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Noujaim J.,Sarcoma Unit | Thway K.,Sarcoma Unit | Sheri A.,Sarcoma Unit | Keller C.,Childrens Cancer Therapy Development Institute | Jones R.L.,Sarcoma Unit
International Journal of Surgical Pathology | Year: 2016

Soft tissue tumors (STTs) are rare mesenchymal neoplasms accounting for less than 1% of adult cancers. More than 50 different subtypes of STTs have been identified, with this number expected to grow as our understanding of the complex genetic landscape of these diseases improves. As the classification of soft tissue neoplasms continues to diversify, so does the approach to therapy. Accurate histopathologic diagnosis, utilizing the appropriate ancillary immunohistochemical and molecular diagnostic platforms, underpins the oncologic management of soft tissue sarcomas. As increasing numbers of reproducible genetic abnormalities in soft tissue neoplasms are defined, molecular genetic and molecular cytogenetic investigations have become a standard part of the ancillary diagnostic repertoire. However, other soft tissue neoplasms lack reproducible genetic abnormalities, and for these, traditional histology and immunohistochemistry remain the cornerstones for diagnosis. Here, we give an overview of histology-driven therapy in STTs, highlighting the critical role of accurate surgical pathology in guiding the systemic treatment of patients with these neoplasms, and the importance of close collaboration between the surgical pathologist and the oncologist. We also summarize what is considered standard practice in nonhistology- and histology-driven therapy. © The Author(s) 2015.

Hooper J.E.,Johns Hopkins Hospital | Cantor E.L.,Oregon Health And Science University | Ehlen M.S.,Oregon Health And Science University | Banerjee A.,Oregon Health And Science University | And 13 more authors.
Sarcoma | Year: 2015

Embryonal rhabdomyosarcoma (eRMS) is one of the most common soft tissue sarcomas in children and adolescents. Parameningeal eRMS is a variant that is often more difficult to treat than eRMS occurring at other sites. A 14-year-old female with persistent headaches and rapid weight loss was diagnosed with parameningeal eRMS. She progressed and died despite chemotherapy with vincristine, actinomycin-D, and cyclophosphamide plus 50.4 Gy radiation therapy to the primary tumor site. Tumor specimens were acquired by rapid autopsy and tumor tissue was transplanted into immunodeficient mice to create a patient-derived xenograft (PDX) animal model. As autopsy specimens had an ALK R1181C mutation, PDX tumor bearing animals were treated with the pan-kinase inhibitor lestaurtinib but demonstrated no decrease in tumor growth, suggesting that single agent kinase inhibitor therapy may be insufficient in similar cases. This unique parameningeal eRMS PDX model is publicly available for preclinical study. © 2015 Jody E. Hooper et al.

Faggi F.,University of Brescia | Faggi F.,Interuniversity Institute of Myology | Chiarelli N.,University of Brescia | Colombi M.,University of Brescia | And 16 more authors.
Laboratory Investigation | Year: 2015

Rhabdomyosarcoma (RMS) is a childhood soft tissue tumor with broad expression of markers that are typically found in skeletal muscle. Cavin-1 is a recently discovered protein actively cooperating with Caveolin-1 (Cav-1) in the morphogenesis of caveolae and whose role in cancer is drawing increasing attention. Using a combined in silico and in vitro analysis here we show that Cavin-1 is expressed in myogenic RMS tumors as well as in human and primary mouse RMS cultures, exhibiting a broad subcellular localization, ranging from nuclei and cytosol to plasma membrane. In particular, the coexpression and plasma membrane interaction between Cavin-1 and Cav-1 characterized the proliferation of human and mouse RMS cell cultures, while a downregulation of their expression levels was observed during the myogenic differentiation. Knockdown of Cavin-1 or Cav-1 in the human RD and RH30 cells led to impairment of cell proliferation and migration. Moreover, loss of Cavin-1 in RD cells impaired the anchorage-independent cell growth in soft agar. While the loss of Cavin-1 did not affect the Cav-1 protein levels in RMS cells, Cav-1 overexpression and knockdown triggered a rise or depletion of Cavin-1 protein levels in RD cells, respectively, in turn reflecting on increased or decreased cell proliferation, migration and anchorage-independent cell growth. Collectively, these data indicate that the interaction between Cavin-1 and Cav-1 underlies the cell growth and migration in myogenic tumors. © 2015 USCAP, Inc.

Geltzeiler M.,Oregon Health And Science University | Li G.,Oregon Health And Science University | Abraham J.,Oregon Health And Science University | Keller C.,Oregon Health And Science University | Keller C.,Childrens Cancer Therapy Development Institute
Frontiers in Oncology | Year: 2015

Rhabdomyosarcomas of the parotid and submandibular glands have the histological appearance of a skeletal muscle tumor yet can be found in tissue with no striated muscular elements. We examine the potential cell-of-origin for rhabdomyosarcoma and whether salivary tumors represent primary malignancy or metastasis. We have previously established genetically engineered mouse models of rhabdomyosarcoma. In these mice, rhabdomyosarcoma is only induced when a Pax3:Foxo1 fusion oncogene is activated with concurrent loss of p53 function (for alveolar rhabdomyosarcoma) or loss of p53 function alone (for embryonal rhabdomyosarcoma) using Cre-lox technology. These mutations are only activated under the control of promoters specific for selected cell lineages, previously thought to be myogenesis-restricted. RT-PCR and immunohistochemistry for lineage-specific promoter gene products reveal these promoters are active in wild-type mouse salivary gland. Given that mouse rhabdomyosarcoma frequently originates in the salivary glands and these myogenic-related promoters are normally expressed in salivary tissue, a high likelihood exists that the salivary gland contains a cell-of-origin of this muscle-related cancer. © 2015 Geltzeiler, Li, Abraham and Keller.

Faggi F.,University of Brescia | Faggi F.,Interuniversity Institute of Myology | Codenotti S.,University of Brescia | Codenotti S.,Interuniversity Institute of Myology | And 16 more authors.
PLoS ONE | Year: 2015

The purpose of this study was to investigate whether MURC/cavin-4, a plasma membrane and Z-line associated protein exhibiting an overlapping distribution with Caveolin-3 (Cav-3) in heart and muscle tissues, may be expressed and play a role in rhabdomyosarcoma (RMS), an aggressive myogenic tumor affecting childhood. We found MURC/cavin-4 to be expressed, often concurrently with Cav-3, in mouse and human RMS, as demonstrated through in silico analysis of gene datasets and immunohistochemical analysis of tumor samples. In vitro expression studies carried out using human cell lines and primary mouse tumor cultures showed that expression levels of both MURC/cavin-4 and Cav-3, while being low or undetectable during cell proliferation, became robustly increased during myogenic differentiation, as detected via semi-quantitative RT-PCR and immunoblotting analysis. Furthermore, confocal microscopy analysis performed on human RD and RH30 cell lines confirmed that MURC/cavin-4 mostly marks differentiated cell elements, colocalizing at the cell surface with Cav-3 and labeling myosin heavy chain (MHC) expressing cells. Finally, MURC/cavin-4 silencing prevented the differentiation in the RD cell line, leading to morphological cell impairment characterized by depletion of myogenin, Cav-3 and MHC protein levels. Overall, our data suggest that MURC/cavin-4, especially in combination with Cav-3, may play a consistent role in the differentiation process of RMS. © 2015 Faggi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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