]] has been observed, and superior tumor growth inhibition has been demonstrated.<ref name=pmid21821699/>
+The over-expression of [[epidermal growth factor receptor]] (EGFR) has been reported in a majority of epithelioid sarcomas.<ref name=pmid21821699/><ref name=pmid20118913>{{cite journal |last1=Cascio |first1=Michael J |last2=O'Donnell |first2=Richard J |last3=Horvai |first3=Andrew E |title=Epithelioid sarcoma expresses epidermal growth factor receptor but gene amplification and kinase domain mutations are rare |journal=Modern Pathology |volume=23 |issue=4 |pages=574–80 |year=2010 |pmid=20118913 |doi=10.1038/modpathol.2010.2 |s2cid=11592703 |doi-access=free }}</ref> EGFR is a member of the [[ErbB|HER receptor family]]. Upon [[ligand binding]], EGFR phosphorylation triggers the activation of downstream signaling pathways involved in critical cellular functions such as [[Cell growth|proliferation]], survival, and [[angiogenesis]].<ref>{{cite journal |last1=Yang |first1=J.-L. |last2=Hannan |first2=M.T. |last3=Russell |first3=P.J. |last4=Crowe |first4=P.J. |title=Expression of HER1/EGFR protein in human soft tissue sarcomas |journal=European Journal of Surgical Oncology |volume=32 |issue=4 |pages=466–8 |year=2006 |pmid=16524687 |doi=10.1016/j.ejso.2006.01.012 }}</ref> [[In-vitro]] and [[in-vivo]] laboratory experiments have demonstrated that the blockade of EGFR in epithelioid sarcoma results in decreased cell proliferation, increased apoptosis, and abrogated invasion and migration capacities.<ref name=pmid21821699/> While the blockade of EGFR with a medication has shown limited results in the clinical setting, when used as part of a combination with another drugs, such as an mTOR inhibitor, synergy has been observed, and superior tumor growth inhibition has been demonstrated.<ref name=pmid21821699/>
 ===CD109===
-[[CD109]] is often expressed in advanced epithelioid sarcoma and is thought to mark the [[cancer stem cell]] (or cancer initiating cell) of the disease.<ref name=pmid24376795>{{cite journal |last1=Ahmad |first1=Aamir |last2=Emori |first2=Makoto |last3=Tsukahara |first3=Tomohide |last4=Murase |first4=Masaki |last5=Kano |first5=Masanobu |last6=Murata |first6=Kenji |last7=Takahashi |first7=Akari |last8=Kubo |first8=Terufumi |last9=Asanuma |first9=Hiroko |last10=Yasuda |first10=Kazuyo |last11=Kochin |first11=Vitaly |last12=Kaya |first12=Mitsunori |last13=Nagoya |first13=Satoshi |last14=Nishio |first14=Jun |last15=Iwasaki |first15=Hiroshi |last16=Sonoda |first16=Tomoko |last17=Hasegawa |first17=Tadashi |last18=Torigoe |first18=Toshihiko |last19=Wada |first19=Takuro |last20=Yamashita |first20=Toshihiko |last21=Sato |first21=Noriyuki |title=High Expression of CD109 Antigen Regulates the Phenotype of Cancer Stem-Like Cells/Cancer-Initiating Cells in the Novel Epithelioid Sarcoma Cell Line ESX and Is Related to Poor Prognosis of Soft Tissue Sarcoma |journal=PLoS ONE |volume=8 |issue=12 |pages=e84187 |year=2013 |pmid=24376795 |pmc=3869840 |doi=10.1371/journal.pone.0084187 |bibcode=2013PLoSO...884187E }}</ref> Its level of expression has also been shown to be predictive of outcome. Cancer stem cells are a small population of tumor cells characterized by general chemo-resistance, the ability to self-renew, multi-differentiation potential, dormancy capabilities, and tumorigenesis. Therefore, cancer stem cells are thought to play key roles in the progression and relapse of cancer.
+[[CD109]], usually found on lymphocytes, is also expressed in epithelioid sarcoma, and is thought to mark the [[cancer stem cell]] (or cancer initiating cell) of the disease.<ref name=pmid24376795>{{cite journal |last1=Ahmad |first1=Aamir |last2=Emori |first2=Makoto |last3=Tsukahara |first3=Tomohide |last4=Murase |first4=Masaki |last5=Kano |first5=Masanobu |last6=Murata |first6=Kenji |last7=Takahashi |first7=Akari |last8=Kubo |first8=Terufumi |last9=Asanuma |first9=Hiroko |last10=Yasuda |first10=Kazuyo |last11=Kochin |first11=Vitaly |last12=Kaya |first12=Mitsunori |last13=Nagoya |first13=Satoshi |last14=Nishio |first14=Jun |last15=Iwasaki |first15=Hiroshi |last16=Sonoda |first16=Tomoko |last17=Hasegawa |first17=Tadashi |last18=Torigoe |first18=Toshihiko |last19=Wada |first19=Takuro |last20=Yamashita |first20=Toshihiko |last21=Sato |first21=Noriyuki |title=High Expression of CD109 Antigen Regulates the Phenotype of Cancer Stem-Like Cells/Cancer-Initiating Cells in the Novel Epithelioid Sarcoma Cell Line ESX and Is Related to Poor Prognosis of Soft Tissue Sarcoma |journal=PLOS ONE |volume=8 |issue=12 |pages=e84187 |year=2013 |pmid=24376795 |pmc=3869840 |doi=10.1371/journal.pone.0084187 |bibcode=2013PLoSO...884187E |doi-access=free }}</ref> Its expression has also been shown to be predictive of outcome. Cancer stem cells are a small population of tumor cells characterized by general chemo-resistance, the ability to self-renew, multi-differentiation potential, dormancy capabilities, and tumorigenesis. In this way, cancer stem cells are thought to play key roles in the progression and relapse of cancer.
 ===Cyclin D1===
-[[Cyclin D1]] is a protein requisite for cell cycle progression and has been shown to be up-regulated in epithelioid sarcoma.<ref name=pmid15578074/> Cyclin D-1 is a regulator of cyclin-dependent kinases ([[CDK4]] and [[CDK6]]). It has been shown to interact with the [[retinoblastoma protein]] (a tumor suppressor gene), CDK4 and CDK6, [[thyroid hormone receptor beta]], and [[nuclear receptor coactivator 1]], among others.<ref name=pmid15578074/> Cyclin D and CDKs promote cell cycle progression by releasing [[transcription factors]] that are important for the initiation of [[DNA replication]]. Abnormal levels of cyclin D-1 may promote rapid cell division in epithelioid sarcoma.
+[[Cyclin D1]] is a protein requisite for cell cycle progression and has been shown to be up-regulated in epithelioid sarcoma.<ref name=pmid15578074/> Cyclin D1 is a regulator of cyclin-dependent kinases (specifically, [[CDK4]] and [[CDK6]]). It has been shown to interact with the [[retinoblastoma protein]] (a tumor suppressor gene), CDK4 and CDK6, [[thyroid hormone receptor beta]], and [[nuclear receptor coactivator 1]], among others.<ref name=pmid15578074/> Cyclin D and CDKs promote cell cycle progression by releasing [[transcription factors]] that are important for the initiation of [[DNA replication]]. Abnormal levels of cyclin D1 may be associated with more rapid cell division in epithelioid sarcoma.
 ==Diagnosis==
-Tissue [[biopsy]] is the diagnostic modality of choice. Due to a high incidence of lymph node involvement, a [[sentinel lymph node biopsy]] is often performed. A common characteristic of epithelioid sarcoma (observed in 80% of all cases) is the loss of function of the [[SMARCB1]] gene (also termed BAF47, INI1, or hSNF5). Immunohistochemical staining of INI1 is available and can be used for the diagnosis of epithelioid sarcoma. [[MRI]] is the diagnostic modality of choice for imaging prior to biopsy and pathologic diagnosis, with the primary role being the determination of anatomic boundaries.{{citation needed|date=October 2015}}
+Tissue [[biopsy]] is the diagnostic modality of choice. Due to a high incidence of lymph node involvement, a [[sentinel lymph node biopsy]] may be performed. A common characteristic of epithelioid sarcoma (observed in 80% of all cases) is the loss of function of the ''[[SMARCB1]]'' gene (whose protein product is termed BAF47, INI1, or hSNF5). Immunohistochemical staining of INI1 is available and helps to diagnose of epithelioid sarcoma. [[MRI]] is the diagnostic modality of choice for imaging prior to biopsy and pathologic diagnosis for most patients.
 ===Staging===
@@ Line 66: / Line 67: @@
 ==Treatment==
+Surgery, radiation, and systemic therapy such as chemotherapy are all used at various times in the treatment of patients who have epitheloid sarcoma. Since sarcomas are considered very rare, it is not surprising that outcomes for patients with this type of cancer are better when patients are evaluated in expert centers, and when possible, treated there.<ref>{{Cite journal |last1=Blay |first1=J.-Y. |last2=Honoré |first2=C. |last3=Stoeckle |first3=E. |last4=Meeus |first4=P. |last5=Jafari |first5=M. |last6=Gouin |first6=F. |last7=Anract |first7=P. |last8=Ferron |first8=G. |last9=Rochwerger |first9=A. |last10=Ropars |first10=M. |last11=Carrere |first11=S. |last12=Marchal |first12=F. |last13=Sirveaux |first13=F. |last14=Di Marco |first14=A. |last15=Le Nail |first15=L. R. |date=2019-07-01 |title=Surgery in reference centers improves survival of sarcoma patients: a nationwide study |journal=Annals of Oncology|volume=30 |issue=7 |pages=1143–1153 |doi=10.1093/annonc/mdz124 |issn=1569-8041 |pmc=6637376 |pmid=31081028}}</ref>
-Surgical resection of the tumor with wide margins remains the preferred method of treatment,<ref name=pmid16804932>{{cite journal |last1=de Visscher |first1=Sebastiaan A. H. J. |last2=van Ginkel |first2=Robbert J. |last3=Wobbes |first3=Theo |last4=Veth |first4=René P. H. |last5=ten Heuvel |first5=Suzanne E. |last6=Suurmeijer |first6=Albert J. H. |last7=Hoekstra |first7=Harad J. |title=Epithelioid sarcoma: Still an only surgically curable disease |journal=Cancer |volume=107 |issue=3 |pages=606–12 |year=2006 |pmid=16804932 |doi=10.1002/cncr.22037 }}</ref> and has shown the most success against the disease.<ref name=pmid16804932/><ref>{{cite journal |last1=Rao |first1=Bhaskar N. |last2=Rodriguez-Galindo |first2=Carlos |title=Local control in childhood extremity sarcomas: Salvaging limbs and sparing function |journal=Medical and Pediatric Oncology |volume=41 |issue=6 |pages=584–7 |year=2003 |pmid=14595726 |doi=10.1002/mpo.10405 }}</ref><ref>{{cite journal |last1=Ferrari |first1=Andrea |last2=Miceli |first2=Rosalba |last3=Rey |first3=Annie |last4=Oberlin |first4=Odile |last5=Orbach |first5=Daniel |last6=Brennan |first6=Bernadette |last7=Mariani |first7=Luigi |last8=Carli |first8=Modesto |last9=Bisogno |first9=Gianni |last10=Cecchetto |first10=Giovanni |last11=Salvo |first11=Gian Luca De |last12=Casanova |first12=Michela |last13=Vannoesel |first13=Max M. |last14=Kelsey |first14=Anna |last15=Stevens |first15=Michael C. |last16=Devidas |first16=Meenakshi |last17=Pappo |first17=Alberto S. |last18=Spunt |first18=Sheri L. |title=Non-metastatic unresected paediatric non-rhabdomyosarcoma soft tissue sarcomas: Results of a pooled analysis from United States and European groups |journal=European Journal of Cancer |volume=47 |issue=5 |pages=724–31 |year=2011 |pmid=21145727 |pmc=3539303 |doi=10.1016/j.ejca.2010.11.013 }}</ref> Recently, [[limb-sparing techniques|limb-sparing surgery]] has been explored with moderate success.<ref>{{cite web |last1=DeGroot |first1=Henry |last2=Ellison |first2=Bruce |title=Limb Salvage Surgery for Extremity Sarcomas |url=http://www.bonetumor.org/tumors/images/Limbsal1.doc |access-date=2015-04-23 |archive-url=https://web.archive.org/web/20150208193251/http://www.bonetumor.org/tumors/images/Limbsal1.doc |archive-date=2015-02-08 |url-status=dead }}{{MEDRS|date=October 2015}}</ref>
+Surgical resection of epithelioid sarcoma with wide margins remains the preferred method of treatment,<ref name="pmid16804932">{{cite journal |last1=de Visscher |first1=Sebastiaan A. H. J. |last2=van Ginkel |first2=Robbert J. |last3=Wobbes |first3=Theo |last4=Veth |first4=René P. H. |last5=ten Heuvel |first5=Suzanne E. |last6=Suurmeijer |first6=Albert J. H. |last7=Hoekstra |first7=Harad J. |title=Epithelioid sarcoma: Still an only surgically curable disease |journal=Cancer |volume=107 |issue=3 |pages=606–12 |year=2006 |pmid=16804932 |doi=10.1002/cncr.22037 |s2cid=25833518 |doi-access=free }}</ref> and as of 2023, remains the only curative approach for the cancer, sometimes in concert with radiation or chemotherapy.<ref name="pmid16804932" /><ref>{{cite journal |last1=Rao |first1=Bhaskar N. |last2=Rodriguez-Galindo |first2=Carlos |title=Local control in childhood extremity sarcomas: Salvaging limbs and sparing function |journal=Medical and Pediatric Oncology |volume=41 |issue=6 |pages=584–7 |year=2003 |pmid=14595726 |doi=10.1002/mpo.10405 }}</ref><ref>{{cite journal |last1=Ferrari |first1=Andrea |last2=Miceli |first2=Rosalba |last3=Rey |first3=Annie |last4=Oberlin |first4=Odile |last5=Orbach |first5=Daniel |last6=Brennan |first6=Bernadette |last7=Mariani |first7=Luigi |last8=Carli |first8=Modesto |last9=Bisogno |first9=Gianni |last10=Cecchetto |first10=Giovanni |last11=Salvo |first11=Gian Luca De |last12=Casanova |first12=Michela |last13=Vannoesel |first13=Max M. |last14=Kelsey |first14=Anna |last15=Stevens |first15=Michael C. |last16=Devidas |first16=Meenakshi |last17=Pappo |first17=Alberto S. |last18=Spunt |first18=Sheri L. |title=Non-metastatic unresected paediatric non-rhabdomyosarcoma soft tissue sarcomas: Results of a pooled analysis from United States and European groups |journal=European Journal of Cancer |volume=47 |issue=5 |pages=724–31 |year=2011 |pmid=21145727 |pmc=3539303 |doi=10.1016/j.ejca.2010.11.013 }}</ref> [[Limb-sparing techniques|Limb-sparing surgery]] is the standard of care for treating all sarcomas, and is used wherever possible for treatment of epithelioid sarcoma as well.<ref>{{cite web |last1=DeGroot |first1=Henry |last2=Ellison |first2=Bruce |title=Limb Salvage Surgery for Extremity Sarcomas |url=http://www.bonetumor.org/tumors/images/Limbsal1.doc |access-date=2015-04-23 |archive-url=https://web.archive.org/web/20150208193251/http://www.bonetumor.org/tumors/images/Limbsal1.doc |archive-date=2015-02-08 |url-status=dead }}{{MEDRS|date=October 2015}}</ref>
-In cases of advanced, recurrent, or metastasized disease, or if the tumor is inoperable, chemotherapy and radiation are the standard of care,<ref name="NCCN Soft Tissue Sarcoma">{{cite book |publisher=National Comprehensive Cancer Network |series=Clinical Practice Guidelines in Oncology |title=Soft Tissue Sarcoma |url=http://www.nccn.org/patients/guidelines/sarcoma/index.html }}{{page needed|date=October 2015}}</ref> although the overall success rates with these remains low.<ref>{{cite journal |last1=Wolf |first1=Patrick S. |last2=Flum |first2=David R. |last3=Tanas |first3=Munir R. |last4=Rubin |first4=Brian P. |last5=Mann |first5=Gary N. |title=Epithelioid sarcoma: the University of Washington experience |journal=The American Journal of Surgery |volume=196 |issue=3 |pages=407–12 |year=2008 |pmid=18436180 |doi=10.1016/j.amjsurg.2007.07.029 }}</ref>
+In cases of advanced, recurrent, or metastasized disease, or if the tumor is inoperable, chemotherapy and radiation are the standard of care.<ref name="NCCN Soft Tissue Sarcoma">{{cite book |publisher=National Comprehensive Cancer Network |series=Clinical Practice Guidelines in Oncology |title=Soft Tissue Sarcoma |url=http://www.nccn.org/patients/guidelines/sarcoma/index.html |access-date=2015-10-06 |archive-date=2018-08-05 |archive-url=https://web.archive.org/web/20180805200411/https://www.nccn.org/patients/guidelines/sarcoma/index.html |url-status=dead }}{{page needed|date=October 2015}}</ref> The benefit for standard medications such as doxorubicin, ifosfamide, and combinations involving gemcitabine is generally measured in months, not years.<ref>{{cite journal |last1=Wolf |first1=Patrick S. |last2=Flum |first2=David R. |last3=Tanas |first3=Munir R. |last4=Rubin |first4=Brian P. |last5=Mann |first5=Gary N. |title=Epithelioid sarcoma: the University of Washington experience |journal=The American Journal of Surgery |volume=196 |issue=3 |pages=407–12 |year=2008 |pmid=18436180 |doi=10.1016/j.amjsurg.2007.07.029 }}</ref>
-==Prognosis==
-The 5-year survival rate for epithelioid sarcoma patients is 50-70%, and the 10-year survival rate is 42-55%. Children with epithelioid sarcoma tend to have slightly better outcomes than adults, with 5 year survival rates around 65%.<ref name=pmid16353216/> Pediatric patients also tend to display less lymphatic spread and metastasis.<ref name=pmid16353216/> In addition to stage and grade of the tumor, gender, site, age at diagnosis, tumor size and microscopic pathology have all been shown to affect prognosis.<ref name=pmid3392084/><ref name=pmid4014539>{{cite journal |last1=Chase |first1=DR |last2=Enzinger |first2=FM |title=Epithelioid sarcoma. Diagnosis, prognostic indicators, and treatment |journal=The American Journal of Surgical Pathology |volume=9 |issue=4 |pages=241–63 |year=1985 |pmid=4014539 |doi=10.1097/00000478-198504000-00001|url=https://zenodo.org/record/1234740 }}</ref> Advanced stage and grade are associated with worse outcomes. Females tend to have more favorable outcomes than males, proximal cases show worse outcomes than distal cases, and younger age is associated with more positive outcomes. Tumors more than 2&nbsp;cm in diameter and tumors with [[necrosis]] and [[vascular invasion]] have been correlated with a worse outcome.<ref name=pmid4014539/>
+In January 2020, The U.S. Food and Drug Administration approved the oral medication [[tazemetostat]] (trade name Tazverik), a drug that blocks the [[EZH2]] methyltransferase, for the treatment of epithelioid sarcoma in patients aged 16 years and older with either metastatic or locally advanced (unable to be completely removed surgically) disease.<ref>{{cite press release |title=FDA approves first treatment option specifically for patients with epithelioid sarcoma, a rare soft tissue cancer |date= January 23, 2020 |publisher= FDA |url= https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-option-specifically-patients-epithelioid-sarcoma-rare-soft-tissue |access-date= 2020-03-03}}</ref> The data that led to the drug's authorization have been supported by post-marketing studies. As with standard chemotherapy, the effectiveness of tazemetostat is generally measured in months, though some patients will fare better for a longer period of time.
-The gold standard for chemotherapy is a combination of [[doxorubicin]] and [[ifosfamide]]. However, recent studies have suggested that the addition of ifosfamide to doxorubicin does not necessarily lead to an increase in overall survival.<ref>{{cite journal |last1=Judson |first1=Ian |last2=Verweij |first2=Jaap |last3=Gelderblom |first3=Hans |last4=Hartmann |first4=Jörg T |last5=Schöffski |first5=Patrick |last6=Blay |first6=Jean-Yves |last7=Kerst |first7=J Martijn |last8=Sufliarsky |first8=Josef |last9=Whelan |first9=Jeremy |last10=Hohenberger |first10=Peter |last11=Krarup-Hansen |first11=Anders |last12=Alcindor |first12=Thierry |last13=Marreaud |first13=Sandrine |last14=Litière |first14=Saskia |last15=Hermans |first15=Catherine |last16=Fisher |first16=Cyril |last17=Hogendoorn |first17=Pancras C W |last18=dei Tos |first18=A Paolo |last19=van der Graaf |first19=Winette T A |title=Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial |journal=The Lancet Oncology |volume=15 |issue=4 |pages=415–23 |year=2014 |pmid=24618336 |doi=10.1016/S1470-2045(14)70063-4 }}</ref> [[Etoposide]], [[vincristine]], [[dactinomycin]], and [[cyclophosphamide]] have also traditionally been given.<ref name="NCCN Soft Tissue Sarcoma"/>  Newer chemotherapies, such as [[gemcitabine]] and [[pazopanib]], are currently being tested in clinical trials.{{citation needed|date=November 2018}}
+==Prognosis==
+The 5-year survival rate for epithelioid sarcoma patients is usually quoted as 50-70%, with the 10-year survival rate is 42-55%. Children with epithelioid sarcoma may have somewhat better outcomes than adults, with 5 year survival rates around 65%.<ref name=pmid16353216/> Pediatric patients also less often demonstrate lymphatic spread and metastasis than adults with this diagnosis.<ref name=pmid16353216/> In addition to stage and grade of the tumor, gender, site, age at diagnosis, tumor size and microscopic pathology all have been shown to affect prognosis.<ref name=pmid3392084/><ref name=pmid4014539>{{cite journal |last1=Chase |first1=DR |last2=Enzinger |first2=FM |title=Epithelioid sarcoma. Diagnosis, prognostic indicators, and treatment |journal=The American Journal of Surgical Pathology |volume=9 |issue=4 |pages=241–63 |year=1985 |pmid=4014539 |doi=10.1097/00000478-198504000-00001|s2cid=36504524 |url=https://zenodo.org/record/1234740 }}</ref> Unsurprisingly, advanced stage and grade are associated with worse outcomes. Females tend to have more favorable outcomes than males, proximal cases show worse outcomes than distal cases. Tumors more than 2&nbsp;cm in diameter and tumors with [[necrosis]] and [[vascular invasion]] also have been correlated with a worse outcome.<ref name=pmid4014539/>
 [[Radiation therapy]] is also a treatment option when tumors are deemed inoperable or wide surgical margins are not achievable. Radiation therapy in combination with chemotherapy has so far resulted in only minimal improvements to response rates. Trials with [[brachytherapy]] (an internal radiation treatment that delivers a high dose of radiation directly to the tumor and is thought to have fewer long-term side effects) have produced some positive results.{{citation needed|date=October 2015}}
+==Research==
-==New therapeutic strategies==
-Epithelioid sarcoma (especially advanced stage, recurrent, or metastasized disease) has been shown to be resistant to traditional cancer therapies, necessitating further exploration of novel treatment methods and techniques. Because of the relatively poor response of epithelioid sarcoma to traditional cancer treatments (surgery, chemotherapy, and radiation), new treatment strategies are being looked to.{{citation needed|date=October 2015}}
+Epithelioid sarcoma (especially advanced stage, recurrent, or metastasized disease) has been shown to become resistant to traditional cancer therapies, necessitating further exploration of novel treatment methods and techniques. Because of the relatively poor duration of the benefit of treatment of epithelioid sarcoma using traditional cancer treatments (such as chemotherapy and radiation), new treatment strategies are being examined.
-===New chemotherapies===
+===Chemotherapy===
-New chemotherapies are being explored in current clinical trials for epithelioid sarcoma, although, thus far, none has shown significant improvement over the efficacy of doxorubicin/ifosfamide. These new agents include gemcitabine, pazopanib, cixutumumab, temozolomide, dasatanib, bevacizumab, taxanes, and vinorelbine.<ref name="NCCN Soft Tissue Sarcoma"/>
+New chemotherapies are being explored in current clinical trials for epithelioid sarcoma, although, thus far, none has shown significant improvement over the efficacy of doxorubicin and/or ifosfamide. Newer agents include gemcitabine, taxanes, vinorelbine and pazopanib.<ref name="NCCN Soft Tissue Sarcoma"/>
-[[Aldoxorubicin]] is a new [[pro-drug]] of doxorubicin. Doxorubicin is the standard of care for advanced or metastic epithelioid sarcoma, but has dose-limiting toxicities, namely acute and chronic [[cardiac toxicity]].<ref>{{cite journal |last1=Lefrak |first1=Edward A. |last2=Piťha |first2=Jan |last3=Rosenheim |first3=Sidney |last4=Gottlieb |first4=Jeffrey A. |title=A clinicopathologic analysis of adriamycin cardiotoxicity |journal=Cancer |volume=32 |issue=2 |pages=302–14 |year=1973 |pmid=4353012 |doi=10.1002/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2 }}</ref><ref>{{cite journal |last1=Lipshultz |first1=Steven E. |last2=Colan |first2=Steven D. |last3=Gelber |first3=Richard D. |last4=Perez-Atayde |first4=Antonio R. |last5=Sallan |first5=Stephen E. |last6=Sanders |first6=Stephen P. |title=Late Cardiac Effects of Doxorubicin Therapy for Acute Lymphoblastic Leukemia in Childhood |journal=New England Journal of Medicine |volume=324 |issue=12 |pages=808–15 |year=1991 |pmid=1997853 |doi=10.1056/NEJM199103213241205 }}</ref> Doxorubicin has achieved response rates in the 12-23% range for patients with soft tissue sarcomas. Aldoxorubicin is a new version of doxorubicin that is designed to safely deliver a higher dose of the drug directly to the tumor, resulting in increased efficacy and less toxicity. It works by entering the bloodstream, binding to the [[albumin]] in the blood, traveling throughout the body, and releasing a doxorubicin payload when it encounters the acidic microenvironment of a tumor.<ref>{{cite journal |last1=Chawla |first1=Sant P. |last2=Chua |first2=Victoria S. |last3=Hendifar |first3=Andrew F. |last4=Quon |first4=Doris V. |last5=Soman |first5=Neelesh |last6=Sankhala |first6=Kamalesh K. |last7=Wieland |first7=D. Scott |last8=Levitt |first8=Daniel J. |title=A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma |journal=Cancer |volume=121 |issue=4 |pages=570–9 |year=2015 |pmid=25312684 |doi=10.1002/cncr.29081 }}</ref> Several phase I and II studies are ongoing, and, thus far at least, little if any cardiac toxicity has been observed.  A maximum tolerated dose of aldoxorubicin has been established at 3.5 times the MTD of doxorubicin, and studies have indicated increased response rates for patients with soft tissue sarcomas. What is unknown at this time are the potential long-term side-effects of this increased dose of doxorubicin. Several studies have shown increased risk of the development of secondary cancers associated with exposure to high-dose anthracyclines (such as doxorubicin).<ref>{{cite journal |last1=Henderson |first1=T. O. |last2=Whitton |first2=J. |last3=Stovall |first3=M. |last4=Mertens |first4=A. C. |last5=Mitby |first5=P. |last6=Friedman |first6=D. |last7=Strong |first7=L. C. |last8=Hammond |first8=S. |last9=Neglia |first9=J. P. |last10=Meadows |first10=A. T. |last11=Robison |first11=L. |last12=Diller |first12=L. |title=Secondary Sarcomas in Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study |journal=Journal of the National Cancer Institute |volume=99 |issue=4 |pages=300–8 |year=2007 |pmid=17312307 |doi=10.1093/jnci/djk052 }}</ref>
+[[Aldoxorubicin]] is a newer [[pro-drug]] version of doxorubicin that has been studied. Doxorubicin is the standard of care for advanced or metastatic epithelioid sarcoma, but it has dose-limiting toxicities, namely acute and chronic [[cardiac toxicity]].<ref>{{cite journal |last1=Lefrak |first1=Edward A. |last2=Piťha |first2=Jan |last3=Rosenheim |first3=Sidney |last4=Gottlieb |first4=Jeffrey A. |title=A clinicopathologic analysis of adriamycin cardiotoxicity |journal=Cancer |volume=32 |issue=2 |pages=302–14 |year=1973 |pmid=4353012 |doi=10.1002/1097-0142(197308)32:2<302::AID-CNCR2820320205>3.0.CO;2-2 |s2cid=41537913 }}</ref><ref>{{cite journal |last1=Lipshultz |first1=Steven E. |last2=Colan |first2=Steven D. |last3=Gelber |first3=Richard D. |last4=Perez-Atayde |first4=Antonio R. |last5=Sallan |first5=Stephen E. |last6=Sanders |first6=Stephen P. |title=Late Cardiac Effects of Doxorubicin Therapy for Acute Lymphoblastic Leukemia in Childhood |journal=New England Journal of Medicine |volume=324 |issue=12 |pages=808–15 |year=1991 |pmid=1997853 |doi=10.1056/NEJM199103213241205 |doi-access=free }}</ref>  Aldoxorubicin was designed to safely deliver a higher dose of the drug directly to the tumor, resulting in less toxicity. Phase I and II studies of aldoxorubicin were undertaken and little cardiac toxicity was observed. While usefulness was seen in some patients, the place of aldoxorubicin in treatment of patients with epithelioid sarcoma or other sarcomas, in particular compared to doxorubicin, has not been defined.
-[[TH-302]] is another novel prodrug in current development. It targets [[tumor hypoxia]], a common event in tumorigenesis where the tumor microenvironment is depleted of oxygen and becomes [[Tumor hypoxia|hypoxic]].<ref name=pmid22147748>{{cite journal |last1=Meng |first1=F. |last2=Evans |first2=J. W. |last3=Bhupathi |first3=D. |last4=Banica |first4=M. |last5=Lan |first5=L. |last6=Lorente |first6=G. |last7=Duan |first7=J.-X. |last8=Cai |first8=X. |last9=Mowday |first9=A. M. |last10=Guise |first10=C. P. |last11=Maroz |first11=A. |last12=Anderson |first12=R. F. |last13=Patterson |first13=A. V. |last14=Stachelek |first14=G. C. |last15=Glazer |first15=P. M. |last16=Matteucci |first16=M. D. |last17=Hart |first17=C. P. |title=Molecular and Cellular Pharmacology of the Hypoxia-Activated Prodrug TH-302 |journal=Molecular Cancer Therapeutics |volume=11 |issue=3 |pages=740–51 |year=2012 |pmid=22147748 |doi=10.1158/1535-7163.MCT-11-0634 }}</ref> Hypoxic niches in tumors tend to harbor slower-growing cancer cells,<ref>{{cite journal |last1=Wilson |first1=William R. |last2=Hay |first2=Michael P. |title=Targeting hypoxia in cancer therapy |journal=Nature Reviews Cancer |volume=11 |issue=6 |pages=393–410 |year=2011 |pmid=21606941 |doi=10.1038/nrc3064 }}</ref> making many chemotherapies ineffective in these areas. TH-302 directly targets these deep hypoxic regions, and once within them, it releases a cytotoxic payload of bromo-isophosphoramide mustard directly to the cancer cells.<ref name=pmid22147748/> Given that epithelioid sarcoma is a slow-growing tumor, it is reasonable to hypothesize that ES tumors would be highly hypoxic and show a favorable response to TH-302. Several studies have observed increased efficacy of TH-302 when the hypoxic tumor microenvironment has been exasperated.<ref>{{cite journal |last1=Wojtkowiak |first1=Jonathan W |last2=Cornnell |first2=Heather C |last3=Matsumoto |first3=Shingo |last4=Saito |first4=Keita |last5=Takakusagi |first5=Yoichi |last6=Dutta |first6=Prasanta |last7=Kim |first7=Munju |last8=Zhang |first8=Xiaomeng |last9=Leos |first9=Rafael |last10=Bailey |first10=Kate M |last11=Martinez |first11=Gary |last12=Lloyd |first12=Mark C |last13=Weber |first13=Craig |last14=Mitchell |first14=James B |last15=Lynch |first15=Ronald M |last16=Baker |first16=Amanda F |last17=Gatenby |first17=Robert A |last18=Rejniak |first18=Katarzyna A |last19=Hart |first19=Charles |last20=Krishna |first20=Murali C |last21=Gillies |first21=Robert J |title=Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302 |journal=Cancer & Metabolism |volume=3 |issue=1 |pages=2 |year=2015 |pmid=25635223 |pmc=4310189 |doi=10.1186/s40170-014-0026-z }}</ref> Several phase I, II, and III trials with TH-302 and TH-302 in combination with doxorubicin are ongoing, and promising results have thus far been observed.<ref>{{cite journal |last1=Chawla |first1=S. P. |last2=Cranmer |first2=L. D. |last3=Van Tine |first3=B. A. |last4=Reed |first4=D. R. |last5=Okuno |first5=S. H. |last6=Butrynski |first6=J. E. |last7=Adkins |first7=D. R. |last8=Hendifar |first8=A. E. |last9=Kroll |first9=S. |last10=Ganjoo |first10=K. N. |title=Phase II Study of the Safety and Antitumor Activity of the Hypoxia-Activated Prodrug TH-302 in Combination With Doxorubicin in Patients With Advanced Soft Tissue Sarcoma |journal=Journal of Clinical Oncology |volume=32 |issue=29 |pages=3299–306 |year=2014 |pmid=25185097 |doi=10.1200/JCO.2013.54.3660 |pmc=4588714}}</ref> Two phase 3 trials failed in 2015.
+[[TH-302]] was another research drug studied in sarcomas such as epithelioid sarcoma. It targets [[tumor hypoxia]], a common event in tumorigenesis where the tumor microenvironment is depleted of oxygen and becomes [[Tumor hypoxia|hypoxic]].<ref name=pmid22147748>{{cite journal |last1=Meng |first1=F. |last2=Evans |first2=J. W. |last3=Bhupathi |first3=D. |last4=Banica |first4=M. |last5=Lan |first5=L. |last6=Lorente |first6=G. |last7=Duan |first7=J.-X. |last8=Cai |first8=X. |last9=Mowday |first9=A. M. |last10=Guise |first10=C. P. |last11=Maroz |first11=A. |last12=Anderson |first12=R. F. |last13=Patterson |first13=A. V. |last14=Stachelek |first14=G. C. |last15=Glazer |first15=P. M. |last16=Matteucci |first16=M. D. |last17=Hart |first17=C. P. |title=Molecular and Cellular Pharmacology of the Hypoxia-Activated Prodrug TH-302 |journal=Molecular Cancer Therapeutics |volume=11 |issue=3 |pages=740–51 |year=2012 |pmid=22147748 |doi=10.1158/1535-7163.MCT-11-0634 |s2cid=11701323 |doi-access=free }}</ref> Phase I, II, and III trials with TH-302 alone and in combination were undertaken,<ref>{{cite journal |last1=Chawla |first1=S. P. |last2=Cranmer |first2=L. D. |last3=Van Tine |first3=B. A. |last4=Reed |first4=D. R. |last5=Okuno |first5=S. H. |last6=Butrynski |first6=J. E. |last7=Adkins |first7=D. R. |last8=Hendifar |first8=A. E. |last9=Kroll |first9=S. |last10=Ganjoo |first10=K. N. |title=Phase II Study of the Safety and Antitumor Activity of the Hypoxia-Activated Prodrug TH-302 in Combination With Doxorubicin in Patients With Advanced Soft Tissue Sarcoma |journal=Journal of Clinical Oncology |volume=32 |issue=29 |pages=3299–306 |year=2014 |pmid=25185097 |doi=10.1200/JCO.2013.54.3660 |pmc=4588714}}</ref> but two phase 3 trials failed in 2015, such that the drug is no longer actively being studied.
 ===Immunotherapies===
 [[Immunotherapy]] is the strategy of using the body's own immune system to fight cancer. It usually involves “training” or “tweaking” the immune system so that it can better recognize and reject cancer cells. Different immunotherapies can include manipulation of the body's [[T-cells]], [[NK cells]], or [[Dendritic cells]] so they are more effective against cancer cells. They can also include the administration of laboratory-produced [[antibodies]] specific to tumor [[antigens]] to create or boost an [[immune response]].{{citation needed|date=October 2015}}
-[[Vaccine therapy]] is perhaps the [[immunotherapeutic]] strategy with the most ongoing exploration in sarcomas at the current time,<ref name=WilkyGoldberg2014>{{cite journal |last1=Wilky |first1=Breelyn |last2=Goldberg |first2=John M. |date=April 14, 2014 |title=Immunotherapy in sarcoma: A new frontier |journal=Discovery Medicine |volume=17 |issue=94 |pages=201–6 |url=http://www.discoverymedicine.com/Breelyn-A-Wilky/2014/04/14/immunotherapy-in-sarcoma-a-new-frontier/ |pmid=24759624 }}</ref> although, thus far at least, little evidence has emerged indicating that active vaccination alone can lead to tumor regression.<ref name="Hu et al 2014"/> Multiple techniques and treatment strategies are currently being studied in an effort to improve the objective response rate of vaccine therapy.<ref name=WilkyGoldberg2014/> Vaccines can deliver various tumor-associated factors (tumor antigens) to the immune system, resulting in a natural antibody and T-cell response to the tumor.<ref name=WilkyGoldberg2014/><ref name=pmid21716856>{{cite journal |last1=Pedrazzoli |first1=Paolo |last2=Secondino |first2=Simona |last3=Perfetti |first3=Vittorio |last4=Comoli |first4=Patrizia |last5=Montagna |first5=Daniela |title=Immunotherapeutic Intervention against Sarcomas |journal=Journal of Cancer |volume=2 |issue= |pages=350–6 |year=2011 |pmid=21716856 |pmc=3119402 |doi=10.7150/jca.2.350 }}</ref>
+[[Vaccine therapy]] is perhaps the simplest [[immunotherapeutic]] strategy,<ref name=WilkyGoldberg2014>{{cite journal |last1=Wilky |first1=Breelyn |last2=Goldberg |first2=John M. |date=April 14, 2014 |title=Immunotherapy in sarcoma: A new frontier |journal=Discovery Medicine |volume=17 |issue=94 |pages=201–6 |url=http://www.discoverymedicine.com/Breelyn-A-Wilky/2014/04/14/immunotherapy-in-sarcoma-a-new-frontier/ |pmid=24759624 }}</ref> although, thus far, little to no evidence has emerged indicating that vaccination with any compound leads to shrinking of epithelioid sarcoma or other sarcomas.<ref name="Hu et al 2014"/> Multiple techniques and treatment strategies are currently being studied in many cancers in an effort to improve the usefulness of vaccine therapy.<ref name=WilkyGoldberg2014/> Vaccines can deliver various tumor-associated factors (tumor antigens) to the immune system, resulting in a natural antibody and T-cell response to the tumor. Unforunately, no such molecules that are specific to epithelioid sarcoma have been identified for testing such an approach.<ref name=WilkyGoldberg2014/><ref name=pmid21716856>{{cite journal |last1=Pedrazzoli |first1=Paolo |last2=Secondino |first2=Simona |last3=Perfetti |first3=Vittorio |last4=Comoli |first4=Patrizia |last5=Montagna |first5=Daniela |title=Immunotherapeutic Intervention against Sarcomas |journal=Journal of Cancer |volume=2 |pages=350–6 |year=2011 |pmid=21716856 |pmc=3119402 |doi=10.7150/jca.2.350 }}</ref>
-[[Adoptive immunotherapy]] seeks to expand a population of the body's T-cells that will recognize a specific tumor antigen. T-cells can be harvested and then expanded and genetically manipulated to recognize certain tumor markers.<ref name=WilkyGoldberg2014/><ref name=pmid21716856/> In one case, a patient with advanced epithelioid sarcoma who had failed multiple therapies showed a strong response to expanded lymphocytes and natural killer cells.<ref>{{cite journal |last1=Ratnavelu |first1=Kananathan |last2=Subramani |first2=Baskar |last3=Pullai |first3=Chithra Ramanathan |last4=Krishnan |first4=Kohila |last5=Sugadan |first5=Sheela Devi |last6=Rao |first6=Manjunath Sadananda |last7=Veerakumarasivam |first7=Abhi |last8=Deng |first8=Xuewen |last9=Hiroshi |first9=Terunuma |title=Autologous immune enhancement therapy against an advanced epithelioid sarcoma: A case report |journal=Oncology Letters |volume=5 |issue=5 |pages=1457–1460 |year=2013 |pmid=23761810 |pmc=3678875 |doi=10.3892/ol.2013.1247 }}</ref>
+[[Adoptive immunotherapy]] seeks to expand a population of the body's T cells that will recognize a specific tumor antigen. T-cells can be harvested and then expanded and genetically manipulated to recognize certain tumor markers.<ref name=WilkyGoldberg2014/><ref name=pmid21716856/> In one case, a patient with advanced epithelioid sarcoma who had failed multiple therapies showed a strong response to expanded lymphocytes and natural killer cells.<ref>{{cite journal |last1=Ratnavelu |first1=Kananathan |last2=Subramani |first2=Baskar |last3=Pullai |first3=Chithra Ramanathan |last4=Krishnan |first4=Kohila |last5=Sugadan |first5=Sheela Devi |last6=Rao |first6=Manjunath Sadananda |last7=Veerakumarasivam |first7=Abhi |last8=Deng |first8=Xuewen |last9=Hiroshi |first9=Terunuma |title=Autologous immune enhancement therapy against an advanced epithelioid sarcoma: A case report |journal=Oncology Letters |volume=5 |issue=5 |pages=1457–1460 |year=2013 |pmid=23761810 |pmc=3678875 |doi=10.3892/ol.2013.1247 }}</ref> However, as of 2023, no specific clinical trials are examining cellular therapy for epithelioid sarcoma specifically.
-[[Immune checkpoint inhibitor]]s have recently shown promise against several cancers and may hold promise against sarcomas as well. Tumors often evolve during disease progression, and they can develop an expression of inhibitory proteins that deter recognition by the immune system and allow the tumor to escape immune surveillance.<ref name="Hu et al 2014">{{cite journal |last1=Hu |first1=James S |last2=Skeate |first2=Joseph G |last3=Kast |first3=Wijbe Martin |year=2014 |title=Immunotherapy in sarcoma: A brief review |journal=Sarcoma Research International |volume=1 |issue=1 |pages=id1003 |url=https://www.researchgate.net/publication/265843233 }}</ref> By targeting these inhibitory proteins, a pathway is opened for the immune system to recognize the tumor. Two of these inhibitory proteins that have been studied recently are [[CTLA-4]] and PD1,<ref name="Hu et al 2014"/> and drugs targeting these proteins are in development and showing some promise.
+[[Immune checkpoint inhibitor]]s are approved for use in many types of cancer, though there are no FDA approvals for such agents for patients with epithelioid sarcoma. Some cancers are known to deter recognition by the immune system and allow the tumor to escape immune surveillance.<ref name="Hu et al 2014">{{cite journal |last1=Hu |first1=James S |last2=Skeate |first2=Joseph G |last3=Kast |first3=Wijbe Martin |year=2014 |title=Immunotherapy in sarcoma: A brief review |journal=Sarcoma Research International |volume=1 |issue=1 |pages=id1003 |url=https://www.researchgate.net/publication/265843233 }}</ref> By targeting these inhibitory proteins, a pathway is opened for the immune system to recognize the tumor. Two of these inhibitory proteins are [[CTLA-4]] and PD1,<ref name="Hu et al 2014"/> and medications targeting these immune system blockers are being examined in patients with sarcomas, such as epithelioid sarcoma.
 ===Anti-angiogenic therapies===
-Several [[anti-angiogenic]] agents are being explored in epithelioid sarcoma,{{citation needed|date=October 2015}} a cancer that likely relies on angiogenesis for survival and progression. These agents interfere with various pro-angiogenic factors, several of which are known to be over-expressed in epithelioid sarcoma<ref name=pmid10782895/><ref name=pmid20118913/> (VEGF and EGFR for example).<ref>{{cite journal |last1=Ciardiello |first1=F |last2=Troiani |first2=T |last3=Bianco |first3=R |last4=Orditura |first4=M |last5=Morgillo |first5=F |last6=Martinelli |first6=E |last7=Morelli |first7=MP |last8=Cascone |first8=T |last9=Tortora |first9=G |title=Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy |journal=Annals of Oncology |volume=17 |issue=Suppl 7 |pages=vii109–14 |year=2006 |pmid=16760272 |doi=10.1093/annonc/mdl962 }}</ref><ref>{{cite journal |last1=Hirata |first1=Akira |last2=Ogawa |first2=Soh-ichiro |last3=Kometani |first3=Takuro |last4=Kuwano |first4=Takashi |last5=Naito |first5=Seiji |last6=Kuwano |first6=Michihiko |last7=Ono |first7=Mayumi |title=ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase |journal=Cancer Research |volume=62 |issue=9 |pages=2554–60 |year=2002 |pmid=11980649 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11980649 }}</ref> Tumors require a blood supply to provide them with oxygen and nutrients necessary for their survival. As tumors expand and grow, they send out various signals (such as HIF1) that encourage new blood vessel development to the tumor.<ref>{{cite journal |last1=Carmeliet |first1=Peter |last2=Dor |first2=Yuval |last3=Herbert |first3=Jean-Marc |last4=Fukumura |first4=Dai |last5=Brusselmans |first5=Koen |last6=Dewerchin |first6=Mieke |last7=Neeman |first7=Michal |last8=Bono |first8=Françoise |last9=Abramovitch |first9=Rinat |last10=Maxwell |first10=Patrick |last11=Koch |first11=Cameron J. |last12=Ratcliffe |first12=Peter |last13=Moons |first13=Lieve |last14=Jain |first14=Rakesh K. |last15=Collen |first15=Désiré |last16=Keshet |first16=Eli |title=Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis |journal=Nature |volume=394 |issue=6692 |pages=485–90 |year=1998 |pmid=9697772 |doi=10.1038/28867 |bibcode=1998Natur.394..485C }}</ref> Anti-angiogenic agents, such as [[bevacizumab]], attempt to slow or block the growth of tumors by essentially cutting off their blood supply.
+Several [[anti-angiogenic]] agents are being explored in epithelioid sarcoma,{{citation needed|date=October 2015}} a cancer that likely relies on angiogenesis for survival and progression. These agents interfere with various pro-angiogenic factors, several of which are known to be over-expressed in epithelioid sarcoma<ref name=pmid10782895/><ref name=pmid20118913/> (VEGF and EGFR for example).<ref>{{cite journal |last1=Ciardiello |first1=F |last2=Troiani |first2=T |last3=Bianco |first3=R |last4=Orditura |first4=M |last5=Morgillo |first5=F |last6=Martinelli |first6=E |last7=Morelli |first7=MP |last8=Cascone |first8=T |last9=Tortora |first9=G |title=Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy |journal=Annals of Oncology |volume=17 |issue=Suppl 7 |pages=vii109–14 |year=2006 |pmid=16760272 |doi=10.1093/annonc/mdl962 |doi-access=free }}</ref><ref>{{cite journal |last1=Hirata |first1=Akira |last2=Ogawa |first2=Soh-ichiro |last3=Kometani |first3=Takuro |last4=Kuwano |first4=Takashi |last5=Naito |first5=Seiji |last6=Kuwano |first6=Michihiko |last7=Ono |first7=Mayumi |title=ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase |journal=Cancer Research |volume=62 |issue=9 |pages=2554–60 |year=2002 |pmid=11980649 |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11980649 }}</ref> Tumors require a blood supply to provide them with oxygen and nutrients necessary for their survival. As tumors expand and grow, they send out various signals (such as HIF1) that encourage new blood vessel development to the tumor.<ref>{{cite journal |last1=Carmeliet |first1=Peter |last2=Dor |first2=Yuval |last3=Herbert |first3=Jean-Marc |last4=Fukumura |first4=Dai |last5=Brusselmans |first5=Koen |last6=Dewerchin |first6=Mieke |last7=Neeman |first7=Michal |last8=Bono |first8=Françoise |last9=Abramovitch |first9=Rinat |last10=Maxwell |first10=Patrick |last11=Koch |first11=Cameron J. |last12=Ratcliffe |first12=Peter |last13=Moons |first13=Lieve |last14=Jain |first14=Rakesh K. |last15=Collen |first15=Désiré |last16=Keshet |first16=Eli |title=Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis |journal=Nature |volume=394 |issue=6692 |pages=485–90 |year=1998 |pmid=9697772 |doi=10.1038/28867 |bibcode=1998Natur.394..485C |s2cid=4419118 }}</ref> The antiangioenic agent pazopanib is approved in many countries for use in sarcomas such as epithelioid sarcoma.
-===Targeted therapies===
+==="Targeted" therapies===
-Given the multiple genetic abnormalities and disrupted biological pathways observed in epithelioid sarcoma, drugs targeting these unique tumor characteristics are being looked at for more effective treatments.
+Given the multiple genetic abnormalities and disrupted biological pathways observed in epithelioid sarcoma, drugs targeting unique tumor characteristics are being examine for more effective treatments.
 ====Tyrosine kinase inhibitors====
-[[Tyrosine kinase inhibitors]] (such as [[sunitinib]], [[pazopanib]], and [[dasatinib]]) have shown some effect against several cancer types, most notably [[Imatinib]]-mesylate in [[gastrointestinal stromal tumors]] (GISTs).<ref>{{cite journal |last1=Demetri |first1=GD |title=Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571) |journal=European Journal of Cancer |volume=38 |issue=Suppl 5 |pages=S52–9 |year=2002 |pmid=12528773 |doi=10.1016/s0959-8049(02)80603-7}}</ref> Tyrosine kinase (a subclass of protein kinases) is an [[enzyme]] that transfers a [[phosphate group]] from an [[Adenosine triphosphate|ATP]] molecule to a [[protein]] in a cell.<ref name=pmid16002463>{{cite journal |last1=Arora |first1=Amit |last2=Scholar |first2=Eric M. |title=Role of Tyrosine Kinase Inhibitors in Cancer Therapy |journal=Journal of Pharmacology and Experimental Therapeutics |volume=315 |issue=3 |pages=971–9 |year=2005 |pmid=16002463 |doi=10.1124/jpet.105.084145 |url=https://semanticscholar.org/paper/1a449ab83e045e37a7e1dd127aef1bd8983efdc5 }}</ref> It functions as an “on” or “off” switch for many cellular functions, including signaling within the cell, and cell division.
+[[Tyrosine kinase inhibitors]] (such as [[sunitinib]], [[pazopanib]], and [[dasatinib]]) have shown some effect against several cancer types, one example among sarcomas being [[Imatinib]] in [[gastrointestinal stromal tumors]] (GISTs).<ref>{{cite journal |last1=Demetri |first1=GD |title=Identification and treatment of chemoresistant inoperable or metastatic GIST: experience with the selective tyrosine kinase inhibitor imatinib mesylate (STI571) |journal=European Journal of Cancer |volume=38 |issue=Suppl 5 |pages=S52–9 |year=2002 |pmid=12528773 |doi=10.1016/s0959-8049(02)80603-7}}</ref> Tyrosine kinase (a subclass of protein kinases) is an [[enzyme]] that transfers a [[phosphate group]] from an [[Adenosine triphosphate|ATP]] molecule to a [[protein]] in a cell.<ref name=pmid16002463>{{cite journal |last1=Arora |first1=Amit |last2=Scholar |first2=Eric M. |s2cid=33720 |title=Role of Tyrosine Kinase Inhibitors in Cancer Therapy |journal=Journal of Pharmacology and Experimental Therapeutics |volume=315 |issue=3 |pages=971–9 |year=2005 |pmid=16002463 |doi=10.1124/jpet.105.084145 }}</ref> It functions as an “on” or “off” switch for many cellular functions, including signaling within the cell, and cell division.
-Tyrosine kinases can contain mutations that cause them to become constitutively active,<ref>{{cite journal |last1=Lengyel |first1=Ernst |last2=Sawada |first2=Kenjiro |last3=Salgia |first3=Ravi |title=Tyrosine Kinase Mutations in Human Cancer |journal=Current Molecular Medicine |volume=7 |issue=1 |pages=77–84 |year=2007 |pmid=17311534 |doi=10.2174/156652407779940486 }}</ref> or stuck in the “on” position, resulting in unregulated cell division (a hallmark of cancer). Tyrosine kinase Inhibitors block the action of these enzymes. Tyrosine kinase inhibitors have been shown to inhibit the VEGF, EGFR, and MET,<ref name=pmid16002463/> pathways that are frequently over-expressed in epithelioid sarcoma. They also can be used against the [[c-KIT]] and [[JAK-STAT signaling pathway]]s,<ref name=pmid16002463/> which are involved in many cancers and may be involved in epithelioid sarcoma. [[Temsirolimus]] is a tyrosine kinase inhibitor that blocks the effects of the mTOR protein and inhibits the mTOR pathway. Because of crosstalk between cell signaling pathways, it has been shown that, while interfering with the mTOR pathway alone produces only limited results in halting tumorigenesis, inhibiting both the mTOR and the EGFR pathways concurrently shows an increased effect.<ref name=pmid21821699/>
+Tyrosine kinases can contain mutations that cause them to become constitutively active,<ref>{{cite journal |last1=Lengyel |first1=Ernst |last2=Sawada |first2=Kenjiro |last3=Salgia |first3=Ravi |title=Tyrosine Kinase Mutations in Human Cancer |journal=Current Molecular Medicine |volume=7 |issue=1 |pages=77–84 |year=2007 |pmid=17311534 |doi=10.2174/156652407779940486 }}</ref> or stuck in the “on” position, resulting in unregulated cell division (a hallmark of cancer). Tyrosine kinase Inhibitors block the action of these enzymes. Tyrosine kinase inhibitors have been shown to inhibit the VEGF, EGFR, and MET,<ref name=pmid16002463/> pathways that are frequently over-expressed in epithelioid sarcoma. They also can be used against the [[KIT (gene)|KIT]] and [[JAK-STAT signaling pathway]]s,<ref name=pmid16002463/> which are involved in many cancers and may be involved in epithelioid sarcoma. [[Temsirolimus]] is a tyrosine kinase inhibitor that blocks the effects of the mTOR protein and inhibits the mTOR pathway. Because of crosstalk between cell signaling pathways, it has been shown that, while interfering with the mTOR pathway alone produces only limited results in halting tumorigenesis, inhibiting both the mTOR and the EGFR pathways concurrently shows an increased effect.<ref name=pmid21821699/>
 ====SINE====
-Selective inhibitors of nuclear export ([[Selective inhibitors of nuclear export|SINE]]) compounds, such as [[selinexor]] and [[CBS9106]], are being investigated in several sarcomas and have recently shown promising results across a broad spectrum of both [[hematological malignancies]] and [[solid tumors]].<ref name=pmid25281264>{{cite journal |last1=Gerecitano |first1=John |title=SINE (selective inhibitor of nuclear export) – translational science in a new class of anti-cancer agents |journal=Journal of Hematology & Oncology |volume=7 |issue= |pages=67 |year=2014 |pmid=25281264 |pmc=4197302 |doi=10.1186/s13045-014-0067-3 }}</ref><ref>{{cite journal |last1=Sakakibara |first1=K. |last2=Saito |first2=N. |last3=Sato |first3=T. |last4=Suzuki |first4=A. |last5=Hasegawa |first5=Y. |last6=Friedman |first6=J. M. |last7=Kufe |first7=D. W. |last8=VonHoff |first8=D. D. |last9=Iwami |first9=T. |last10=Kawabe |first10=T. |title=CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity |journal=Blood |volume=118 |issue=14 |pages=3922–31 |year=2011 |pmid=21841164 |doi=10.1182/blood-2011-01-333138 |url=https://semanticscholar.org/paper/da7acac1fbeab22ab5e0e26e03ec1d686e5d5146 }}</ref> These compounds work by blocking the export of tumor suppressor genes from the cell's nucleus to the cell's cytoplasm,<ref name=pmid25281264/><ref name=pmid25476752>{{cite journal |last1=Gravina |first1=Giovanni |last2=Senapedis |first2=William |last3=McCauley |first3=Dilara |last4=Baloglu |first4=Erkan |last5=Shacham |first5=Sharon |last6=Festuccia |first6=Claudio |title=Nucleo-cytoplasmic transport as a therapeutic target of cancer |journal=Journal of Hematology & Oncology |volume=7 |issue= |pages=85 |year=2014 |pmid=25476752 |pmc=4272779 |doi=10.1186/s13045-014-0085-1 }}</ref> where they are rendered nonfunctional.<ref name=pmid24429466>{{cite journal |last1=Hill |first1=Richard |last2=Cautain |first2=Bastien |last3=de Pedro |first3=Nuria |last4=Link |first4=Wolfgang |title=Targeting nucleocytoplasmic transport in cancer therapy |journal=Oncotarget |volume=5 |issue=1 |pages=11–28 |year=2014 |pmid=24429466 |pmc=3960186 |doi=10.18632/oncotarget.1457 }}</ref> [[Exportin 1]] (a.k.a. XPO1 or CRM1) is a nuclear export protein responsible for the export of over 200 proteins, including the vast majority of tumor suppressor proteins.<ref name=pmid25281264/> For tumor suppressor genes to carry out their normal function (appropriately initiating apoptosis), they must be located in the nucleus of the cell.<ref name=pmid24429466/> Many cancer cells have been shown to express high levels of exportin1,<ref name=pmid25281264/><ref name=pmid25476752/> resulting in the increased export of tumor suppressor proteins out of the nucleus and therefore counteracting the natural apoptic processes that protect the body from cancer. SINE compounds prevent the transport of these tumor suppressor proteins out of the nucleus, allowing them to function normally and encourage apoptosis. Recently, researchers have observed a synergistic effect when using SINE compounds in combination with traditional chemotherapies (such as doxorubicin).<ref>{{cite journal |last1=Turner |first1=Joel G. |last2=Dawson |first2=Jana |last3=Cubitt |first3=Christopher L. |last4=Baz |first4=Rachid |last5=Sullivan |first5=Daniel M. |title=Inhibition of CRM1-dependent nuclear export sensitizes malignant cells to cytotoxic and targeted agents |journal=Seminars in Cancer Biology |volume=27 |issue= |pages=62–73 |year=2014 |pmid=24631834 |pmc=4108511 |doi=10.1016/j.semcancer.2014.03.001 }}</ref> It has been demonstrated that a loss of INI1 expression can result in the “unmasking” of a nuclear export signal,<ref>{{cite journal |last1=Craig |first1=Errol |last2=Zhang |first2=Zhi‐Kai |last3=Davies |first3=Kelvin P. |last4=Kalpana |first4=Ganjam V. |title=A masked NES in INI1/hSNF5 mediates hCRM1-dependent nuclear export: implications for tumorigenesis |journal=The EMBO Journal |volume=21 |issue=1–2 |pages=31–42 |year=2002 |pmid=11782423 |pmc=125819 |doi=10.1093/emboj/21.1.31 }}</ref> resulting in the transport of tumor suppressor proteins out of the nucleus of the cell, thus favoring tumorigenesis. It is therefore reasonable to suspect that a SINE inhibitor would show efficacy against epithelioid sarcoma, as the disease is characterized by a loss of INI1 function.
+Selective inhibitors of nuclear export ([[Selective inhibitors of nuclear export|SINE]]) compounds, such as [[selinexor]] and [[CBS9106]], are being investigated in several sarcomas and have shown promising results in both [[hematological malignancies]] and [[solid tumors]].<ref name=pmid25281264>{{cite journal |last1=Gerecitano |first1=John |title=SINE (selective inhibitor of nuclear export) – translational science in a new class of anti-cancer agents |journal=Journal of Hematology & Oncology |volume=7 |pages=67 |year=2014 |pmid=25281264 |pmc=4197302 |doi=10.1186/s13045-014-0067-3 |doi-access=free }}</ref><ref>{{cite journal |last1=Sakakibara |first1=K. |last2=Saito |first2=N. |last3=Sato |first3=T. |last4=Suzuki |first4=A. |last5=Hasegawa |first5=Y. |last6=Friedman |first6=J. M. |last7=Kufe |first7=D. W. |last8=VonHoff |first8=D. D. |last9=Iwami |first9=T. |last10=Kawabe |first10=T. |s2cid=16936188 |title=CBS9106 is a novel reversible oral CRM1 inhibitor with CRM1 degrading activity |journal=Blood |volume=118 |issue=14 |pages=3922–31 |year=2011 |pmid=21841164 |doi=10.1182/blood-2011-01-333138 |doi-access=free }}</ref> However, a randomized trial of selinexor in liposarcoma, a distant cousin of epithelioid sarcoma, was negative. [[Selinexor]] does have approval for other cancer diagnoses.
 ====HDAC inhibitors====
-Histone deacetylase ([[HDAC]]) inhibitors, such as [[vorinostat]], have shown some promise in epithelioid sarcoma. Researchers in Texas are investigating whether or not [[HDAC inhibitors]] can reverse the loss of INI1 function that is characteristic of epithelioid sarcoma.<ref name=LevDina/> HDAC inhibitors work by blocking events involved in DNA replication and, therefore, in cell division.<ref>{{cite journal |last1=Demicco |first1=Elizabeth G. |last2=Maki |first2=Robert G. |last3=Lev |first3=Dina C. |last4=Lazar |first4=Alexander J. |title=New Therapeutic Targets in Soft Tissue Sarcoma |journal=Advances in Anatomic Pathology |volume=19 |issue=3 |pages=170–80 |year=2012 |pmid=22498582 |pmc=3353406 |doi=10.1097/PAP.0b013e318253462f }}</ref> Blocking HDAC has been shown to encourage cancer cells to enter apoptosis.<ref name=LevDina/> Several dietary [[phytochemicals]] have been shown to be effective HDAC inhibitors.<ref>{{cite journal |last1=Rajendran |first1=Praveen |last2=Ho |first2=Emily |last3=Williams |first3=David E |last4=Dashwood |first4=Roderick H |title=Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells |journal=Clinical Epigenetics |volume=3 |issue=1 |pages=4 |year=2011 |pmid=22247744 |pmc=3255482 |doi=10.1186/1868-7083-3-4 }}</ref> These include sulphorphane, [[indole-3-carbinol]], and phenethyl isothiocyanates, found in broccoli, kale, and watercress, and epigallocatecehin-3-gallate, found in green tea.{{citation needed|date=October 2015}}
+Histone deacetylase ([[HDAC]]) inhibitors, such as [[vorinostat]], have shown some promise in epithelioid sarcoma. Researchers in Texas are investigating whether or not [[HDAC inhibitors]] can reverse the loss of INI1 function that is characteristic of epithelioid sarcoma.<ref name=LevDina/> HDAC inhibitors work by blocking events involved in DNA replication and, therefore, in cell division.<ref>{{cite journal |last1=Demicco |first1=Elizabeth G. |last2=Maki |first2=Robert G. |last3=Lev |first3=Dina C. |last4=Lazar |first4=Alexander J. |title=New Therapeutic Targets in Soft Tissue Sarcoma |journal=Advances in Anatomic Pathology |volume=19 |issue=3 |pages=170–80 |year=2012 |pmid=22498582 |pmc=3353406 |doi=10.1097/PAP.0b013e318253462f }}</ref> Blocking HDAC has been shown to encourage cancer cells to enter apoptosis.<ref name=LevDina/> Several dietary [[phytochemicals]] have been shown to be effective HDAC inhibitors.<ref>{{cite journal |last1=Rajendran |first1=Praveen |last2=Ho |first2=Emily |last3=Williams |first3=David E |last4=Dashwood |first4=Roderick H |title=Dietary phytochemicals, HDAC inhibition, and DNA damage/repair defects in cancer cells |journal=Clinical Epigenetics |volume=3 |issue=1 |pages=4 |year=2011 |pmid=22247744 |pmc=3255482 |doi=10.1186/1868-7083-3-4 |doi-access=free }}</ref> These include sulphorphane, [[indole-3-carbinol]], and phenethyl isothiocyanates, found in broccoli, kale, and watercress, and epigallocatecehin-3-gallate, found in green tea.{{citation needed|date=October 2015}}
 ====CDK inhibitors====
-Because of the association (see above) with [[cyclin D1]] CDK inhibitors are being studied.
+Because of the association (see above) with [[cyclin D1]] CDK inhibitors are being studied in a variety of cancers. [[Palbociclib]] is a [[CDK inhibitor]] (approved for some [[breast cancer]] by virtue of its blockade of CDK4 and CDK6). Other experimental CDK4/6 inhibitors include [[abemaciclib]] and [[ribociclib]].
-[[palbociclib]] is a [[CDK inhibitor]] (approved for some [[breast cancer]]).
-Other experimental CDK inhibitors include [[abemaciclib]] and [[ribociclib]].
 ===Targeting the cancer stem cell===
-[[Cancer stem cells]] (or cancer-initiating cells) are thought to be a small population of cells within the tumor that are directly responsible for tumor formation. They are thought to be resistant to treatment and to have the ability to form all the cells needed for tumor development. They are suspected to be a major contributing factor in cancer progression and relapse after treatment. Certain “stem-like” cells have been found in epithelioid sarcoma that are marked by [[CD109]] (cluster of differentiation 109),<ref name=pmid24376795/> providing a potentially drug-able target on the cancer stem cell for the disease. Certain challenges to targeting CD109 do exist, however, as CD109 is expressed in other areas of the body and not only in tumor cells.{{citation needed|date=October 2015}}
+[[Cancer stem cells]] (or cancer-initiating cells) are thought to be a small population of cells within the tumor that are directly responsible for tumor formation. They are thought to be resistant to treatment and to have the ability to form all the cells needed for tumor development. They are suspected to be a contributing factor in cancer progression and relapse after treatment. Certain “stem-like” cells have been found in epithelioid sarcoma that are marked by [[CD109]] (cluster of differentiation 109),<ref name=pmid24376795/> providing a theoretically druggable target for epithelioid sarcoma. However, CD109 is expressed in many normal cells of the body, such as T cells and endothelial cells lining every blood vessel, making CD109 a poor target for immunotherapy.
 ===Oncolytic viral therapy===
-[[Oncolytic viral therapy]] is an emerging cancer therapy that attempts to infect cancer cells with a genetically engineered virus that can penetrate the DNA of the cell. The virus then 1.) does direct damage to the cancer cell, 2.) is spread throughout the cells of the tumor via cellular (DNA) multiplication (tumor cell division and replication), and 3.) provides a target for a direct immune response from the patient.<ref name=pmid22701332/><ref name="Pol et al 2012">{{cite journal |first1=Jonathan G |last1=Pol |first2=Julien |last2=Rességuier |first3=Brian D |last3=Lichty |date=2012 |title=Oncolytic viruses: a step into cancer immunotherapy |journal=Virus Adaptation and Treatment |volume=4 |pages=1–21 |doi=10.2147/VAAT.S12980 }}</ref>
+[[Oncolytic viral therapy]] is an emerging cancer therapy that attempts to infect cancer cells with a genetically engineered virus that can penetrate the DNA of the cell. The virus then (1) cann do direct damage to the cancer cell, (2) is passed on throughout the cells of the tumor via viral reproduction, and (3) provides a target for an immune response from the patient.<ref name=pmid22701332/><ref name="Pol et al 2012">{{cite journal |first1=Jonathan G |last1=Pol |first2=Julien |last2=Rességuier |first3=Brian D |last3=Lichty |date=2012 |title=Oncolytic viruses: a step into cancer immunotherapy |journal=Virus Adaptation and Treatment |volume=4 |pages=1–21 |doi=10.2147/VAAT.S12980 |doi-access=free }}</ref>
-It has been noted that the therapeutic potential of [[oncolytic virotherapy]] is not a simple consequence of the [[cytopathic effect]] but strongly relies on the induction of an endogenous immune response against transformed cells.<ref name="Pol et al 2012"/><ref name=pmid24551478/> Superior anticancer effects have been observed when oncolytic viruses are engineered to express (or be co-administered with) immunostimulatory molecules such as GM-CSF.<ref name=pmid24551478/>
+It has been noted that the therapeutic potential of [[oncolytic virotherapy]] is not a simple consequence of the [[cytopathic effect]] but strongly relies on the activation of the body's own immune response against infected cells.<ref name="Pol et al 2012"/><ref name=pmid24551478/> Superior anticancer effects have been observed when oncolytic viruses are engineered to express (or be co-administered with) immunostimulatory molecules such as GM-CSF.<ref name=pmid24551478/>
-[[Telomelysin]] (OBP-301) is an adenovirus that targets [[telomerase]],<ref name=pmid23718223>{{cite journal |last1=Li |first1=Gui-Dong |last2=Kawashima |first2=Hiroyuki |last3=Ogose |first3=Akira |last4=Ariizumi |first4=Takashi |last5=Hotta |first5=Tetsuo |last6=Kuwano |first6=Ryozo |last7=Urata |first7=Yasuo |last8=Fujiwara |first8=Toshiyoshi |last9=Endo |first9=Naoto |title=Telomelysin shows potent antitumor activity through apoptotic and non-apoptotic cell death in soft tissue sarcoma cells |journal=Cancer Science |volume=104 |issue=9 |pages=1178–88 |year=2013 |pmid=23718223 |doi=10.1111/cas.12208 }}</ref> an enzyme that is expressed in practically all cancer cells but not in normal cells. OBP-301 has been studied in epithelioid sarcoma and shown to promote apoptosis and cell death [.<ref name=pmid23718223/>
+[[Telomelysin]] (OBP-301) is an adenovirus that targets [[telomerase]],<ref name=pmid23718223>{{cite journal |last1=Li |first1=Gui-Dong |last2=Kawashima |first2=Hiroyuki |last3=Ogose |first3=Akira |last4=Ariizumi |first4=Takashi |last5=Hotta |first5=Tetsuo |last6=Kuwano |first6=Ryozo |last7=Urata |first7=Yasuo |last8=Fujiwara |first8=Toshiyoshi |last9=Endo |first9=Naoto |title=Telomelysin shows potent antitumor activity through apoptotic and non-apoptotic cell death in soft tissue sarcoma cells |journal=Cancer Science |volume=104 |issue=9 |pages=1178–88 |year=2013 |pmid=23718223 |doi=10.1111/cas.12208 |pmc=7656541 |s2cid=33300842 }}</ref> an enzyme that is expressed in practically all cancer cells but not in normal cells. OBP-301 is not approved for use in cancer patients, but it has been studied in epithelioid sarcoma and shown to promote apoptosis and cell death in the laboratory.<ref name=pmid23718223/>
+[[CGTG-102]] (developed by Oncos Therapeutics) is an adenovirus currently in [[orphan drug status]] for soft tissue sarcomas. It is modified to selectively replicate in p16/Rb-defective cells, which include most human cancer cells. In addition, CGTG-102 codes for the granulocyte–macrophage colony-stimulating factor ([[GM-CSF]]),<ref name=pmid24551478>{{cite journal |last1=Hemminki |first1=Akseli |title=Oncolytic Immunotherapy: Where Are We Clinically? |journal=Scientifica |volume=2014 |pages=1–7 |year=2014 |pmid=24551478 |pmc=3914551 |doi=10.1155/2014/862925 |doi-access=free }}</ref><ref>{{cite journal |last1=Bramante |first1=Simona |last2=Koski |first2=Anniina |last3=Kipar |first3=Anja |last4=Diaconu |first4=Iulia |last5=Liikanen |first5=Ilkka |last6=Hemminki |first6=Otto |last7=Vassilev |first7=Lotta |last8=Parviainen |first8=Suvi |last9=Cerullo |first9=Vincenzo |last10=Pesonen |first10=Saila K |last11=Oksanen |first11=Minna |last12=Heiskanen |first12=Raita |last13=Rouvinen-Lagerström |first13=Noora |last14=Merisalo-Soikkeli |first14=Maiju |last15=Hakonen |first15=Tiina |last16=Joensuu |first16=Timo |last17=Kanerva |first17=Anna |last18=Pesonen |first18=Sari |last19=Hemminki |first19=Akseli |title=Serotype chimeric oncolytic adenovirus coding for GM-CSF for treatment of sarcoma in rodents and humans |journal=International Journal of Cancer |volume=135 |issue=3 |pages=720–30 |year=2014 |pmid=24374597 |doi=10.1002/ijc.28696 |s2cid=22657446 }}</ref> a potent immunostimulatory molecule. While CGTG-102 has shown efficacy as a single agent against several soft tissue sarcomas in the laboratory, as of 2023, clinical research on it appears to have come to a halt.<ref>{{Cite web |title=CTG Labs - NCBI |url=https://clinicaltrials.gov/search?term=CGTG-102 |access-date=2023-11-12 |website=clinicaltrials.gov}}</ref>
-====CGTG-102====
-[[CGTG-102]] (developed by Oncos Therapeutics) is an adenovirus currently in [[orphan drug status]] for soft tissue sarcomas. It is modified to selectively replicate in p16/Rb-defective cells, which include most human cancer cells. In addition, CGTG-102 codes for the granulocyte–macrophage colony-stimulating factor ([[GM-CSF]]),<ref name=pmid24551478>{{cite journal |last1=Hemminki |first1=Akseli |title=Oncolytic Immunotherapy: Where Are We Clinically? |journal=Scientifica |volume=2014 |issue= |pages=1–7 |year=2014 |pmid=24551478 |pmc=3914551 |doi=10.1155/2014/862925 }}</ref><ref>{{cite journal |last1=Bramante |first1=Simona |last2=Koski |first2=Anniina |last3=Kipar |first3=Anja |last4=Diaconu |first4=Iulia |last5=Liikanen |first5=Ilkka |last6=Hemminki |first6=Otto |last7=Vassilev |first7=Lotta |last8=Parviainen |first8=Suvi |last9=Cerullo |first9=Vincenzo |last10=Pesonen |first10=Saila K |last11=Oksanen |first11=Minna |last12=Heiskanen |first12=Raita |last13=Rouvinen-Lagerström |first13=Noora |last14=Merisalo-Soikkeli |first14=Maiju |last15=Hakonen |first15=Tiina |last16=Joensuu |first16=Timo |last17=Kanerva |first17=Anna |last18=Pesonen |first18=Sari |last19=Hemminki |first19=Akseli |title=Serotype chimeric oncolytic adenovirus coding for GM-CSF for treatment of sarcoma in rodents and humans |journal=International Journal of Cancer |volume=135 |issue=3 |pages=720–30 |year=2014 |pmid=24374597 |doi=10.1002/ijc.28696 }}</ref> a potent immunostimulatory molecule.
-While the CGTG-102 oncolytic adenovirus has shown efficacy as a single agent against several soft tissue sarcomas, it would also be appealing to use in combination with other regimes, as [[oncolytic virus]]es have demonstrated very little overlap in side effects with traditional therapies such as chemotherapy and radiation.<ref name="Pol et al 2012"/><ref name=pmid24551478/> CGTG-102 has recently been studied in combination with doxorubicin, and a synergistic effect was observed.<ref name=pmid24975392>{{cite journal |last1=Siurala |first1=Mikko |last2=Bramante |first2=Simona |last3=Vassilev |first3=Lotta |last4=Hirvinen |first4=Mari |last5=Parviainen |first5=Suvi |last6=Tähtinen |first6=Siri |last7=Guse |first7=Kilian |last8=Cerullo |first8=Vincenzo |last9=Kanerva |first9=Anna |last10=Kipar |first10=Anja |last11=Vähä-Koskela |first11=Markus |last12=Hemminki |first12=Akseli |title=Oncolytic adenovirus and doxorubicin-based chemotherapy results in synergistic antitumor activity against soft-tissue sarcoma |journal=International Journal of Cancer |volume=136 |issue=4 |pages=945–54 |year=2015 |pmid=24975392 |doi=10.1002/ijc.29048 }}</ref> At least part of doxorubicin's [[mechanism of action]] is as an inducer of immunogenic cell death, and it has been suggested that immune response contributes to its overall anti-tumor activity. Doxorubicin has been shown to increase adenoviral replication in soft tissue sarcoma cells as well,<ref name=pmid24975392/> potentially contributing to the observed synergistic effect in the virus/doxorubicin combination.
 ==Additional images==
@@ Line 151: / Line 148: @@
 ==Further reading==
-*{{cite journal |last1=Laskin |first1=William B. |last2=Miettinen |first2=Markku |title=Epithelioid sarcoma: new insights based on an extended immunohistochemical analysis |journal=Archives of Pathology & Laboratory Medicine |volume=127 |issue=9 |pages=1161–8 |year=2003 |pmid=12946229 |doi=10.1043/1543-2165(2003)127<1161:ESNIBO>2.0.CO;2 |url=http://www.archivesofpathology.org/doi/abs/10.1043/1543-2165%282003%29127%3C1161%3AESNIBO%3E2.0.CO%3B2 |doi-broken-date=2020-01-22 }}
+*{{cite journal |last1=Laskin |first1=William B. |last2=Miettinen |first2=Markku |title=Epithelioid sarcoma: new insights based on an extended immunohistochemical analysis |journal=Archives of Pathology & Laboratory Medicine |volume=127 |issue=9 |pages=1161–8 |year=2003 |pmid=12946229 |doi=10.5858/2003-127-1161-ESNIBO |url=http://www.archivesofpathology.org/doi/abs/10.1043/1543-2165%282003%29127%3C1161%3AESNIBO%3E2.0.CO%3B2 }}
 == External links ==
@@ Line 165: / Line 162: @@
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 }}
+{{Skin tumors, dermis}}
 [[Category:Sarcoma]]