218 research outputs found
Uterus: Low-grade endometrial stromal sarcoma with t(X;17)(p11.2;q21.33) MBTD1/CXorf6
Short communication on t(X;17)(p11.2;q21.33) MBTD1-CXorf67 in low-grade endometrial stromal sarcoma
Downstream and Intermediate Interactions of Synovial Sarcoma-Associated Fusion Oncoproteins and Their Implication for Targeted Therapy
Synovial sarcoma (SS), an aggressive type of soft tissue tumor, occurs mostly in adolescents and young adults. The origin and molecular mechanism of the development of SS remain only partially known. Over 90% of SS cases are characterized by the t(X;18)(p11.2;q11.2) translocation, which results mainly in the formation of
SS18-SSX1 or SS18-SSX2 fusion genes. In recent years, several reports describing direct and indirect interactions of SS18-SSX1/SSX2 oncoproteins have been published. These reports suggest that the fusion proteins particularly affect the cell growth, cell proliferation, TP53 pathway, and chromatin remodeling mechanisms, contributing to SS oncogenesis. Additional research efforts are required to fully explore the protein-protein interactions of SS18-SSX oncoproteins and the pathways that are regulated by these partnerships for the development of effective targeted therapy
A Sarcoma at the Site of Previous Extravasation of Adriamycin
We report the case of a 66-year-old man presenting with a high-grade pleomorphic sarcoma at the left elbow 16 years after
the extravasation of adriamycin given for a malignant ifbrous histiocytoma of the tibia.We suggest that this sarcoma originated
in a multistep way over many years, out of the chronic inflammatory tissue that developed due to a non-specific cellular
damage at the nuclear level, interfering with normal cell replication necessary for normal healing tissue healing. As a result,
the non-healed chronic inflammatory tissue transformed over several years into a preneoplastic mesenchymal tumour and
later into a high-grade pleomorphic sarcoma
Overcoming Cost Implications of Mutational Analysis in Patients with Gastrointestinal Stromal Tumors: A Pragmatic Approach
Background:
Genetic analysis of tissue derived from patients with advanced gastrointestinal stromal tumors (GISTs) is not uniformly applied on a national and international level, even though mutational data can provide clinically relevant prognostic and predictive information, especially in patients qualifying for treatment with expensive targeted agents.
Methods:
The current article describes the rationale for genetic testing of GIST tissue, looks at financial implications associated with such analysis and speculates on potential cost savings introduced by routine mutational testing and tailored use of tyrosine kinase inhibitors based on genotyping. This work is based on a hypothetical analysis of epidemiological data, drug costs, reimbursement criteria and market research figures.
Results:
The cost burden for routine genotyping of important genes in GISTs, especially in patients at high risk for relapse after primary surgery and in advanced, inoperable metastatic disease, is relatively low. The early identification of GISTs with primary resistance mutations should be the basis for personalized GIST treatment and reimbursement of drugs. As illustrated by Belgian figures, the exclusive use of a drug such as imatinib in patients who are likely to benefit from the agent based on genetic information can lead to significant cost savings, which outweigh the costs for testing.
Conclusions:
Mutational analysis of GIST should be considered early in all patients at risk for relapse after curative surgery and in the case of advanced, inoperable, metastatic disease. The costs for the actual genotyping should not be used as an argument against profiling of the tumor. The adjuvant and palliative systemic treatment of GISTs should be personalized based on the genotype and other known prognostic and predictive factors. Reimbursement criteria for essential agents such as imatinib should be adapted accordingly
Case report: Cardiac intimal sarcoma in a young child
Undifferentiated mesenchymal tumors from the intimal layer (intimal sarcomas) are rare within the ventricles and exceptional in children. A rare case of an intimal sarcoma located in the right ventricle in a young child is presented with need for urgent surgical resection due to mechanical flow obstruction. Tumor cells showed amplification of MDM2 gene and a homozygous loss of CDKN2A on 9p21. A review of the literature regarding primary cardiac malignancies and intimal sarcoma in children is provided
High-grade endometrial stromal sarcoma presenting in a 28-year-old woman during pregnancy: a case report
<p>Abstract</p> <p>Introduction</p> <p>To the best of our knowledge, soft tissue sarcomas have not prevously been reported as a complication during pregnancy.</p> <p>Case presentation</p> <p>A 28-year-old Caucasian woman was diagnosed with a transperitoneal sarcoma during pregnancy. Morphological, immunohistochemical, chromosomal and mutational analyses pointed towards a high-grade endometrial stromal sarcoma. Although surgery and chemotherapy are possible during pregnancy, we were unable to perform these in this case.</p> <p>Conclusion</p> <p>The potential to treat gynecological cancer during pregnancy should always be assessed individually.</p
Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST]
peer-reviewedIn contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood
overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin
in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent
course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type
cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain
metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits
[SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate posttranscriptional
regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases
including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30
gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly
with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst
GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region.
Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wildtype
gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis
of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type,
SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do
express SDHB. All cases with Carney triad within our cohort cluster together tightly.Funding was obtained from the Medical Research Charities Group (http://www.mrcg.ie/) and Health Research Board of Ireland (http://www.hrb.ie)
(MO’S), The Children’s Medical and Research Foundation (http://www.cmrf.org) (MO’S), the GIST Cancer Awareness Foundation [GCAF] (http://www.
gistawareness.org/)(MO’S), and research grants from the Life Raft Group (http://www.liferaftgroup.org/)(MD-R) and from the Fonds voor Wetenschappelijk
Onderzoek Vlaanderen (http://www.fwo.be/)(grant # G.0286.05 MD-R)
Successful Perioperative and Surgical Treatment of a Rare Case of Extra-Gastrointestinal Stromal Tumor Arising in the Prostate Gland
We report a very uncommon case of a primary, non-metastatic gastrointestinal stromal tumor (GIST) arising in the prostate gland in a 60-year-old patient. The morphology and immunohistochemical profile of the disease resembled GIST of gastrointestinal origin, and the molecular driver of this malignancy was a double mutation in exons 11 and 13 of the KIT gene. The tumor was proliferating slowly, did respond to neoadjuvant therapy with the KIT-inhibiting agent imatinib and was cured by radical, retro-pubic prostatectomy followed by adjuvant imatinib treatment. We postulate that primary GIST tumors of the prostate can arise from prostatic interstitial cells, which are the pacemakers of smooth muscle contractility in the gland, and possibly share a common precursor with typical GIST and the interstitial cells of Cajal in the gastrointestinal tract
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p53 Modulation as a Therapeutic Strategy in Gastrointestinal Stromal Tumors
The KIT-inhibitor imatinib mesylate (IM) has greatly improved the treatment of metastatic gastrointestinal stromal tumors (GIST). IM exhibits strong antiproliferative effects but fails to induce sufficient levels of apoptosis resulting in low pathologic complete remission rates and a high rate of secondary progression in the metastatic setting. Upregulation of p53 by MDM2 inhibitors has been shown to induce apoptosis in p53 wildtype tumors. Analyzing a series of 62 mostly untreated, localized and metastatic GIST we detected a low rate (3%) of inactivating p53 mutations, thus providing a rationale for further exploration of p53-directed therapeutic strategies. To this end, we studied nutlin-3, an inhibitor of the p53 antagonist MDM2, and RITA, a putative p53 activator, in GIST cell lines. Nutlin-3 effectively induced p53 at therapeutically relevant levels, which resulted in moderate antiproliferative effects and cell cycle arrest in p53 wildtype GIST cell lines GIST430, GIST48 and GIST48B. P53 reactivation substantially improved the apoptotic response after effective KIT inhibition with sunitinib and 17-AAG in IM-resistant cell lines. The commonly used imatinib-sensitive cell lines GIST882 and GIST-T1 were shown to harbor defective p53 and therefore failed to respond to nutlin-3 treatment. RITA induced p53 in GIST48B, followed by antiproliferative effects and a strong induction of apoptosis. Surprisingly, GIST-T1 was also highly sensitive to RITA despite lacking functional p53. This suggested a more complex, p53-independent mechanism of action for the latter compound. No antagonistic effects from p53-activating drugs were seen with any drug combination. Our data provide first evidence that modulation of the MDM2/p53 pathway may be therapeutically useful to improve the apoptotic response of KIT-inhibitory drugs in the treatment of naïve GIST, with p53 mutation status being a predictive factor of response
Reclassification and subtyping of so-called malignant fibrous histiocytoma of bone: comparison with cytogenetic features
<p>Abstract</p> <p>Background</p> <p>The diagnostic entity malignant fibrous histiocytoma (MFH) of bone is, like its soft tissue counterpart, likely to be a misnomer, encompassing a variety of poorly differentiated sarcomas. When reviewing a series of 57 so-called MFH of bone within the framework of the EuroBoNeT consortium according to up-to-date criteria and ancillary immunohistochemistry, a fourth of all tumors were reclassified and subtyped.</p> <p>Methods</p> <p>In the present study, the cytogenetic data on 11 of these tumors (three myoepithelioma-like sarcomas, two leiomyosarcomas, one undifferentiated pleomorphic sarcoma with incomplete myogenic differentiation, two undifferentiated pleomorphic sarcomas, one osteosarcoma, one spindle cell sarcoma, and one unclassifiable biphasic sarcoma) are presented.</p> <p>Results</p> <p>All tumors were high-grade lesions and showed very complex karyotypes. Neither the overall pattern (ploidy level, degree of complexity) nor specific cytogenetic features distinguished any of the subtypes. The subgroup of myoepithelioma-like sarcomas was further investigated with regard to the status of the <it>EWSR1 </it>and <it>FUS </it>loci; however, no rearrangement was found. Nor was any particular aberration that could differentiate any of the subtypes from osteosarcomas detected.</p> <p>Conclusions</p> <p>chromosome banding analysis is unlikely to reveal potential genotype-phenotype correlations between morphologic subtypes among so-called MFH of bone.</p
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