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PubMed2004

Characterization of large chromosome markers in a malignant fibrous histiocytoma by spectral karyotyping, comparative genomic hybridization (CGH), and array CGH.

In this study, we characterized the chromosomal composition of an intra-abdominal soft tissue sarcoma diagnosed as a malignant fibrous histiocytoma (MFH). By applying a combination of spectral karyotyping, G-banding, and comparative genomic hybridization (CGH), this case was shown to carry large chromosome markers with material mainly from chromosomes 6 and 8. Further characterization of this unique tumor revealed high-level amplifications at the 6q21 approximately q23, 8p21 approximately pter, 8q24 approximately qter, and 12q13 approximately q21 regions. Using array CGH, these amplified regions were found to include MASL1 in 8p, as well s MDM2 and CDK4 in 12q, which have been shown to be amplified in MFH. Similarly, gains of 6q and 8q have also been seen in MFH. In conclusion, our study demonstrates the occurrence of large chromosome markers in MFH and suggests that the regions 6q21 approximately q23, 8p21 approximately pter, 8q24 approximately qter, and 12q13 approximately q21 might harbor oncogenes that could play a role in MFH's tumorigenesis. In addition, gain of 12q13 approximately q21, which is typical of well-differentiated liposarcoma, may also occur in MFH, supporting the previously suggested overlap in genetic etiologies between these two tumor types.

Chromosome Aberrations↗

PubMed1996

Retroperitoneal sarcoma: the University of Florida experience.

BACKGROUND: Retroperitoneal sarcomas are rare mesenchymal neoplasms. Analysis of their characteristics and their impact upon a particular patient population is of significant importance to the surgeon. From 1970 to 1994, 63 adult patients underwent resection of primary retroperitoneal sarcomas at the University of Florida. STUDY DESIGN: A retrospective analysis was performed to determine the biologic behavior of these tumors, surgical management of primary and recurrent disease, predictive variables influencing survival, and the effect of multimodality therapy. RESULTS: There were 39 females and 24 males and the mean age was 55 years. The median weight of the tumors was 1,815 g (range 25 to 10,800 g). There were 33 percent leiomyosarcomas, 30 percent malignant fibrous histiocytomas, and 22 percent liposarcomas. Low-grade tumors accounted for 46 percent of the total, and grade was a significant predictor of survival (p=0.002). Seventy-eight percent of the lesions were totally resected, and this clearly influenced outcome (p<0.0001). In 75 percent of cases, adjacent organs were resected concurrently, and 34 percent of the tumors involved local vascular structures. Survival was enhanced by multiple resections in the 40 percent of patients who had a recurrence (p=0.0001). None of the adjuvant therapy regimens demonstrated survival advantage. Thirty-one percent of the study group patients were alive and 21 percent were disease free at the conclusion of the study. Median survival has been 41 months after total resection, nine months after debulking, and five months after biopsy only. CONCLUSIONS: Complete resection and low grade continue to be the most important prognostic factors for this tumor. The survival advantage of multiple resections has seldom been noted and justifies an aggressive surgical follow-up.

Combined Modality Therapy↗

PubMed2001

[Subfascial lipomatous tumors: management in a series of 37 consecutive cases].

PURPOSE OF THE STUDY: The prognosis of subfascial lipomatous soft tissue tumors depends greatly on their histological type ranging from benign lipomas that cause little local or general problems to the severe prognosis of liposarcomas that exhibit both local and distant extension. However, the clinical presentation of the two types of tumors may be similar and thus quite misleading, sometimes leading to inappropriate management and severe consequences. The main objective of this study was to determine whether the preoperative work-up in patients treated for musculoskeletal tumors within our recruitment zone is adequate, allowing appropriate therapeutic decisions. In addition, we wanted to know what explorations are most pertinent for the differential diagnosis between benign and malignant subfascial lipomatous soft tissue tumors. MATERIAL AND METHODS: Thirty-seven patients with subfascial tumors were included in this study. There were 16 with benign lipomas and 21 with liposarcomas. All the patients with benign lipomas but only 9 (43%) of those with liposarcoma had received initial care within our recruitment zone before final diagnosis. Two cases had been referred after biopsy and 1 after resection by morcellation; the 9 others were secondary referrals after tumor recurrence. Only 5 of these 12 referred patients had had an MRI exploration prior to surgery, 2 with an erroneous interpretation. An MRI series was obtained for all the patients with benign lipoma and for the 9 with liposarcomas who attended our units directly. A biopsy was also obtained in case of suspected liposarcoma. Two radiologists blinded to the final diagnosis reviewed the available MRI to assess their diagnostic value for subfascial lipomatous soft tissue tumors. RESULTS: No case of recurrence, after marginal resection (10 cases) was noted for lipomas. Six are under observation with regular MRI (with no change in size or signal). Four patients with liposarcoma died from their disease (19%) and 2 who had undergone "curative" resection had a recurrence (12%). Incorrect or imprecise (incomplete, incorrectly interpreted or no MRI) preoperative diagnosis led to additional morbidity with 3.4 surgical procedures (mean per patient) compared with 1 in patients who had had undergone a complete work-up and whose diagnosis was established after multidisciplinary discussions. Among the diagnostic elements available before pathology, only MRI findings had diagnostic value for subfascial lipomatous soft tissue tumors: for benign lipoma positive predictive value=92% and negative predictive value=93%. DISCUSSION: The clinical course of the benign lipomas and the sarcomas in this series confirm the radically different prognosis of these two tumors, both in terms of local extension and survival. Inadequate management in the initial diagnostic stages-i.e. lack of MRI with contrast injection, biopsy and multidisciplinary interpretation prior to treatment-raises the risk of higher morbidity, particularly a significantly greater number of reoperations, and progression to a higher grade of malignancy for two tumors. Our retrospective analysis enabled us to develop a decision making tree for patients with subfascial lipomatous tumors. Prospective validation will be necessary.

Decision Trees↗

PubMed1975

[Diagnosis of intermuscular lipomas in children].

According to the data of literature intermuscular lipomas are observed in children, but rarely. The diagnosis of intermuscular lipomas presents certain difficulties since these tumors are frequently taken for sarcomas. Biopsy seems to be an important diagnostic method. From 1967 to 1972 the authors observed intermuscular lipomas in 3 children. One case report of a large intermuscular lipoma of the femur in a 2 year-old child is described. Surgery is considered to be the principal method of treatment for intermuscular lipomas. Recurrent intermuscular lipomas should be regarded as a warning against liposarcoma.

Child, Preschool↗

PubMed1989

Myelodysplastic syndrome and acute leukaemia following treatment of soft tissue sarcoma.

The incidence of secondary myelodysplastic syndromes (MDS) and acute leukaemias (AL) after chemotherapy and/or radiotherapy is increasing. Most cases have been described in patients with Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, polycythemia vera, ovarian cancer and breast cancer. We report 2 patients with secondary MDS and acute myeloblastic leukaemia after combined chemotherapy and radiotherapy for soft tissue sarcoma. Five more cases have been described in the literature. The data of all patients are summarized. The occurrence of secondary MDS/AL in patients with soft tissue sarcoma may become a problem, in particular in children, who have been cured after combined radiotherapy and chemotherapy.

Aged↗

PubMed1997

HMGIC, the gene for an architectural transcription factor, is amplified and rearranged in a subset of human sarcomas.

Amplified segments of the long arm of chromosome 12 are frequently observed in human sarcomas. In most cases there are separate amplified regions around the MDM2 and CDK4 genes. Here we show recurrent amplification of a third region encompassing HMGIC, a human architectural transcription factor gene. Reduced amplification frequency of sequences flanking the gene was observed, indicating that inclusion of this third region in the amplicons is also selected for. In three samples only the 5' part of HMGIC was amplified, suggesting preferential loss of the 3' part of the gene preceding or during amplification. In several other samples rearrangement of the gene was observed. Expression analysis showed transcripts of aberrant sizes, lacking 3' sequences, and 3' RACE of one sample revealed replacement of exons 4 and 5 with ectopic sequences. This truncation of HMGIC resembles that reported for translocations of HMGIC in benign tumors, including lipomas, and it is striking that the gene was frequently amplified or rearranged in well differentiated liposarcomas, the malignant counterpart of lipomas. It seems conceivable that high levels of either full length or truncated hmgic could be relevant for the etiology of these tumors.

Amino Acid Sequence↗

PubMed1997

Immunoreactivity for the human hematopoietic progenitor cell antigen (CD34) in lipomatous tumors.

The human hematopoietic progenitor cell antigen (CD34) recently was shown to react with a variety of nonhematopoietic tissues and their tumors, including vascular endothelium, dendritic interstitial fibroblastic cells, and endoneurial cells as well as with the neoplastic cells in a variety of mesenchymal neoplasms of unknown etiology, such as Kaposi's sarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, gastrointestinal stromal tumors, and solitary fibrous tumors. Additionally, it has been claimed that normal adipocytes may also react with this antibody. We studied a series of 90 lipomatous lesions to examine the pattern of immunoreactivity of the CD34 antigen in adipose tissue neoplasms. The study included 14 lipomas, 19 angiolipomas, 4 atypical lipomas, 18 spindle cell lipomas, 3 renal angiomyolipomas, 1 intramuscular lipoma, and 31 liposarcomas. Immunostains identified a network of CD34+ spindle cells admixed with the adipose tissue elements in all cases of lipoma, angiolipoma, angiomyolipoma, intramuscular lipoma, and well-differentiated lipoma-like liposarcoma. Additionally, the spindle cell component in all cases of spindle cell lipoma were strongly positive for this antigen. Atypical, stellate spindle cells and multinucleated "floret" cells in all cases of atypical lipoma as well as in six of 12 cases of well-differentiated lipoma-like liposarcoma of deep soft tissue were also positive for CD34. Scattered spindle cells in all cases of myxoid liposarcoma and in one case of round cell liposarcoma, as well as the sarcomatous component in one case of "dedifferentiated" liposarcoma, were strongly positive for this antigen. The round cells in myxoid liposarcoma and round cell liposarcoma, the signet-ring and multivacuolated lipoblasts in well-differentiated liposarcoma, and the pleomorphic atypical cells in pleomorphic liposarcoma were uniformly negative. The results of this study appear to indicate that lipomatous tumors may harbor a population of CD34+ interstitial dendritic spindle cells. Overgrowth or clonal expansion of this dendritic cell subpopulation may account for the development of spindle cell lipomas and for the spindle cell component in some cases of "dedifferentiated" liposarcoma.

Antigens, CD34↗

PubMed1983

Scapulectomy revisited: soft part sarcomas of the posterior shoulder.

Scapulectomy with muscle group resection and axillary lymphadenectomy for soft part sarcomas of the posterior shoulder is described. This rarely utilized procedure gives satisfactory tumor control and good functional results in carefully selected patients. The indications and technique for the procedure are discussed.

Aged↗

PubMed2001

Prognostic impact of P53 status, TLS-CHOP fusion transcript structure, and histological grade in myxoid liposarcoma: a molecular and clinicopathologic study of 82 cases.

PURPOSE: A specific TLS-CHOP fusion gene resulting from the t(12;16) is present in at least 95% of myxoid liposarcomas (MLS). Three common forms of the TLS-CHOP fusion have been described, differing by the presence or absence of TLS exons 6-8 in the fusion product. Type 5-2 (also known as type II) consists of TLS exons 1-5 fused to CHOP exon 2; type 7-2 (also known as type I) also includes TLS exons 6 and 7 in the fusion, whereas type 8-2 (also known as type III) fuses TLS exons 1-8 to CHOP exon 2. We sought to determine the impact of TLS-CHOP fusion transcript structure on clinical outcome in a group of well-characterized MLS cases. We also analyzed P53 status, because this parameter has been found to have a significant prognostic impact in other sarcomas with chromosomal translocations. METHODS: We analyzed TLS-CHOP fusion transcripts by reverse-transcription PCR using RNA extracted from frozen tissue in 82 MLS confirmed previously to harbor a CHOP rearrangement either by Southern blotting or by cytogenetic detection of the t(12;16). Parameters analyzed included age, location, size, percentage of round cell (RC) component, areas of increased cellularity, necrosis, and surgical margins. In 71 (87%) cases, adequate tumor tissue was available for immunohistochemical analysis of P53 status, using DO7 antibody. The Kaplan-Meier method, log-rank, and Cox regression tests were used for survival analyses. RESULTS: Most MLS were >10 cm (73%), arising in the thigh (70%), and localized at presentation (89%). RC component was <5% in 47 (57%) cases and > or =5% in 35 (43%). The TLS-CHOP fusion transcript was type 5-2 in 55 (67%), type 7-2 in 16 cases (20%), and type 8-2 in 8 (10%). One tumor had a unique variant fusion, between exon 6 TLS and exon 2 CHOP. Two other cases (2%) showed an EWS-CHOP fusion transcript. Overexpression of P53 (defined as > or =10% nuclear staining) was detected in 12 (17%) cases. High histological grade (defined as > or =5% RC; P < 0.01), presence of necrosis (> or =5% of tumor mass; P < 0.05), and overexpression of P53 (P < 0.001) correlated with reduced metastatic disease-free survival in localized tumors. The presence of negative surgical margins (P < 0.01) and extremity location (P = 0.02) were found to be significant in predicting local recurrence in the entire group as well as localized cases by univariate and multivariate analysis. Although there was no significant correlation between TLS-CHOP transcript type and histological grade or disease-specific survival, an association was found between the P53 status and type 5-2 fusion (P < 0.01). CONCLUSION: In contrast to some other translocation-associated sarcomas, the molecular variability of TLS-CHOP fusion transcript structure does not appear to have a significant impact on clinical outcome in MLS. Instead, high histological grade (> or =5% RC), presence of necrosis, and P53 overexpression are predictors of unfavorable outcome in localized MLS.

Adult↗

PubMed1998

Cytologic features of synovial sarcoma with emphasis on the monophasic fibrous variant: a morphologic and immunocytochemical analysis of bcl-2 protein expression.

BACKGROUND: Monophasic fibrous synovial sarcoma (SS) is the most common variant of SS but few cytologic studies concerning this entity are available. bcl-2 protein immunoexpression has been described as a characteristic marker of SS and is useful for its differentiation from other sarcomas. METHODS: Twelve cytologic specimens from 11 patients with histologically proven SS were reexamined. Ten samples were obtained by fine-needle aspiration and in two cases fluid from cystic tumoral areas was obtained at surgery. Nine cases corresponded to monophasic fibrous tumors and two to biphasic tumors. Immunoexpression of bcl-2 was evaluated in all histologic specimens and in six cytologic samples. bcl-2 protein also was evaluated in 13 soft tissue tumors. RESULTS: All cytologic specimens had a similar appearance. Most smears were highly cellular and were comprised of densely packed, tridimensional groups and numerous isolated, round to oval cells. Remarkable findings included cellular monomorphism and vascular structures within the cell groups. Only one case showed cytologic evidence of epithelial differentiation. Immunoexpression of bcl-2 protein was present in 10 of the 11 histologic specimens (90.9%) and in 5 of the 6 cytologic samples (83.3%). A positive result also was observed in malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, infantile hemangiopericytoma, pleomorphic liposarcoma, and malignant solitary fibrous tumor. CONCLUSIONS: Although cytomorphologic features of SS are characteristic enough to permit its recognition, clinical correlation is necessary for its correct diagnosis. The immunoexpression of bcl-2 protein is not specific of SS and other soft tissue tumors can show a similar positive reaction.

Adolescent↗

PubMed1983

12-0-Tetradecanoylphorbol-13-acetate-induced amplification of mesenchymal tumorigenesis in the mouse skin.

Skin tumors were induced in 6-week-old female Swiss albino mice by a single subcutaneous (SC) injection of 20-methylcholanthrene (MCA) in the right scapular region and the animals were then divided into four groups. Mice in group I did not receive further treatment. Six weeks after MCA injection, those in groups II and III received twice weekly applications of 0.1 ml acetone and 1.8 nmol 12-0-tetradecanoylphorbol-13-acetate (TPA) in 0.1 ml acetone, respectively, at the site of MCA injection until tumor development. Group IV animals were divided into four subsets and administered two, four, six, or eight TPA applications commencing 6 weeks after carcinogen injection. The effect of TPA pretreatment on MCA-induced tumorigenesis was studied in animals in group V. In mice treated with MCA alone, the most predominant mesenchymal tumor type is fibrosarcoma with induction of some rhabdomyosarcomas. Mixed mesenchymal tumors consisting of fibrosarcoma, rhabdomyosarcoma, or hibernoma were observed in only 12% of the animals. The number of animals bearing mixed mesenchymal tumors such as fibrosarcoma, rhabdomyosarcoma, hibernoma, and/or liposarcoma increased to 46% in mice receiving MCA + TPA until tumor development. Interestingly, liposarcomas were not found at all in animals treated with MCA alone. The data indicates that TPA application to precancerous mouse skin enhances mesenchymal tumorigenesis.

Animals↗

PubMedDate not supplied

Logistic regression analysis of high grade spindle cell neoplasms. A fine needle aspiration cytologic study.

OBJECTIVE: To identify primary diagnostic cytologic criteria for various high grade spindle cell neoplasms. STUDY DESIGN: We reviewed 30 osteosarcomas, 29 malignant fibrous histiocytomas (MFH), 26 malignant melanomas, 13 chondrosarcomas, 12 leiomyosarcomas, 7 angiosarcomas and 5 liposarcomas. All specimens were coded as to the presence or absence of the following variables: high or low cellularity, tissuelike fragments, glandlike fragments, single cells, binucleated cells, multinucleated cells, lipoblastlike cells, histiocytelike cells, fibroblastlike cells, signet-ring cells, short spindle cells, long filamentous cells, stellate cells, osteoclastic giant cells, malignant giant cells, background cells, pointed nuclei, cigar-shaped nuclei, fishhook-shaped nuclei, round or ovoid nuclei, intranuclear vacuoles, macronucleoli, small nucleoli, mitotic figures, abnormal mitotic figures, pleomorphism, nuclear/cytoplasmic ratio (mild, moderate, marked increase), amount of cytoplasm (scant, moderate, abundant), fine or coarse granular cytoplasm, intracytoplasmic hemosiderin deposits, melanin, cytoplasmic vacuoles, fat, capillary vessel fragments, storiform pattern, necrosis, large or small amount of myxoid material, filamentous stroma, dense collagenous stroma, osteoid, chondroid and cells in lacunae. A logistic regression analysis was performed to identify the variables predictive of each diagnostic category. RESULTS: The statistical analysis selected positive expression of osteoid, osteoclastic giant cells and low cellularity as the primary criteria associated with osteosarcomas. Positive expression of fibroblastlike cells, large amount of myxoid material and multinucleated cells were identified to be the key criteria for MFH. The analysis selected the presence of melanin as the major criterion for malignant melanomas, cells lying in lacunae for chondrosarcomas, fishhook nuclei for leiomyosarcomas, intracytoplasmic iron deposits for angiosarcomas and lipoblastlike cells for liposarcomas. CONCLUSION: From the previously described cytologic criteria, statistical analysis helped identify several key features that are significant in the evaluation of pleomorphic spindle cell neoplasms.

Biopsy, Needle↗

PubMed1995

KP1/CD68 expression in malignant neoplasms including lymphomas, sarcomas, and carcinomas.

Expression of KP1/CD68 macrophage-associated antigen in a series of 840 selected malignant neoplasms, including immunomorphologically characterized cases of non-Hodgkin's lymphoma (NHL) (434), Hodgkin's disease (HD) (115), soft tissue sarcoma (147), carcinoma (49), and other tumors (95), was examined. KP1 expression was detected in a significant number of NHLs (107 of 434; 24.7%), most of them (65 of 107; 60.7%) of the diffuse small cell subtype. Only 14 of the 155 large cell lymphomas, compared to 10 of the 51 Ki-1/CD30+ anaplastic large cell (ALC) lymphomas examined, were KP1 positive. Conversely, none of the T-lineage NHL--other than Ki-1/CD30+ ALC lymphomas--or the HD cases tested was labeled by KP1 antibody. Among the other neoplasms tested, KP1 was reactive with a variable proportion of cases of malignant fibrous histiocytoma (19 of 24; 79.2%), malignant schwannoma (8 of 22; 36.4%), liposarcoma (3 of 9; 33.3%), leiomyosarcoma (8 of 37; 21.6%), cutaneous or metastatic melanoma (51 of 73; 69.9%), and renal cell carcinoma (3 of 5; 60%). These results indicate that KP1 shows a relatively wide spectrum of immunoreactivity with malignant neoplasms of presumed non-histiocyte origin, thus arguing against its expected specificity and high value in diagnostic pathology. Although the significance of KP1 expression by some subsets of NHLs remains to be elucidated, its close association with B-cell NHLs, mostly of the diffuse small cell type, should stimulate further pathologic and clinical investigations.

Antibodies, Monoclonal↗

PubMed2002

Phase II trial of gemcitabine in advanced sarcomas.

BACKGROUND: Care for patients with advanced sarcomas is mainly palliative. Gemcitabine, a nucleoside antimetabolite, is an analog of deoxycytidine that has shown antitumor activity in several tumors. The aim of the current study was to determine the clinical activity of gemcitabine in patients with sarcomas. METHODS: The authors evaluated gemcitabine in patients with histologically confirmed sarcomas; one prior exposure to chemotherapy treatment was allowed. Prior radiation was allowed if given to non-indicator lesions. Treatment consisted of gemcitabine 1250 mg/m(2) intravenously over 30 minutes, every week x three, cycles repeated q28 days. RESULTS: Twenty nine of 30 patients were evaluable; one patient refused to initiate study treatment. The mean age was 50 years (range, 22-81 years); 59% were male, and 35% had an Eastern Cooperative Oncology Group performance status of 0 (vs. 1 or 2). Patients were histologically classified as leiomyosarcoma (seven gastrointestinal, four retroperitoneal, two inferior vena caval, three of the extremity, and two uterine), synovial (two patients), malignant fibrous histiocytoma (two patients), fibrosarcoma (one patient), osteosarcoma (two patients), liposarcoma (one patient), hemangiosarcoma (one patient), or giant cell (one patient). Patients received an average of two cycles (range, one to eight). Eighty three percent of patients discontinued treatment due to progression and 14% due to toxicity/refusal. Hematologic toxicities >or= Grade 3 were seen in 32% of patients and consisted of leukopenia and thrombocytopenia. Anorexia (Grade 1/2 in 6 patients, Grade 3 in 1 patient), nausea (Grade 1/2 in 7 patients, Grade 3 in 1 patient), and lethargy (Grade 1/2 in 19 patients) were the most frequently observed nonhematologic toxicities. One patient experienced Grade 3 edema and muscle infarction. A different patient experienced unexplained Grade 3 chest pain. One partial response was observed in a uterine leiomyosarcoma patient lasting at least three months. Overall response rate was 3% (95% confidence interval [CI]: 0-15). Median time -to progression was 2.1 months (95% CI: 1.8-3.0). CONCLUSIONS: The current gemcitabine regimen demonstrated acceptable levels of toxicity, but it failed to produce the number of responses needed to justify expansion of the current study. This regimen is not recommended for advanced sarcomas.

Adult↗

PubMed2006

Cytogenetic analysis of myxoid liposarcoma and myxofibrosarcoma by array-based comparative genomic hybridisation.

AIM: To investigate overall chromosomal alterations using array-based comparative genomic hybridisation (CGH) of myxoid liposarcomas (MLSs) and myxofibrosarcomas (MFSs). MATERIALS AND METHODS: Genomic DNA extracted from fresh-frozen tumour tissues was labelled with fluorochromes and then hybridised on to an array consisting of 1440 bacterial artificial chromosome clones representing regions throughout the entire human genome important in cytogenetics and oncology. RESULTS: DNA copy number aberrations (CNAs) were found in all the 8 MFSs, but no alterations were found in 7 (70%) of 10 MLSs. In MFSs, the most frequent CNAs were gains at 7p21.1-p22.1 and 12q15-q21.1 and a loss at 13q14.3-q34. The second most frequent CNAs were gains at 7q33-q35, 9q22.31-q22.33, 12p13.32-pter, 17q22-q23, Xp11.2 and Xq12 and losses at 10p13-p14, 10q25, 11p11-p14, 11q23.3-q25, 20p11-p12 and 21q22.13-q22.2, which were detected in 38% of the MFSs examined. In MLSs, only a few CNAs were found in two sarcomas with gains at 8p21.2-p23.3, 8q11.22-q12.2 and 8q23.1-q24.3, and in one with gains at 5p13.2-p14.3 and 5q11.2-5q35.2 and a loss at 21q22.2-qter. CONCLUSIONS: MFS has more frequent and diverse CNAs than MLS, which reinforces the hypothesis that MFS is genetically different from MLS. Out-array CGH analysis may also provide several entry points for the identification of candidate genes associated with oncogenesis and progression in MFS.

Adult↗

PubMed2006

Angiogenic profile of soft tissue sarcomas based on analysis of circulating factors and microarray gene expression.

BACKGROUND: Broader understanding of diverse angiogenic pathways in a particular cancer can lead to better utilization of anti-angiogenic therapies. The aim of this study was to develop profiles of angiogenesis-related gene and protein expression for various histologic subtypes of soft tissue sarcomas (STS) growing in different sites. MATERIALS AND METHODS: Plasma levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin 2 (Ang2), and leptin were determined in 108 patients with primary STS. Gene expression patterns were analyzed in 38 STS samples and 13 normal tissues using oligonucleotide microarrays. RESULTS: VEGF and bFGF plasma levels were elevated 10-13 fold in STS patients compared to controls. VEGF levels were broadly elevated while bFGF levels were higher in patients with fibrosarcomas and leiomyosarcomas. Ang2 levels correlated with tumor size and were most elevated for tumors located in the trunk, while leptin levels were highest in patients with liposarcomas. Hierarchical clustering of microarray data based on angiogenesis-related gene expression demonstrated that histologic subtypes of STS often shared similar expression patterns, and these patterns were distinctly different from those of normal tissues. Matrix metalloproteinase 2, platelet-derived growth factor receptor, alpha and Notch 4 were among several genes that were up-regulated at least 7-fold in STS. CONCLUSIONS: STS demonstrate significant heterogeneity in their angiogenic profiles based on size, histologic subtype, and location of tumor growth, which may have implications for anti-angiogenic strategies. Comparison of STS to normal tissues reveals a panel of upregulated genes that may be targets for future therapies.

Angiopoietin-2↗

PubMed2004

Abnormal expression of cell cycle regulators in FUS-CHOP carrying liposarcomas.

Myxoid/round cell liposarcomas (MLS/RCLS) are characterized by chromosome translocations that result in formation of FUS-CHOP or EWSR1-CHOP fusion oncogenes. More than 95% of the tumors carry one of these fusion genes. FUS-CHOP transforms 3T3 cells and causes MLS/RCLS-like tumors in transgenic mice. The fusion oncoproteins act as abnormal transcription factors and are believed to induce abnormal expression of growth controlling genes as part of their transforming activities. The aim of this study was to search for recurrent abnormal expression patterns of cell cycle regulating proteins and growth factor receptors. A series of 14 MLS/RCLS, 2 MLS/RCLS derived cell lines and a FUS-CHOP transfected human sarcoma cell line were analyzed using immunohistochemistry, Western blotting, and cDNA microarray based screening. The results revealed a highly abnormal expression pattern of several growth controlling proteins. The G1 cyclins D1 and E and their associated kinases CDK4 and CDK2 were strongly overexpressed in all of the tumors. High expression levels were also found for Cdk4/6 inhibitor P16 and CDK2 inhibitors P27 and P57. The growth factor tyrosine kinase receptors PDGFRB and EGFR were present in most cells of all investigated tumors. We conclude that deregulation of G1 controlling proteins is common in MLS/RCLS and that aberrant expression of these proteins is of importance in the pathogenesis of this tumor type.

Adult↗

PubMed2001

Association of tumor growth on nude mice and poor clinical outcome in soft tissue sarcoma patients.

PURPOSE: Permanent growth in nude mice (PGNM) may be associated with poor clinical outcome. We tested this hypothesis in a group of soft tissue sarcoma (STS) patients. METHODS: Small chunks from fresh tumor biopsies of 81 patients with STS were transplanted subcutaneously into NMRI-nu/nu nude mice. Tumor cell lines exhibiting growth in nude mice for more than three tumor passages were considered as permanently established. Clinical outcome of all patients was monitored with a median follow-up of 38 months. RESULTS: 39/81 (48%) STSs exhibited PGNM. High grade, high S-phase proportion, and aneuploidy were significant predictors of PGNM. Overall survival (OS) at 3 years was 21% (+7% standard error of median) for STS patients with PGNM and 53% (+/-8%) for patients without PGNM (P<0.01). Considering only patients without distant metastasis at the time of biopsy (n = 49), 3-year-OS was 25% (+/-10%) and 71% (+/-9%) for STS with PGNM and without PGNM, respectively (P<0.01). In the univariate analysis, PGNM, aneuploidy high S-phase proportion, tumor location at the trunk, high tumor grade, and non-liposarcoma histology were associated with reduced survival time. In the multivariate analysis, aneuploidy and tumor location at the trunk were the only independent predictors of overall survival. CONCLUSION: Permanent growth of STS on nude mice is associated with poor clinical outcome in the univariate analysis, but is not an independent predictor of survival in the multivariate analysis due to a strong co-correlation to other known adverse prognostic factors.

Adolescent↗