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Search Results: 1 - 10 of 224872 matches for " R. Lor Randall "
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Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis
Ashley A. Kowalewski,R. Lor Randall,Stephen L. Lessnick
Sarcoma , 2011, DOI: 10.1155/2011/598704
Abstract: Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis. This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered.
Classification, Molecular Characterization, and the Significance of Pten Alteration in Leiomyosarcoma
Allie H. Grossmann,Lester J. Layfield,R. Lor Randall
Sarcoma , 2012, DOI: 10.1155/2012/380896
Abstract: Leiomyosarcoma is a malignant smooth muscle neoplasm with a complicated histopathologic classification scheme and marked differences in clinical behavior depending on the anatomic site of origin. Overlapping morphologic features of benign and borderline malignant smooth muscle neoplasms further complicate the diagnostic process. Likewise, deciphering the complex and heterogeneous patterns of genetic changes which occur in this cancer has been challenging. Preliminary studies suggest that reproducible molecular classification may be possible in the near future and new prognostic markers are emerging. Robust recapitulation of leiomyosarcoma in mice with conditional deletion of Pten in smooth muscle and the simultaneous discovery of a novel role for Pten in genomic stability provide a fresh perspective on the mechanism of leiomyosarcomagenesis and promise for therapeutic intervention.
Squamous Differentiation and Cytokeratin Expression in an Osteosarcoma: A Case Report and Review of the Literature
Lester J. Layfield, Lyska Emerson, Julia R. Crim and Lor Randall
Clinical Medicine Insights: Pathology , 2012,
Abstract: Cytokeratin expression has been documented in a variety of sarcomas including synovial sarcomas, epithelioid sarcomas, Ewing’s sarcomas and, rarely, osteosarcomas. In osteosarcomas immunohistochemically shown to expression cytokeratins, a component of epithelioid cells is generally present. These epithelioid cytokeratin positive cells raise the possibility of metastatic disease with prognostic and therapeutic implications differing from primary osteosarcoma. The cytokeratin-expressing cells of the cases reported in the literature have not shown definitive squamous differentiation with keratin pearl formation. We report a case of osteosarcoma in which islands of malignant squamous cells were present showing keratin pearl formation and expression of cytokeratins.
Squamous Differentiation and Cytokeratin Expression in an Osteosarcoma: A Case Report and Review of the Literature
Lester J. Layfield,Lyska Emerson,Julia R. Crim,Lor Randall
Clinical Medicine : Pathology , 2008,
Abstract: Cytokeratin expression has been documented in a variety of sarcomas including synovial sarcomas, epithelioid sarcomas, Ewing’s sarcomas and, rarely, osteosarcomas. In osteosarcomas immunohistochemically shown to expression cytokeratins, a component of epithelioid cells is generally present. These epithelioid cytokeratin positive cells raise the possibility of metastatic disease with prognostic and therapeutic implications differing from primary osteosarcoma. The cytokeratin-expressing cells of the cases reported in the literature have not shown definitive squamous differentiation with keratin pearl formation. We report a case of osteosarcoma in which islands of malignant squamous cells were present showing keratin pearl formation and expression of cytokeratins.
Classification, Molecular Characterization, and the Significance of Pten Alteration in Leiomyosarcoma
Allie H. Grossmann,Lester J. Layfield,R. Lor Randall
Sarcoma , 2012, DOI: 10.1155/2012/380896
Abstract: Leiomyosarcoma is a malignant smooth muscle neoplasm with a complicated histopathologic classification scheme and marked differences in clinical behavior depending on the anatomic site of origin. Overlapping morphologic features of benign and borderline malignant smooth muscle neoplasms further complicate the diagnostic process. Likewise, deciphering the complex and heterogeneous patterns of genetic changes which occur in this cancer has been challenging. Preliminary studies suggest that reproducible molecular classification may be possible in the near future and new prognostic markers are emerging. Robust recapitulation of leiomyosarcoma in mice with conditional deletion of Pten in smooth muscle and the simultaneous discovery of a novel role for Pten in genomic stability provide a fresh perspective on the mechanism of leiomyosarcomagenesis and promise for therapeutic intervention. 1. Introduction Smooth muscle tumors constitute a spectrum of diseases with wide-ranging clinical behaviors. In general, clinical behavior correlates with patient age, tumor site, histologic appearance, and stage. Leiomyosarcomas (LMSs), the malignant variety, are less common than their benign counterpart, leiomyomas (LMs), and most frequently occur in middle-aged to elderly adults [1]. Children and adolescents generally do not develop LM or LMS, and those rare neoplasms occurring in this population are typically associated with Epstein Barr virus expression, owing to an immunocompromised state [1–3]. Excluding the extremely rare LMS of bone [3], LMS represents approximately 24% of all sarcomas [4] and is, therefore, one of the most common mesenchymal malignancies. The two most frequent sites of origin are the uterus and retroperitoneum, but LMS has been reported in a variety of soft tissue sites, visceral organs, skin, and bone [2, 3]. The diagnostic histopathologic features of smooth muscle tumors are well defined [2]. Architecturally, LM and well-differentiated LMS are composed of bundles and fascicles of cells, intersecting at perpendicular angles. The smooth muscle cells are typically elongate with abundant eosinophilic cytoplasm, cigar-shaped nuclei, and perinuclear vacuoles. Most well-differentiated lesions stain diffusely for actins (smooth muscle actin or muscle-specific actin), and many also stain for desmin, and h-caldesmon. These markers are not specific for smooth muscle, however, and should be interpreted in the context of appropriate clinical and morphologic features. Up to 38% of LMSs will also stain focally for cytokeratins [5], warranting careful
Cell Cycle Deregulation in Ewing's Sarcoma Pathogenesis
Ashley A. Kowalewski,R. Lor Randall,Stephen L. Lessnick
Sarcoma , 2011, DOI: 10.1155/2011/598704
Abstract: Ewing's sarcoma is a highly aggressive pediatric tumor of bone that usually contains the characteristic chromosomal translocation t(11;22)(q24;q12). This translocation encodes the oncogenic fusion protein EWS/FLI, which acts as an aberrant transcription factor to deregulate target genes necessary for oncogenesis. One key feature of oncogenic transformation is dysregulation of cell cycle control. It is therefore likely that EWS/FLI and other cooperating mutations in Ewing's sarcoma modulate the cell cycle to facilitate tumorigenesis. This paper will summarize current published data associated with deregulation of the cell cycle in Ewing's sarcoma and highlight important questions that remain to be answered. 1. Introduction First described by James Ewing in 1921, Ewing’s sarcoma is characterized as a highly aggressive, undifferentiated tumor of the bone [1]. Although it is the second most common primary bone tumor in children and adolescents, Ewing’s sarcoma can also develop in extraosseous sites as a soft-tissue malignancy [2, 3]. The etiology of Ewing’s sarcoma remains unknown, but there appears to be a predominance of cases within the Caucasian population, with males being slightly more susceptible than females [3, 4]. This disease is highly invasive with approximately one-fourth of all Ewing’s sarcoma patients presenting with metastases at the time of diagnosis [2, 5]. Current treatment methods include surgery, radiation, and systemic chemotherapy [6]. Despite such an aggressive regimen, the 5-year disease-free survival rate for patients with localized Ewing’s sarcoma is only 60–70% and that for individuals presenting with metastases drops to a mere 30% [5, 7]. Approximately 85% of Ewing’s sarcoma tumors harbor the reciprocal translocation t(11;22)(q24;q12), which fuses the portion of EWSR1 from chromosome 22 with the portion of FLI1 from chromosome 11 [8, 9]. EWSR1 encodes the EWS protein, which belongs to the TLS/EWS/TAF15 (TET) family of putative RNA-binding proteins [10, 11]. Understanding the physiologic roles of TET proteins has recently become of greater scientific interest as data continues to surface identifying these members as being intrinsic to the development of other sarcomas arising from similar chromosomal translocations. Currently, EWS has been hypothesized to perform a number of functions, including, but not limited to: RNA transcription and/or processing, neuronal cell differentiation, meiosis, B-lymphocyte development, and proneural cell survival in the developing zebrafish embryo [12]. Interestingly, it also appears that EWS may
Extra-Abdominal Desmoid Tumors Associated with Familial Adenomatous Polyposis
George T. Calvert,Michael J. Monument,Randall W. Burt,Kevin B. Jones,R. Lor Randall
Sarcoma , 2012, DOI: 10.1155/2012/726537
Abstract: Extra-abdominal desmoid tumors are a significant cause of morbidity in patients with familial adenomatous polyposis syndrome. Understanding of the basic biology and natural history of these tumors has increased substantially over the past decade. Accordingly, medical and surgical management of desmoid tumors has also evolved. This paper analyzes recent evidence pertaining to the epidemiology, molecular biology, histopathology, screening, and treatment of extra-abdominal desmoid tumors associated with familial adenomatous polyposis syndrome.
Extra-Abdominal Desmoid Tumors Associated with Familial Adenomatous Polyposis
George T. Calvert,Michael J. Monument,Randall W. Burt,Kevin B. Jones,R. Lor Randall
Sarcoma , 2012, DOI: 10.1155/2012/726537
Abstract: Extra-abdominal desmoid tumors are a significant cause of morbidity in patients with familial adenomatous polyposis syndrome. Understanding of the basic biology and natural history of these tumors has increased substantially over the past decade. Accordingly, medical and surgical management of desmoid tumors has also evolved. This paper analyzes recent evidence pertaining to the epidemiology, molecular biology, histopathology, screening, and treatment of extra-abdominal desmoid tumors associated with familial adenomatous polyposis syndrome. 1. Introduction Desmoid tumors (DTs), also known as aggressive fibromatosis, are fibroblastic neoplasms which are often locally aggressive but lack metastatic potential. They may occur sporadically or in association with familial adenomatous polyposis (FAP) syndrome. Among individuals with FAP, desmoids most frequently occur in intra-abdominal and abdominal wall locations with most arising from the peritoneum. These abdominal desmoids range in severity from indolent, asymptomatic lesions to highly invasive, sometimes fatal tumors. Although less common than abdominal desmoids and very rarely fatal, extra-abdominal desmoids are also a significant cause of morbidity in this population. This paper will review recent developments in the diagnosis, screening, treatment, and prognosis of FAP-associated extra-abdominal DTs. 2. Epidemiology of FAP-Associated Desmoid Tumors The overall incidence of DTs has frequently been quoted at 2–4 per million people per year [1, 2]. This estimate is derived from a 1986 Finnish study which used the pathologic records of several regional hospitals and their known catchment area populations to calculate an incidence figure [3]. Recently, the Dutch national pathology database was analyzed, and 519 total desmoid cases in patients over the age of ten were identified from 1999 to 2009. There were 480 sporadic DTs and 39 FAP-DTs. The annual incidence was 3.7 per million overall [4] consistent with the earlier Finnish study. The same nationwide study from The Netherlands identified 1400 patients over the age of ten with FAP during the 1999 to 2009 period. FAP-associated DTs (FAP-DTs) made up 7.5% of all DTs, and the relative risk of an FAP patient developing a DT was over 800-fold higher than the general population [4]. The Dutch study was limited by the use of pathologic specimens as many DTs may be identified based upon history, physical exam, and imaging but not biopsied or surgically excised especially in the FAP cohort. Additionally, some individuals with sporadic DTs may have had as yet
Potential for Modulation of the Fas Apoptotic Pathway by Epidermal Growth Factor in Sarcomas
David E. Joyner,Kevin B. Jones,Stephen L. Lessnick,Joshua D. Schiffman,R. Lor Randall
Sarcoma , 2011, DOI: 10.1155/2011/847409
Abstract: One important mechanism by which cancer cells parasitize their host is by escaping apoptosis. Thus, selectively facilitating apoptosis is a therapeutic mechanism by which oncotherapy may prove highly advantageous. One major apoptotic pathway is mediated by Fas ligand (FasL). The death-inducing signaling Ccmplex (DISC) and subsequent death-domain aggregations are created when FasL is bound by its receptor thereby enabling programmed cell death. Conceptually, if a better understanding of the Fas pathway can be garnered, an oncoselective prodeath therapeutic approach can be tailored. Herein, we propose that EGF and CTGF play essential roles in the regulation of the Fas apoptotic pathway in sarcomas. Tumor and in vitro data suggest viable cells counter the prodeath signal induced by FasL by activating EGF, which in turn induces prosurvival CTGF. The prosurvival attributes of CTGF ultimately predominate over the death-inducing FasL. Cells destined for elimination inhibit this prosurvival response via a presently undefined pathway. This scenario represents a novel role for EGF and CTGF as regulators of the Fas pathway in sarcomas.
Sarcoma Immunotherapy
Launce G. Gouw,Kevin B. Jones,Sunil Sharma,R. Lor Randall
Cancers , 2011, DOI: 10.3390/cancers3044139
Abstract: Much of our knowledge regarding cancer immunotherapy has been derived from sarcoma models. However, translation of preclinical findings to bedside success has been limited in this disease, though several intriguing clinical studies hint at the potential efficacy of this treatment modality. The rarity and heterogeneity of tumors of mesenchymal origin continues to be a challenge from a therapeutic standpoint. Nonetheless, sarcomas remain attractive targets for immunotherapy, as they can be characterized by specific epitopes, either from their mesenchymal origins or specific alterations in gene products. To date, standard vaccine trials have proven disappointing, likely due to mechanisms by which tumors equilibrate with and ultimately escape immune surveillance. More sophisticated approaches will likely require multimodal techniques, both by enhancing immunity, but also geared towards overcoming innate mechanisms of immunosuppression that favor tumorigenesis.
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