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PTEN mutations in uterine sarcomas.

OBJECTIVE: Uterinesarcomas comprise three main types: carcinosarcomas, leiomyosarcomas, and endometrial stromal sarcomas. Carcinosarcomas are highly aggressive neoplasms with a biphasic histology of carcinomatous and sarcomatous elements. It is now generally accepted that carcinosarcomas are biphasic tumors that have to be regarded as endometrial carcinomas where metaplasia occurs. Mutations of the PTEN tumor suppressor gene, located on 10q23, play a significant role in the pathogenesis of the endometrioid type of endometrial carcinoma. Loss of heterozygosity of chromosome 10q has been reported in uterine leiomyosarcoma. Since little is known about the molecular pathobiology, our goal was to investigate the potential role of the PTEN gene in the carcinogenesis of uterine sarcomas. METHODS: We examined 21 carcinosarcomas, 21 leiomyosarcomas, and 5 endometrial stromal sarcomas using exon-by-exon polymerase chain reaction-single-strand conformation polymorphism analysis. RESULTS: Overall 8.5% (4/47) of uterine sarcomas were found to harbor somatic PTEN mutations. Of these, approximately 17% (3/18) were carcinosarcomas with endometrioid-type carcinoma components and approximately 5% (1/21) were leiomyosarcomas. No mutations were detected in carcinosarcomas with nonendometrioid carcinoma components (0/3) and in endometrial stromal sarcomas (0/5). CONCLUSIONS: These data suggest that intragenic PTEN mutations are involved in the genesis of uterine carcinosarcomas with endometrioid-type carcinoma components but rarely contribute to the pathobiology of uterine leiomyosarcomas.

Exons↗

Solution structure and dynamics of the Rous sarcoma virus capsid protein and comparison with capsid proteins of other retroviruses.

The solution structure and dynamics of the recombinant 240 amino acid residue capsid protein from the Rous sarcoma virus has been determined by NMR methods. The structure was determined using 2200 distance restraints and 330 torsion angle restraints, and the dynamics analysis was based on (15)N relaxation parameters (R(1), R(2), and (1)H-(15)N NOE) measured for 153 backbone amide groups. The monomeric protein consists of independently folded N- and C-terminal domains that comprise residues Leu14-Leu146 and Ala150-Gln226, respectively. The domains exhibit different rotational correlation times (16.6(+/-0.1) ns and 12.6(+/-0.1) ns, respectively), are connected by a flexible linker (Ala147-Pro149), and do not give rise to inter-domain NOE values, indicating that they are dynamically independent. Despite limited sequence similarity, the structure of the Rous sarcoma virus capsid protein is similar to the structures determined recently for the capsid proteins of retroviruses belonging to the lentivirus and human T-cell leukemia virus/bovine leukemia virus genera. Structural differences that exist in the C-terminal domain of Rous sarcoma virus capsid relative to the other capsid proteins appear to be related to the occurrence of conserved cysteine residues. Whereas most genera of retroviruses contain a pair of conserved and essential cysteine residues in the C-terminal domain that appear to function by forming an intramolecular disulfide bond during assembly, the Rous sarcoma virus capsid protein does not. Instead, the Rous sarcoma virus capsid protein contains a single cysteine residue that appears to be conserved among the avian C-type retroviruses and is positioned in a manner that might allow the formation of an intermolecular disulfide bond during capsid assembly.

Amino Acid Sequence↗

Sequences and functions of Rous sarcoma virus RNA.

A procedure has been developed to map the genetic elements of avian tumor virus RNA, which has a molecular weight of about 3 X 10(6) daltons and a poly(A) sequence at the 3' end. For this purpose, about 30 RNase T1-resistant oligonucleotides were ordered relative to the 3'-poly(A) terminus of the RNA, to construct an oligonucleotide map of viral RNAs. A cluster of seven envelope gene (env)-specific oligonucleotides, identified by their absence from the otherwise very similar oligonucleotide map of an envelope-defective deletion mutant (which lacks the major viral glycoprotein), mapped at a distance of 0.9 to 1.6 X 10(6) daltons from the poly(A) end of sarcoma virus RNA. A cluster of three sarcoma gene (src)-specific oligonucleotides, identified by their absence from the otherwise nearly identical oligonucleotide map of a transformation-defective deletion mutant mapped at a distance of 0.2 to 0.6 X 10(6) daltons from the poly(A) end of sarcoma virus RNA. The oligonucleotide maps of sarcoma viruses and of related deletion mutants were the same from the poly(A) end up to 0.2 X 10(6) daltons and included one terminal oligonucleotide, termed C, which is found in all avian tumor viruses tested so far. Preliminary mapping experiments ordering the src-specific and env-specific oligonucleotides of recombinants, selected for sarcoma and envelope genes of different parents, agree with those obtained by comparing maps of wild type viruses and deletion mutants. A partial genetic map consistent with these results suggests that the src gene maps between the env gene and the 3'-poly(A) end of viral RNA. This map reads: poly(A)-src-env-(pol, gag).

Avian Sarcoma Viruses↗

Correlation of neuropathologic findings, computerized tomographic and high-resolution ultrasound scans of canine avian sarcoma virus-induced brain tumors.

The location, size, geometry and neuropathological findings of anaplastic astrocytomas (AA), gliosarcomas and sarcomas induced by the avian sarcoma virus (ASV) in dogs were compared with images generated using computerized tomography (CT) and real time high-resolution ultrasound (HRUS). Seven AA showed a wide range of findings on CT. Pre-contrast CT scans showed that the tumors could be hyper, hypo, or isodense. Three of seven AA had no contrast enhancement; two of these tumors were also isodense which resulted in a false-negative CT exam. Partial enhancement was seen in one tumor. This resulted in a sensitivity of detection of 72%. Real time HRUS was able to define tumor location, size and geometry of the AA missed or incompletely imaged by CT. All tumors were hyperechoic. Inhomogeneity of the echo pattern was due to hemorrhage, cyst formation, and necrosis within the tumors. Such secondary tumor characteristics were more accurately defined by HRUS compared to CT. Vasogenic edema in the brain surrounding tumors was of low density on CT and hypoechoic or indistinguishable from normal brain on US. Similar findings were seen in six gliosarcomas, two of which were not visualized by either pre- or post-contrast enhanced CT scans (sensitivity of 66%). Sarcomas differed in that they were either hyper or isodense; none were hypodense. The area of increased density matched the tumor geometry and correlated with dense cellularity and reticulin deposition. All 13 sarcomas showed contrast enhancement (100% sensitivity), but in two tumors, contrast enhanced CT underestimated the size of the tumor. Because of the large size and multiplicity of the sarcomas, HRUS imaging was not able to resolve the entire tumor volume because of limited imaging access. Intravenously injected horseradish peroxidase (HRP) crossed the tumor blood-brain barrier (BBB) only in those tumors in which contrast enhancement was seen. These studies suggest that intraoperative HRUS imaging may be useful in detecting and delineating human AA incompletely visualized by CT.

Animals↗

[Incidence of malignant soft tissue tumors (sarcomas) after previous radiotherapy].

The causal agent for sarcomas is mostly unknown. Unlike solid epithelial carcinomas, the correlation to the exposition to carcinogenic agents is unknown. Besides hereditary neurofibromatosis ("Recklinghausen"), radiation therapy has been reported to induce malignant tumors. In this retrospective study during the last 10 years we observed that in 7 of 356 (approximately 2%) patients treated for sarcomas in our Department of Surgery, the sarcoma was located in the area where radiation therapy had been given earlier for another primary malignant tumor. The interval between this radiation therapy and the diagnosis of sarcoma was 9 to 30 years, corroborated by findings in the literature based on approximately 100 radiation-induced tumors. The median survival time after diagnosis of sarcoma was 3 years. Because radiation therapy is often used in the treatment of malignant tumors this late complication is a clinically relevant problem in long-time survival.

Follow-Up Studies↗

Synovial sarcoma. A clinicopathological study of 31 cases.

Thirty-one surgically treated cases of synovial sarcoma were reviewed. The mean age of the patients at primary surgery was 37 years (range 10-78 years). Twenty-nine of the tumors were of the biphasic type and two were monophasic. Currently a monophasic synovial sarcoma can be considered as a specific entity. In contrast to other soft-tissue sarcomas, synovial sarcomas present the characteristics of a carcinosarcoma. The 5-year survival rate in this study was 55% and the 6-year survival rate 50%; after 6 years there were no recurrences. The primary treatment should follow the same guidelines that are currently given for other soft-tissue sarcomas: wide and radical excisional margins should be aimed at. Excisional treatment even of repeated pulmonary recurrences may be rewarding.

Adolescent↗

Methylcholanthrene-induced tumors in resistant and sensitive Jensen sarcoma rats. i. effect of fresh prepared MC emulsion.

By two subcutaneous or intramuscular injections of 20-methylcholanthrene (MC), 5 mg/animal in vegetal oil, followed after 74 days by 10 mg of MC emulsion, sarcomata were obtained in 63.6% of Jensen sarcoma-resistant rats (R) and in 36.8% of Jensen sarcoma-sensitive rats (S). One of the induces sarcomas, transplanted from R to R and then to S rats, presented a very high antigenicity: it strongly immunised receptive rats against the induced sarcoma and also, in a lower degree, against the Jensen sarcoma. Antigenicity was maintained up to the tenth passage.

Animals↗

A light and electron microscopic study of endometrial sarcomas of the uterus.

38 endometrial sarcomas were studied light microscopically, 5 of them additionally with the electron microscope. According to their histological appearance these tumours were classified as homologous stromal sarcomas (13 cases), pure heterologous (4) and mixed mesodermal sarcomas (21). The ultrastructure is described with reference to the cytoplasmic differentiation of the tumour cells. A basic immature cell type was present in all endometrial sarcomas irrespective whether they were of pure homologous or of mixed type. In regard to the striking similarity between this cell and cells of the early proliferating endometrium an origin of all endometrial sarcomas from immature stromal cell is suggested. The mixed tumours contain a number of highly differentiated cells like smooth muscle cells, rhabdomyoblasts, fibroblasts etc. As there was a number of cells intermediate in cytoplasmic appearances between immature and differentiated end stages it seems likely that the latter develop from the former. Thus the undifferentiated cell represents the stem cell from which the differentiation processes of all cell lines take their origin. A transition from neoplastic epithelium to neoplastic mesenchyme could not be demonstrated in thed that the mixed epithelial-mesenchymal endometrial tumours originate by a simultaneous malignant transformation of cells with a fixed differentiation potency.

Cell Differentiation↗

Primary intracranial sarcomas: radiological diagnosis with emphasis on arteriography.

The radiological manifestations of primary intracranial sarcomas may be non-specific and they vary widely according to their histological variations. Reticulum cell sarcomas, however, can be included in the differential diagnosis with a high degree of reliability when one observes a hypovascular mass with arterial encasement and deep medullary veins. Tumor vessels and tumor stains supplied by dilated feeding arteries suggest the possibility of a sarcoma of the brain or of the meninges in infants. Nine reticulum cell sarcomas, four undifferentiated sarcomas, and one fibrosarcoma are presented here with their radiological manifestations, especially on angiography.

Adolescent↗

A phase II study of ifosfamide in the treatment of recurrent sarcomas in young people.

We have evaluated the activity of ifosfamide in 75 patients with recurrent sarcomas and pediatric solid tumors. All patients had previously received cyclophosphamide in combination with other chemotherapeutic agents. Ifosfamide was administered as a continuous 5 day infusion at a dose of 1800 mg per M2, except in the last 14 patients who received the drug as a daily one hour infusion at the same dose level. Partial response was observed in 9 of 20 patients with Ewing's sarcoma, 2 of 9 patients with rhabdomyosarcoma, 3 of 17 patients with osteogenic sarcoma and 4 of 29 patients with various other neoplasms. A further 6 patients had stable disease, defined as the absence of progression for at least 6 cycles of therapy. Thus overall response rate was 24%, with the highest response rate of 45% being observed in Ewing's sarcoma. Toxicity was acceptable, although there was quite marked leucopenia (median nadir 700) with less profound thrombocytopenia (median nadir 87,000). Sepsis occurred in 3 patients but no patient died as a result of infection. Hematuria occurred in 43% of patients who did not receive mesna, and in 26% of patients who did, although prior pelvic irradiation was found to be a significant risk factor for hematuria. Only 1 of 14 patients without prior pelvic irradiation or hematuria developed hemorrhagic cystitis when treated with ifosfamide and mesna. Confusional states developed in 6 patients. We conclude that ifosfamide is an active agent in patients with relapsed sarcomas and childhood solid tumors, even when such patients have been previously treated with cyclophosphamide.

Adolescent↗

The existence of rhabdoid cells in specified soft tissue sarcomas. Histopathological, ultrastructural and immunohistochemical evidence.

We report the occurrence of rhabdoid cells in several specified soft tissue sarcomas of round cell variety. The rhabdoid cells had an acidophilic cytoplasm containing a globular perinuclear inclusion and were characterised ultrastructurally by the presence of aggregates of 10 nm intermediate filaments. These filaments contained both cytokeratin and vimentin, as demonstrated immunohistochemically. Extensive sampling of soft tissue sarcomas revealed the presence of such cells in different types of soft tissue round cell sarcomas as follows: 12 of 13 cases of epithelioid sarcomas, 8 of 13 synovial sarcomas (composed predominantly of round cells), 6 of 20 extraskeletal myxoid chondrosarcomas and 4 of 4 round celled malignant mesotheliomas. We wish to stress that the appearance of rhabdoid cells is not a monopoly of one particular type of tumour.

Cell Aggregation↗

Successful treatment for solitary brain metastasis from alveolar soft part sarcoma.

Following pulmonary metastases, alveolar soft part sarcoma has an unexplained predisposition to metastasize to the brain. Herein, a case of alveolar soft part sarcoma solitarily metastatic to the brain is described. A 23-year old female underwent the resection of alveolar soft part sarcoma from the right thigh. Three years after the surgery, a brain tumor was resected and pathology proved it was a metastatic alveolar soft part sarcoma. She is currently alive and well 6 years after brain surgery. Our report suggests that surgical resection for solitary brain metastasis from alveolar soft part sarcoma is an effective treatment modality.

Adult↗

New method of evaluating the surgical margin and safety margin for musculoskeletal sarcoma, analysed on the basis of 457 surgical cases.

The evaluation of surgical margin is useful in determining the curative success of surgical treatment of musculoskeletal sarcoma and the degree to which later surgery will be reduced by the preoperative therapy. However, until recently no reliable evaluation method has been developed for these purposes. In this paper we propose a new method for evaluating the surgical margin as drafted in 1989 by the Bone and Soft Tissue Tumor Committee of the Japanese Orthopaedic Association (JOA). In this method, surgical margin was classified into four types based on the distance between the surgical margin and the reactive zone of the tumour. These classifications of surgical margin (in order to surgical extent) are curative wide margin (curative margin), wide margin, marginal margin, and intralesional margin. The surgical margin is said to be curative if the margin is more than 5 cm outside the reactive zone. It is referred to as wide if the margin is less than 5 cm. Similarly, a margin that is in the reactive zone is considered as marginal, and a margin passing through a tumour as intralesional. Moreover, wide margin is classified as adequate (at least 2 cm outside the reactive zone) or inadequate (1 cm). In our evaluation, a "thin" barrier is considered to be a 2-cm thickness of normal tissue, a "thick" barrier as a 3-cm thickness, and joint cartilage is said to be equivalent to a 5-cm thickness. In addition, a surgical margin that is outside a barrier, with normal tissue between the barrier and the reactive zone of the tumour, is considered to be curative. This method was applied in 457 cases (involving 499 surgeries) at the Cancer Institute Hospital to determine clinical significance in the treatment of musculoskeletal sarcoma (1979-1994). From the results of this study we were able to conclude that this evaluation method can be highly useful in clinical practice for establishing optimum surgery. Moreover, we found that the safety margin for high-grade musculoskeletal sarcoma is a curative margin providing an adequate wide margin of 3 cm or more when preoperative therapy is not performed or is not effective, while the safety margin for high-grade sarcoma that responds to preoperative chemo- or radiotherapy seems to be an adequate wide margin of 2 cm. Here, radiotherapy is more effective compared to chemotherapy for reducing surgical margin. An inadequate wide margin, however, combined with radiotherapy, is not enough to ensure local curative success following surgery for musculoskeletal sarcoma.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone Neoplasms↗

Nucleolar organizer regions in uterine sarcomas.

Nucleolar organizer regions demonstrable by silver staining technique (AgNORs) are loops of nucleolar DNA transcribing to ribosomal RNA. This report quantifies AgNORs in normal endometrium and myometrium, and in leiomyomas and homologous sarcomas of the uterus. The mean AgNOR number in leiomyosarcomas was significantly higher than that in normal myometrium and that in leiomyomas, whereas no significant difference was observed between normal myometrium and leiomyomas. The mean AgNOR count in low-grade endometrial stromal sarcomas was significantly higher than that in normal endometrial stroma, and significantly lower than that in the high-grade variant of the same tumour. The epithelial component of malignant mixed müllerian tumours exhibited a significantly higher mean AgNOR number than normal endometrial epithelium, and the stromal component of these tumours showed a significantly higher mean AgNOR count than normal endometrial stroma and normal myometrium, respectively. The AgNOR count was significantly correlated with the mitotic rate in leiomyosarcomas, in high-grade endometrial stromal sarcomas, and in the epithelial and mesenchymal portions of mixed müllerian tumours, whereas no statistically significant correlation was observed in low-grade endometrial stromal sarcomas. Increased AgNOR counts have been reported for some kinds of malignant tumours in various organs, compared with normal tissues and benign tumours. This study demonstrates a similar increase when homologous uterine sarcomas are compared with histogenetically related normal and neoplastic tissues. AgNOR counting might be a useful adjunct in the classification and grading of uterine tumours.

Endometrium↗

Superficial extremity soft tissue sarcoma: an analysis of prognostic factors.

BACKGROUND: Experience with soft tissue sarcoma has suggested that superficial tumors have a favorable prognosis. We evaluated the prognostic features of this subset of sarcoma. METHODS: Prospective data on 215 patients presenting to Memorial Sloan-Kettering Cancer Center with primary extremity superficial soft tissue sarcomas between July 1, 1982 and July 1, 1996 were analyzed. Superficial sarcomas were defined as subcutaneous tumors not invading the investing fascia of the muscle. Analysis was by univariate and multivariate tests for local recurrence, metastasis, and tumor mortality. RESULTS: Ninety (42%) patients were over 50 years of age, 115 (53%) had high-grade tumors, 53 (25%) had tumors > or = 5 cm, and 18 (8%) had positive margins following definitive resection. Median follow-up was 45 months (range 2 days to 151 months), 31 (14%) patients had local recurrences, 20 (9%) had distant metastases, and 15 (7%) died of disease. Five- and 10-year actuarial disease-specific survivals were 91% and 85%, respectively. On multivariate analysis, age > 50 years predicted local recurrence (RR 5.7; 95% CI, 2.4-13.3; p < 0.0001). High grade (RR 4.2; 95% CI, 1.4-12.7; p < 0.006), and size > or = 5 cm (RR 4.4; 95% CI, 1.8-11; p < 0.002) predicted distant metastases. High grade (RR 7; 95% CI, 1.5-31.4; p < 0.003), size > or = 5 cm (RR 6.9; 95% CI, 2.3-20.8; p < 0.0006), and positive margins (RR 3.8; 95% CI, 1.2-12.4; p < 0.006) predicted tumor mortality. CONCLUSION: Primary superficial extremity soft tissue sarcomas have a favorable prognosis. Size and grade of superficial tumors are the strongest factors in predicting survival.

Adolescent↗

The effect of 1, 25-dihydroxyvitamin D3 on the growth of soft-tissue sarcoma cells as mediated by the vitamin D receptor.

BACKGROUND: Soft-tissue sarcomas, malignant neoplasms originating from mesenchymal tissue, are rare but highly aggressive tumors. Present modes of therapy are associated with high rates of recurrence. 1, 25-Dihydroxyvitamin D3, the active metabolite of vitamin D, serves as a potent antiproliferative agent in human cancer cells. METHODS: In this study, six soft-tissue sarcoma cell lines were analyzed for vitamin D receptor (VDR) expression, which was then correlated with the degree of growth inhibition in response to 1, 25-dihydroxyvitamin D3. These cell lines included rhabdomyosarcoma (HS729, A204), fibrosarcoma (HS913t), synovial sarcoma (SW982), liposarcoma (SW872), and leiomyosarcoma (SKLMS-1). The level of VDR messenger RNA (mRNA) expression was determined using a ribonuclease protection assay, and functional receptor content was determined by using a ligand-binding assay. Growth studies, including [3H]thymidine uptake and growth curves, were performed on two of the six cell lines that expressed the highest and lowest receptor levels. RESULTS: Ribonuclease protection and ligand-binding assays demonstrated variable levels of VDR, with HS729 showing high expression and A204 showing no expression. In HS729, [3H]thymidine uptake was significantly decreased at 10(-7) M (33%) and 10(-6) M (40%) 1, 25-dihydroxyvitamin D3. Growth curve studies showed significant growth inhibition of 55% at 10(-6) M. A204 cells showed no growth inhibition upon treatment with 1, 25-dihydroxyvitamin D3. CONCLUSION: This study demonstrates the existence of VDR in soft-tissue sarcoma cells and suggests a correlation between the level of VDR in cells and the degree of growth inhibition caused by 1, 25-dihydroxyvitamin D3 which may potentially serve as an alternative form of therapy for soft-tissue sarcomas.

Calcitriol↗

Resection of brain metastases from sarcoma.

BACKGROUND: Brain metastases from sarcoma are rare, and data concerning the treatment and results of therapy are sparse. METHODS: We retrospectively reviewed 25 patients with brain metastases from sarcoma of skeletal or soft-tissue origin, surgically treated in a single institution during 20 years. RESULTS: In 18 patients the brain lesion was located supratentorially, and in 7 patients infratentorially. Median age at brain metastasis diagnosis was 25 years. Median time from primary diagnosis to diagnosis of brain metastasis was 26.7 months. Lung metastases were present in 19 patients and in 8 patients they were synchronous with the brain lesion. Pulmonary metastases were resected in 12 patients (48% of total, and 63% of those with pulmonary lesions). The overall median survival from diagnosis of the primary sarcoma was 38 months and from craniotomy was 7 months. The presence or absence of lung lesions did not alter the median survival as calculated from diagnosis of brain metastasis. Overall percent survival was 40% at 1 year and 16% at 2 years. CONCLUSIONS: Because brain metastases from sarcoma are refractory to alternative treatment, surgical excision is indicated when feasible. Brain metastases from sarcoma are uncommon, usually occurring with or after lung metastasis. Long-term survival is possible in some patients.

Adolescent↗

Preoperative chemoradiation treatment strategies for localized sarcoma.

BACKGROUND: Over the past 2 decades, there has been increasing interest in chemoradiation treatment strategies for patients with soft tissue sarcomas. Investigators have evaluated: (1) the optimal route for chemotherapy administration (intra-arterial vs. intravenous); (2) the possible advantages of protracted infusion of the radiosensitizer versus brief infusion; (3) the efficacy and toxicity of various intravenous and oral radiation sensitizers; and (4) the efficacy of sequential versus concurrent combined modality treatment. METHODS: The English-language literature addressing chemoradiation for localized and locally advanced extremity and retroperitoneal sarcomas was reviewed. RESULTS: All studies have been pilot, phase I, or phase II designs. The most commonly used radiosensitizer for concurrent chemoradiation has been doxorubicin, administered intravenously in most recent reports. In the studies that have included assessment of recurrence-free survival, preoperative chemoradiation combined with surgery has resulted in favorable local control rates, often in excess of 90% for patients with localized and locally advanced extremity sarcomas. CONCLUSIONS: The toxicities and recurrence-free outcome with chemoradiation plus surgery for soft tissue sarcoma still need to be compared to these with surgery and pre- or postoperative radiation. However, the generally favorable local control rates reported for chemoradiation justify continued investigation of preoperative chemoradiation strategies for localized sarcoma.

Antineoplastic Agents↗