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PubMed2026

Targeting eIF4A-dependent translation in genetically complex sarcoma.

Dedifferentiated liposarcoma (DDLS), myxofibrosarcoma (MFS), and undifferentiated pleomorphic sarcoma (UPS) are the most common types of genetically complex sarcoma. There is an urgent need to develop effective targeted therapy for these deadly sarcoma types. Despite their genetic complexity, these sarcomas share genomic alterations causing PI3K/Akt/mTOR and MAPK pathway activation, and both pathways control translation mediated by the RNA helicase eIF4A. We therefore investigated eIF4A inhibition as a therapeutic strategy. The eIF4A inhibitor CR-1-31B effectively suppressed tumor growth and induced apoptosis in DDLS, MFS, and UPS patient-derived cell lines and mouse xenografts. Transcriptome-scale ribosome footprinting identified eIF4A-dependent mRNAs such as the Hippo pathway transcriptional coactivators YAP1 (YAP) and WWTR1 (TAZ). Combined knockdown of YAP and TAZ induced apoptosis in DDLS, MFS, and UPS cell lines, and their ectopic expression partially rescued cells from apoptosis induced by CR-1-31B. Genomic analysis of patient tumors revealed that YAP and WWTR1 were frequently amplified or gained in DDLS, MFS, and UPS and were associated with worse clinical outcomes. Together, our findings identify a strategy for targeting the Hippo pathway in incurable forms of sarcoma based on inhibition of eIF4A-dependent translation of the key oncogenic transcription factors YAP and TAZ.

Humans↗
PubMed1987

Regional chemotherapy with the use of cisplatin and doxorubicin as primary treatment for advanced sarcomas in shoulder, pelvis, and thigh.

Eight patients who had large sarcomas in the hip, thigh, or shoulder girdle have been described. Three had osteogenic sarcomas, and one each had Ewing's sarcoma, biphasic synovial sarcoma, pleomorphic liposarcoma, undifferentiated spindling sarcoma, and malignant fibrous histiocytoma. All eight tumors showed evidence of regression after intraarterial infusion of cisplatin and Adriamycin (doxorubicin) given over 48 hours at 3-week intervals, for a total of between three and seven courses. Tru-cut needle biopsy specimens of five of the lesions were normal after chemotherapy. However, after resection of the regressed fibrotic tumor in seven of the patients, four contained foci of probably viable malignant cells. These cell foci were intraosseous in three cases and in the wall of a cyst in one case. In the remaining case, tumor in the distribution of the infused artery regressed, but tumor in a region supplied by an artery that was not infused continued to enlarge. In one patient with osteogenic sarcoma in the pelvis, despite a good response to intraarterial chemotherapy that was followed by surgical resection and radiotherapy, tumor recurred in an adjacent area in tissues supplied by an artery not infused. A hindquarter amputation subsequently was required. With the exception of the two cases in which adequate tumor arterial infusion was not achieved, local primary tumor control was accomplished by intraarterial infusion chemotherapy followed by local resection or radiotherapy and local resection in all patients. Four patients are well without evidence of residual or metastatic sarcoma 3.5 years after presentation in the case of an osteogenic sarcoma of shoulder, 2.5 years after presentation in the case of a large pleomorphic liposarcoma of thigh and groin, 20 months after presentation in the case of lower-thigh malignant fibrous histiocytoma, and 1 year after presentation in a child with an osteogenic sarcoma of lower femur.

Adolescent↗
PubMed1995

[Specific chromosome aberrations in human soft-tissue tumors and their diagnostic significance].

Recent cytogenetic studies have revealed that several types of benign and malignant human soft tissue tumors are characterized by highly specific chromosome abnormalities. In this article, we review the primary and secondary chromosome aberrations detected in lipoma, uterine leiomyoma, Ewing sarcoma, rhabdomyosarcoma, myxoid liposarcoma, synovial sarcoma, and clear cell sarcoma of tendons and aponeuroses. The primary aberrations are unique for the particular tumor type and therefore are of diagnostic value. Most recent molecular studies indicate that several sarcoma-specific translocations result in the gene fusion and creation of tumor-specific proteins that are novel DNA transcription factors.

Chromosome Aberrations↗
PubMed1999

Microsatellite alterations in various sarcomas in Japanese patients.

To determine the usefulness of microsatellite analysis in the differential diagnosis of various sarcomas, we investigated microsatellite alterations at 12 microsatellite loci by polymerase chain reaction and electrophoresis in 39 Japanese patients with sarcomas. The sarcomas were: osteosarcoma, Ewing's sarcoma, chondrosarcoma, liposarcoma, leiomyosarcoma, epithelioid leiomyosarcoma, rhabdomyosarcoma, synovial sarcoma, and malignant fibrous histiocytoma. We also examined ten leiomyomas to contrast with leiomyosarcoma. No microsatellite instability (MSI) or loss of heterozygosity (LOH) were found in Ewing's sarcoma, chondrosarcoma, epithelioid leiomyosarcoma, malignant fibrous histiocytoma, and leiomyoma. Only three patients, one each with liposarcoma, leiomyosarcoma, and synovial sarcoma, manifested MSI, whereas, osteosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, and synovial sarcoma manifested LOH, with an incidence of 43%, 14%, 86%, 20%, and 75%, respectively. Interestingly, three patients showed unusual patterns of LOH, probably due to intratumoral heterogeneity. Kaplan-Meier analysis revealed that LOH on 11p was predictive of poor prognosis in osteosarcoma. The low incidence of MSI indicates that MSI is not necessary for neoplastic transformation in sarcomas. However, the very high incidence of LOH in leiomyosarcoma indicates that microsatellite analysis may serve for the differential diagnosis of leiomyosarcoma versus leiomyoma. Microsatellite analysis may also predict prognosis in osteosarcoma.

Adolescent↗
PubMed1998

Expressions of basic fibroblast growth factor and fibroblast growth factor receptor mRNA in soft tissue tumors by in situ hybridization.

Basic fibroblast growth factor (bFGF) is a mitogenic and angiogenic polypeptide produced by diverse cell types, including the cells derived from normal tissue and neoplastic lesions. To evaluate the possible differential expression of bFGF in soft tissue tumors, we examined 17 frozen primary soft tissue tumors including extra-abdominal desmoids, leiomyosarcomas, synovial sarcomas, myxoid liposarcomas, and alveolar soft part sarcomas by nucleic acid in situ hybridization. Three of the four leiomyosarcomas and two of the three synovial sarcomas studied expressed bFGF mRNA, whereas all of the myxoid liposarcomas and alveolar soft part sarcomas were negative. Two of the leiomyosarcomas were also positive for FGF receptor mRNA. These results indicated the possibility of an autocrine or paracrine mechanism in the function of bFGF and also lent support to the opinion that in situ hybridization is useful for examining cell character.

Adolescent↗
PubMed1984

Chromosome changes in soft tissue sarcomas.

An analysis of chromosome aberrations in human tumors was performed in 29 cases of soft tissue sarcoma. The tumor tissues were disaggregated with collagenase and the cells cultured for 2-3 days. Analyzable metaphases were obtained in 15 cases, 4 of which showed only normal karyotypes. The remaining 11 tumors showed various numerical and structural abnormalities in their karyotypes: 8 tumors were near-diploid and the remaining 3 were near-triploid. G- and Q-banding analyses revealed clonal abnormalities in the 11 cases with the presence of marker chromosomes; 15 different chromosomes were involved in chromosome rearrangements, chromosomes 1 and 2 being the most frequently affected. Because of the heterogeneity of the tumor group investigated (neurogenic sarcoma, 2 liposarcomas, neurofibrosarcoma, synovial cell sarcoma, fibrosarcoma, mesothelioma, leiomyosarcoma, rhabdomyosarcoma, Ewing's sarcoma, and hemangiopericytoma), it was impossible to reach any conclusion on the specificity of the cytogenetic abnormalities for a particular tumor type.

Adult↗
PubMed1977

Alterations of serum enzymes during therapy directed at human malignant sarcomas: a radiological follow-up study of tumor transformation.

1. When a malignant growth is developing in a patient, one often observes in the serum an increased activity of serum enzymes due to necrosis and increased membrane permeability caused by the altered metabolism of malignant cells. Conversely, I considered it interesting to check the enzymes of the malate-aspartate shuttle in addition to LDH enzyme when a neoplastic growth is regressing due to radiation therapy. The patients who were selected for this study had histologically proved sarcomas (reticulosarcoma, liposarcoma, and post-nosal sarcoma). 2. The data obtained indicated that tumor regression is heralded by progressive decline (to the normal level) of LDH, GOT and MDH activities in serum. Normalization of these systems suggested that reticulosarcoma, liposarcoma, and post-nosal sarcoma are sensitive to the therapeutic agent used. 3. In viewing the data herein reported a definitive conclusion regarding the diagnostic usefulness of these assays is apparent. It seems possible that the measurement of these enzymes in serum of patients with proved sarcomas, may prove to be useful laboratory adjunct to diagnostic radiology and in the management of patients whose diagnosis has already been established.

Aspartate Aminotransferases↗
PubMed1982

Variability of histologic pattern in recurrent soft tissue sarcomas originally diagnosed as liposarcoma.

The histopathologic classification of liposarcoma and its clinicopathologic significance are well delineated in previous studies, but the literature is inexplicably mute on recurrent liposarcomas. Supposition and experience may have led to the assumption that the microscopic features remained static over a period of years and multiple recurrences. Thirteen sarcomas originally classified as liposarcoma were reviewed to assess patterns of histologic change with recurrence. A total of 52 recurrences was studied. In 7 of the 13 cases, multiple morphologic sarcomatous patterns were identified, either as a change with recurrence or as multiple discrete patterns within a tumor. All changes except in one case occurred before irradiation or chemotherapy. The variations included patterns such as malignant fibrous histiocytoma, hemangiopericytoma, malignant schwannoma, and unclassified spindle-cell sarcoma as well as the various liposarcoma subtypes. This variability of patterns can cause significant diagnostic difficulties and can cause one to question the validity of using monomorphic diagnoses in all cases. In addition, the polymorphic differentiation of these tumors supports the concept that soft tissue sarcomas are derived from a pluripotential mesenchymal stem cell.

Adult↗
PubMed2002

Validity and reproducibility of histologic diagnosis and grading for adult soft-tissue sarcomas.

Soft-tissue sarcomas in adults show great variations in histologic type and grade. A valid and reproducible prognostication system is needed to select patients with soft-tissue sarcomas who could benefit from adjuvant chemotherapy. This study was conducted to assess the validity and reproducibility of diagnosis of the histologic type, MIB-1 grade, and mitosis grade, as well as of the 3 components of these grading systems. MIB-1 grade is a recently proposed grading system for predicting the prognosis of patients with adult soft-tissue sarcomas on the basis of 3 criteria (tumor differentiation, necrosis, and MIB-1 score) and replaces the mitotic count in the French system with MIB-1 immunohistochemical staining. Four surgical pathologists from 4 institutions who had experience in diagnostic soft-tissue tumor pathology reviewed 130 cases of soft-tissue sarcoma and independently determined histologic type and grade. The validity of histologic diagnosis was measured by sensitivity and specificity, and that of grading was measured by kappa statistics and percentage agreement with the diagnosis of the expert panel at the National Cancer Center, which was defined as a gold standard. Interobserver reproducibility was measured by kappa and by percentage agreement between the diagnoses of the 4 pathologists. The validity of the diagnosis of histologic type was high for synovial sarcoma, small round-cell sarcoma, and liposarcoma (sensitivity 89% to 100%; specificity, 98% to 100%) but low for malignant fibrous histiocytoma (MFH) and spindle-cell sarcoma (73% to 75%; 93% to 95%). For the grading, the validity of the MIB-1 grade was substantial (kappa = 0.68; agreement, 79%) and higher than that of the mitosis grade (0.54; 69%). The most valid component was tumor differentiation (kappa = 0.79), followed by tumor necrosis (0.66), MIB-1 score (0.59), and mitotic score (0.37). Interobserver reproducibility of histologic diagnosis was high for small round-cell sarcoma, synovial sarcoma, and liposarcoma (kappa = 0.92, 0.90, 0.87; percentage agreement = 99%, 97%, 96%, respectively); for grading, reproducibility was highest for tumor differentiation (0.78; 87%) and second highest for MIB-1 grade (0.68; 79%). We conclude that diagnosis of the type of soft-tissue sarcoma for synovial sarcoma, small round-cell sarcoma, and liposarcoma and the MIB-1 grading system based on tumor differentiation are highly valid and reproducible among Japanese pathologists who are familiar with the grading system, whereas re-evaluation of histologic criteria is essential for other histologic types such as MFH and spindle-cell sarcoma.

Antigens, Nuclear↗
PubMed1977

Malignant tumors of the intestine: a review of 37 cases.

Malignant tumors of the small bowel are rare but carry a grave prognosis. Thirty-seven cases from the Tumor Registries of Brooke Army Medical Center. Fort Sam Houston, Texas, and Fitzsimons Army Medical Center, Denver, Colorado, were retrospectively studied. Twenty-nine males and eight females ranging from five to 86 years were included in the combined series. Thirteen carcinoid tumors, eight adenocarcinomas, seven lymphosarcomas, five leiomyosarcomas, two reticulum cell sarcomas, one liposarcoma, and one mesenchymal cell sarcoma were found. Symptoms included intermittent crampy abdominal pain, intestinal obstruction, intestinal bleeding with anemia, and weight loss. The diagnosis was made on the basis of the clinical picture in addition to physical findings and pertinent x-ray contrast studies. The overall survival rate was 25%. The treatment of choice is surgical extirpation of the tumor whenever possible followed by appropriate adjunctive modalities.

Adenocarcinoma↗
PubMed1976

[Study of the antitumor activity of carminomycin in malignant tumors in children (a preliminary report)].

Side reactions and therapeutic effect of carminomycin were studied in 21 children with various malignant tumors. Carminomycin was administered intravenously in doses of 0.15-0.2 mg/kg twice a week for 2-3 weeks. The treatment courses were repeated in a month. The drug was better tolerated by children than by adults. After the treatment course leucopenia may develop. When used alone or in combination with vincristin or cyclophosphan carminomycin proved to be effective in treatment of sarcoma of the soft tissues (liposarcoma, synovial sarcoma), chondrosarcoma and reticulosarcoma.

Adolescent↗
PubMed1997

Purification and characterization of human lung fibroblast motility-stimulating factor for human soft tissue sarcoma cells: identification as an NH2-terminal fragment of human fibronectin.

Paracrine motogenic factors, including motility cytokines and extracellular matrix molecules secreted by normal cells, can stimulate metastatic cell invasion. Both intact extracellular matrix molecules and their degradative products may exhibit these activities. We have found that human lung fibroblasts produce paracrine motility-stimulating factors for recently established human sarcoma cell strains. We purified the major fibroblast motility-stimulating factor (FMSF) from human lung fibroblast-conditioned medium by sequential heparin affinity chromatography and DEAE anion exchange chromatography. Lysylendopeptidase C digestion of FMSF and sequencing of peptides purified by reverse-phase high-pressure liquid chromatography identified FMSF as an NH2-terminal fragment of human fibronectin. Using SYN-1 sarcoma cells, FMSF predominantly stimulated chemotaxis and some chemokinesis, and it was chemotactic for a variety of human sarcoma cells, including fibrosarcoma, leiomyosarcoma, liposarcoma, synovial sarcoma, and neurofibrosarcoma cells. The FMSF activity present in human lung fibroblast-conditioned medium was completely eliminated by either neutralization or immunodepletion with a rabbit antihuman-fibronectin antibody, thus further confirming that the NH2-terminal fibronectin fragment was the FMSF responsible for the motility stimulation of human soft tissue sarcoma cells. Because human soft tissue sarcomas have a distinctive hematogenous metastatic pattern (predominantly lung), and lung-derived fibroblasts secrete large amounts of FMSF, FMSF and fibronectin may play a role in stimulating sarcoma invasion into lung tissue.

Amino Acid Sequence↗
PubMed1998

Preoperative vs. postoperative radiotherapy in the treatment of soft tissue sarcomas: a matter of presentation.

PURPOSE: Radiotherapy for soft tissue sarcoma is typically preoperative or postoperative, with advocates of each. In this study, the relationship of the sequencing of radiotherapy and surgery to local control was examined. METHODS AND MATERIALS: The cohort consisted of 453 patients with Grade 2-3 malignant fibrous histiocytoma, synovial sarcoma, or liposarcoma treated from 1965-1992. Retroperitoneal sarcomas were excluded. Median follow-up was 97 months. There were 3 groups of patients that were classified by the treatment administered at our institution: preoperative radiotherapy to a median dose of 50 Gy given before excision at MDACC (Preop; n = 128); postoperative radiotherapy to a median dose of 64 Gy given after excision at MDACC (Postop; n = 165); and radiotherapy to a median dose of 65 Gy without excision at MDACC (RT Alone; n = 160). Those in the RT Alone Group had gross total excision at an outside center prior to referral. RESULTS: Histological classification, whether locally recurrent at referral, and final MDACC margins were independent determinants of local control in Cox proportional hazards multivariate analysis using the entire cohort. The type of treatment was not significant; however, tumor status at presentation (gross disease vs. excised) affected these findings greatly. Gross disease treated with Preop was controlled locally in 88% at 10 years, as compared to 67% with Postop (p = 0.01). This association was independently significant for patients treated primarily (not for recurrence). In contrast, for those presenting after excision elsewhere, 10-year local control was better with Postop (88% vs. 73%,p = 0.07), particularly for patients treated primarily (91% vs. 72%, p = 0.02 in univariate analysis; p = 0.06 in multivariate analysis). Re-excision at MDACC (Postop) resulted in enhanced 10-year local control over that with RT Alone (88% vs. 75%, p = 0.06), and was confirmed to be an independent predictor in multivariate analysis (p = 0.02). CONCLUSION: Local control was highest with Preop in patients presenting primarily with gross disease, and with Postop in patients presenting primarily following gross total excision. The data suggest that 50 Gy is inadequate after gross total excision, possibly due to hypoxia in the surgical bed.

Adolescent↗