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Adjuvant chemotherapy for localised resectable soft tissue sarcoma in adults. Sarcoma Meta-analysis Collaboration (SMAC).

BACKGROUND: Individually, randomised trilas have not shown conclusively whether adjuvant chemotherapy benefits adult patients with localised resectable soft-tissue sarcoma. OBJECTIVES: Adjuvant chemotherapy aims to lessen the recurrence of cancer after surgery with or without radiotherapy. The objective of this review was to assess the effects of adjuvant chemotherapy in adults with resectable soft tissue sarcoma after such local treatment. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, UKCCCR Register of Cancer Trials, Physicians Data Query, EMBASE, MEDLINE and CancerLit. SELECTION CRITERIA: Randomised trials of adjuvant chemotherapy after local treatment in adults with localised resectable soft tissue sarcoma were included. Only trials in which accrual was completed by December 1992 were included. DATA COLLECTION AND ANALYSIS: Individual patient data were obtained. Accuracy of data and quality of randomisation and follow-up of trials was assessed. MAIN RESULTS: Fourteen trials of doxorubicin-based adjuvant chemotherapy involving 1568 patients were included. Median follow-up was 9.4 years. For local recurrence-free interval the hazard ratio with chemotherapy was 0.73 (95% Confidence Interval 0.56-0.94). For distant recurrence-free interval it was 0. 70 (95% CI 0.57-0.85). For overall recurrence-free survival it was 0. 75 (95% CI 0.64-0.87). These correspond to significant absolute benefits of 6-10% at 10 years. For overall survival the hazard ratio of 0.89 (95% CI 0.76-1.03) was not significant but potentially represents an absolute benefit of 4% (95% CI -1 to 9) at 10 years. There was no consistent evidence of a difference in effect according to age, sex, stage, site, grade, histology, extent of resection, tumour size or exposure to radiotherapy. However, the strongest evidence of a beneficial effect on survival was shown in patients with sarcoma of the extremities. REVIEWER'S CONCLUSIONS: Doxorubicin-based adjuvant chemotherapy appears to significantly improve time to local and distant recurrence and overall recurrence-free survival in adults with localised resectable soft tissue sarcoma. There is some evidence of a trend towards improved overall survival.

Adult↗

Human herpesvirus 8 (Kaposi's sarcoma-associated herpesvirus) DNA in Kaposi's sarcoma lesions, AIDS Kaposi's sarcoma cell lines, endothelial Kaposi's sarcoma simulators, and the skin of immunosuppressed patients.

We used the polymerase chain reaction on 63 tissue specimens of histologically staged classic Kaposi's sarcoma (KS) from 40 patients, 14 specimens from 14 acquired immune deficiency syndrome (AIDS)-KS cases (all from the same geographic area over a 10-year period), and peripheral blood mononuclear cells from 1 of the non-AIDS KS patients to amplify a specific 210-bp genomic sequence of the newly discovered KS-associated herpesvirus (KSHV). Also tested were 86 benign and malignant endothelial lesions, which potentially simulated each KS histological stage and were further matched by age approximation and by sex with a classical KS specimen. The lesions included hemangioma, lymphangioma, pyogenic granuloma, and angiosarcoma. KSHV was also sought in multiple well characterized vascular endothelial cell lines from AIDS-KS lesions and in 20 mainly cutaneous benign and malignant lesions from 15 immunosuppressed transplant patients. Overall, 92% of KS tissue specimens, representing 88% of classical KS and 100% of AIDS-KS patients, and in addition the sample of peripheral blood mononuclear cell DNA, were positive as visualized on ethidium bromide gels and confirmed by Southern blot hybridization (only 1 case was negative on gell visualization but positive on Southern blot), thus confirming the close association of KSHV with KS of different clinical forms. None of the various other endothelial lesion, skin lesions in immunosuppressed patients, or AIDS-KS endothelial cell lines contained amplifiable KSHV DNA, which indicates that reactivation of KSHV is not present in the skin lesions of immunosuppressed patients and probably is not a ubiquitous agent that secondarily infects proliferative endothelium. The absence of amplifiable virus DNA in the cultured endothelium of KS suggests that the stimulus for angioproliferation originates in another host cell or under conditions not reproduced in culture. The polymerase chain reaction is a specific and sensitive means of verifying KS in the differential diagnosis of angioproliferative lessons.

Acquired Immunodeficiency Syndrome↗

Ultrastructural similarities and differences of synovial sarcoma, epithelioid sarcoma, and clear cell sarcoma of the tendons and aponeuroses.

The ultrastructural features of synovial sarcoma, epithelioid sarcoma, and clear cell sarcoma of the tendons and aponeuroses were compared to identify differential markers and similarities. A continuous spectrum of modulation of morphologic features of synovial and epithelioid sarcomas was observed. Biphasic synovial sarcoma with pseudoglandular and stromal components represents one extreme of this spectrum. The gradual disappearance of the pseudoglands and the formation of nests of epithelial-like cells, which are characteristic of epithelioid sarcoma, were observed. The cells of clear cell sarcoma, as well as those of synovial and epithelioid sarcomas, form epithelial-like islands; however, the presence of premelanosomes in the former is a feature of neural crest derivatives.

Humans↗

Monophasic synovial sarcoma, epithelioid sarcoma and chordoid sarcoma: ultrastructural evidence for a common histogenesis, despite light microscopic diversity.

Ultrastructural examination of six rare sarcomas--four monophasic spindle cell tumours, one epithelioid sarcoma, one chordoid sarcoma--has revealed marked similarities at the electron microscopic level despite widely divergent light microscopic appearances. These features consisted of: 1 the presence of two cell types, viz. a clear cell and a cell resembling the fibroblast; 2 pseudoglandular spaces with projecting microvilli or filopodia, and with related tight junctions; 3 an amorphous intercellular ground substance with focal condensation into recognizable basement membrane. The findings suggest a common maturation of these diverse tumours to synovial-like tissue, and support the proposal of Hajdu Shiu & Fortner (1977) that these be considered variants of synovial sarcoma. Published ultrastructural studies of synovial, epithelioid and chordoid sarcoma are reviewed in the light of these findings. The ultrastructural differentiation of synovial sarcoma from extraskeletal myxoid chondrosarcoma, chordoma and the spectrum of malignant spindle cell tumours is discussed.

Adult↗

Cell surface antigens of chemically induced sarcomas of the mouse. I. Murine leukemia virus-related antigens and alloantigens on cultured fibroblasts and sarcoma cells: description of a unique antigen on BALB/c Meth A sarcoma.

As background for a serological definition of the unique antigens of chemically induced sarcomas, we have typed a series of fibroblast and sarcoma cell lines of BALB/c and C57BL/6 origin by cytoxicity and absorption tests for murine leukemia virus (MuLV)-related cell surface antigens and known alloantigens. 7 of the 17 cultured lines expressed the range of cell surface antigens associated with MuLV (GIX, GCSA, gp70, p30), and this was invariably associated with MuLV production. In nonproducer lines of C57BL/6 (but not BALB/c) origin, a MuLV-gp70-like molecule was found on the surface of fibroblasts and sarcoma cells. The alloantigenic phenotype of these MuLV+ and MuLV- cell lines was H-2D+, H-2K+, Thy-1.2+ or -, PC.1+ or -, Lyt-1.2-, Lyt-2.2-, Ia.7-, and TL.2-. A unique antigen was defined on the BALB/c ascites sarcoma Meth A with antisera prepared in BALB/c or (BALB/c X C57BL/6)F1 mice. Tissue culture lines derived from this tumor were MuLV-, which facilitated serological study of the antigen. Absorption analysis indicated that the antigen was restricted to Meth A; it could not be detected in normal or fetal BALB/c tissue MuLV+ or MuLV- fibroblast lines, 12 syngeneic or allogeneic sarcomas, or normal lymphoid cells from 13 different inbred mouse strains.

Animals↗

Molecular cloning of Snyder-Theilen feline leukemia and sarcoma viruses: comparative studies of feline sarcoma virus with its natural helper virus and with Moloney murine sarcoma virus.

Extrachromosomal DNA obtained from mink cells acutely infected with the Snyder-Theilen (ST) strain of feline sarcoma virus (feline leukemia virus) [FeSV(FeLV)] was fractionated electrophoretically, and samples enriched for FeLV and FeSV linear intermediates were digested with EcoRI and cloned in lambda phage. Hybrid phages were isolated containing either FeSV or FeLV DNA "inserts" and were characterized by restriction enzyme analysis, R-looping with purified 26 to 32S viral RNA, and heteroduplex formation. The recombinant phages (designated lambda FeSV and lambda FeLV) contain all of the genetic information represented in FeSV and FeLV RNA genomes but lack one extended terminally redundant sequence of 750 bases which appears once at each end of parental linear DNA intermediates. Restriction enzyme and heteroduplex analyses confirmed that sequences unique to FeSV (src sequences) are located at the center of the FeSV genome and are approximately 1.5 kilobase pairs in length. With respect to the 5'-3' orientation of genes in viral RNA, the order of genes in the FeSV genome is 5'-gag-src-env-c region-3'; only 0.9 kilobase pairs of gag and 0.6 kilobase pairs of env-derived FeLV sequences are represented in ST FeSV. Heteroduplex analyses between lambda FeSV or lambda FeLV DNA and Moloney murine sarcoma virus DNA (strain m1) were performed under conditions of reduced stringency to demonstrate limited regions of base pair homology. Two such regions were identified: the first occurs at the extreme 5' end of the leukemia and both sarcoma viral genomes, whereas the second corresponds to a 5' segment of leukemia virus "env" sequences conserved in both sarcoma viruses. The latter sequences are localized at the 3' end of FeSV src and at the 5' end of murine sarcoma virus src and could possibly correspond to regions of helper virus genomes that are required for retroviral transforming functions.

Bacteriophage lambda↗

Kaposi's sarcoma-associated herpesvirus and Kaposi's sarcoma in Africa. Uganda Kaposi's Sarcoma Study Group.

BACKGROUND: Endemic Kaposi's sarcoma (KS) is a clinically and epidemiologically distinct human immunodeficiency virus negative form of KS occurring in Africa. Kaposi's sarcoma is now the most frequently reported cancer in some areas of Africa. OBJECTIVE: To determine if a KS-associated herpesvirus (KSHV) is present in both endemic HIV-seronegative and HIV-seropositive KS lesions from African patients. METHODS: Paraffin-embedded tissue specimens from Ugandan patients with KS and non-KS tumor control patients attending a university-based oncology clinic were examined in a blinded case-control study. Tissue DNA specimens were examined for detectable KSHV genome by nested polymerase chain reaction performed at two independent laboratories. RESULTS: We identified KSHV in 17 (85%) of 20 KS tissue specimens from HIV-seronegative patients and 22 (92%) of 24 KS tissue specimens from HIV-infected persons. Kaposi's sarcoma lesions from four HIV-infected persons and four HIV-seronegative persons were positive for KSHV. Unlike previous studies in North America and Europe, three (14%) of 22 non-KS cancer control patients' tissue specimens were also positive for KSHV that resulted in an overall odds ratio of 49.2 (95% confidence interval, 9.1 to 335) for detecting KSHV in KS lesions from patients in Uganda. CONCLUSION: As in North America and Europe, KSHV infection is strongly associated with both HIV-seropositive and HIV-seronegative KS in Africa. However, it is likely that infection with this virus is more highly prevalent in Uganda.

Case-Control Studies↗

Isolation of genes differentially expressed between the Yoshida sarcoma and long-survival Yoshida sarcoma variants: origin of Yoshida sarcoma revisited.

The Yoshida sarcoma (YS) is characterized by growth as "free cells" in ascites. Long-survival Yoshida sarcoma (LY) variants, which develop after transplantation of YS into immunologically conditioned Donryu rats, in contrast, form "islands" in ascites. A representational difference analysis (RDA) approach was adopted to isolate genes differentially expressed between YS and LY variants to elucidate the molecular mechanism of their development. Fifteen clones presenting differences in expression were characterized. Nine genes (those encoding for the high-affinity IgE receptor gamma chain, pJG116 repetitive sequence, non neuronal enolase, proteasome subunit RC1, cytotoxic T lymphocyte-associated gene transcript CTLA-1, interleukin-2 receptor gamma chain, and three unknown sequences) expressed mRNA in YS, but showed lower or no expression of mRNA in LYs. The mRNAs of the other six genes (those encoding for cytokeratin 8, cytokeratin18 (Endo B), TIMP2 and three unknown sequences) were not found in YS, but were present in LYs. Interestingly, CTLA-1 is a non-epithelial (hematopoietic) cell-specific gene in terms of transcription, while cytokeratin 8 and cytokeratin 18 are both epithelium-specific genes. Immunohistochemically, YS expressed T-cell specific antigens CD2 and CD3, and T cell receptor beta and gamma chain genes were rearranged in YS, but not in LYs. Moreover, using restriction fragment length polymorphism probes, we found that LYs exhibited different cell lineage from YS. Thus, our present findings, unexpectedly, raise fundamental questions concerning the cellular origins of YS and LY variants rather than pointing to any specific mechanism to explain the LY phenomenon.

Animals↗

Comparison of Rous sarcoma virus-specific deoxyribonucleic acid polymerases in virions of Rous sarcoma virus and in Rous sarcoma virus-infected chicken cells.

Labeled virions of Rous sarcoma virus (RSV) were disrupted with detergent and analyzed on equilibrium sucrose density gradients. A core fraction at a density of approximately 1.24 g/cc contained all of the (3)H-uridine label and about 30% of the (3)H-leucine label from the virions. Endogenous viral deoxyribonucleic acid (DNA) polymerase activity was only found in the same location. Additional ribonucleic acid (RNA)- and DNA-dependent DNA polymerase activities were found at the top of the gradients. RNA-dependent and DNA-dependent DNA polymerase activities were also found in RSV-converted chicken cells. Particles containing these activities were released from cells by detergent and were shown to contain viral RNA. These particles were analyzed on equilibrium sucrose density gradients and were found to have densities different from virion cores.

Animals↗

Endometrial stromal sarcoma and poorly differentiated endometrial sarcoma.

U.T.M.D. Anderson Hospital cases filed as endometrial sarcoma were reviewed. Malignant mixed Müllerian tumors, Müllerian adenosarcomas, and poorly differentiated sarcomas of uncertain origin were excluded, and a minimum of 36 months follow-up was required. On pathologic examination, the remaining cases fell into two distinct groups: endometrial stromal sarcoma (11 cases) and poorly differentiated endometrial sarcoma (seven cases). The former were characterized histologically by small to medium-sized uniform cells and distinctive arterial vasculature resembling the spiral arteries to the normal endometrium; they were thus considered to exhibit endometrial stromal differentiation. The latter showed topographic configurations indicative of endometrial origin but did not demonstrate endometrial stromal differentiation; they were composed of generally larger cells with nuclear hyperchromatism and pleomorphism and had no distinctive vascular pattern. The mitotic rate was usually low in endometrial stromal sarcoma and high in poorly differentiated endometrial sarcoma, although two examples of the former had more than 20 mitoses per 10 high-power fields. All but one of the patients with endometrial stromal sarcoma were less than 50 years of age, whereas all of those with poorly differentiated endometrial sarcoma were older than 50 years. One patient with endometrial stromal sarcoma died of tumor, two were living with tumor at latest follow-up, and eight were clinically tumor-free. By contrast, six of those with poorly differentiated endometrial sarcoma died of tumor, all within 34 months. The extent of tumor was the major prognostic factor in both groups; the three patients with endometrial stromal sarcoma who were dead or living with tumor all had extrauterine extension at the time of hysterectomy (only one of the other eight did so) and all six who died with poorly differentiated endometrial sarcoma had myometrial invasion (the one survivor had a tumor limited to the endometrium). Other pathologic factors, including mitotic rate, had no prognostic significance in either category; of particular interest was that both patients who had endometrial stromal sarcomas with high mitotic rates were tumor-free. It is concluded that endometrial stromal sarcoma is a distinct tumor entity whose diagnosis should not depend on mitotic rate, and it is suggested that poorly differentiated endometrial sarcoma is closely related to malignant mixed Müllerian tumor, in view of clinical and pathologic similarities.

Adult↗

The postoperative prognosis of primary pulmonary sarcomas. A review with a comparison between the histological forms and the other primary endothoracal sarcomas based on 474 cases.

On the basis of 41 personally observed cases from 1957 to 1974 and 435 case reports in the literature from 1957 to 1972, a scale of malignancy of the histological forms of primary pulmonary sarcomas is presented. A fairly continuous rise in the rate of malignancy according to the differentiation of the tissues can be convincingly recognized. The more mature a pulmonary sarcoma is, the better is the postoperative prognosis. The rate of malignancy increases from the relatively differentiated and tissue matured fibrosarcomas over the spindle cell sarcomas and round cell sarcomas, to the completely non-differentiated polymorph cell sarcomas. Primary myosarcomas, neurosarcomas and reticulum sarcomas of the lungs take an isolated position within this scale of malignancy. Primary lymphosarcomas are the most common and have clearly the best postoperative prognosis. The greatest malignancy is found with the carcinosarcomas. The characteristics of each of the histomorphological forms of primary sarcoma of the lungs are discussed. At the same time it is shown that the postoperative prognosis of endothoracal sarcomas is determined not only by their histological structure, but also by their localization in the lungs, mediastinum, or chest wall. Forty-one primary pulmonary sarcomas were compared with 22 sarcomas of the mediastinum and 17 sarcomas of the chest wall. Due to their long period of development, with rare symptoms and late diagnosis, sarcomas of the lungs and the mediastinum have a similar postoperative prognosis, in contrast to the endothoracal sarcomas of the chest wall which have a clearly more favourable prognosis.

Fibrosarcoma↗

Kaposi's sarcoma-associated herpesvirus-like DNA sequences (KSHV/HHV-8) in oral AIDS-Kaposi's sarcoma: a PCR and clinicopathologic study.

Recently, a new human herpesvirus (KSHV/HHV-8) has been identified in classic, transplant, endemic, and AIDS Kaposi's sarcoma that may be involved in the pathogenesis of Kaposi's sarcoma. The purpose of this study was to evaluate oral AIDS-Kaposi's sarcoma for detection of KSHV/HHV-8 DNA. DNA extracted from 54 oral AIDS-Kaposi's sarcoma lesions (47 initial, 7 postvinblastine treated), 5 non-Kaposi's sarcoma HIV-positive lesions, and 3 non-Kaposi's sarcoma HIV-negative lesions was evaluated by polymerase chain reaction (KS330(233bp)amplicon) for KSHV/HHV-8. The AIDS-Kaposi's sarcoma study population consisted of 52 patients (51:1, men:woman; 92% men having sex with men, 8% heterosexual; mean age, 38 years; mean, CD4 59/mm3) Opportunistic infections occurred in 88% (candidiasis, 65%; Pneumocystis carinii pneumonia, 31%; nonoral Kaposi's sarcoma, 25%; mycobacterium avium-intracellulare (MAI), 16%; cytomegalovirus, 14%; herpes simplex virus, 14%). Sexually transmitted diseases occurred in 73% (gonorrhea, 37%; syphilis, 23%; condyloma, 22%; HSV, 16%). Most frequent lesion sites were palate (74%) and gingiva (17%). Most common lesion types were purple nodular (48%) and macular (42%). Histopathologic subtypes were nodular (71%), plaque (27%), and patch (2%). Polymerase chain reaction analysis detected KSHV/HHV-8 DNA in 53 of 54 AIDS-Kaposi's sarcoma lesions (47 of 47 initial, 6 of 7 postvinblastine treatment). KSHV/HHV-8 DNA was not detected in non-Kaposi's sarcoma lesions in HIV-positive or HIV-negative persons. KSHV/HHV-8 DNA sequence is present in a high proportion of oral AIDS-Kaposi's sarcoma lesions. Whether KSHV/HHV-8 is an etiologic agent or a cofactor in the development of this vascular neoplasm is uncertain and remains to be proven. Polymerase chain reaction analysis for KSHV/HHV-8 DNA sequence detection may be helpful in identifying Kaposi's sarcoma in early vascular proliferations, when the characteristic histopathologic features are not present.

AIDS-Related Opportunistic Infections↗

Seroconversion to antibodies against Kaposi's sarcoma-associated herpesvirus-related latent nuclear antigens before the development of Kaposi's sarcoma.

BACKGROUND: If Kaposi's sarcoma-associated herpesvirus (KSHV) is the cause of Kaposi's sarcoma, serologic evidence of infection should be present in patients before the disease develops. METHODS: Using an immunoblot assay for two latent nuclear antigens of KSHV, we tested serum samples from homosexual male patients with the acquired immunodeficiency syndrome (AIDS) with and without Kaposi's sarcoma (HIV-infected men with hemophilia), HIV-seronegative blood donors, and HIV-seronegative patients with high titers of antibodies against Epstein-Barr virus (EBV). Serial serum samples obtained from patients with Kaposi's sarcoma before the diagnosis of the disease were tested for evidence of seroconversion. RESULTS: Of 40 patients with Kaposi's sarcoma, 32 (80 percent) were positive for antibodies against KSHV antigens by the immunoblot assay, as compared with only 7 of 40 homosexual men (18 percent) without Kaposi's sarcoma immediately before the onset of AIDS. Of 122 blood donors, 22 EBV-infected patients, and 20 HIV-infected men with hemophilia, none were seropositive. When studied by the immunoblot assay over a period of 13 to 103 months, 21 of the 40 patients with Kaposi's sarcoma (52 percent) seroconverted 6 to 75 months before the clinical appearance of Kaposi's sarcoma. The median duration of antibody seropositivity for KSHV-related latent nuclear antigens before the diagnosis of Kaposi's sarcoma was 33 months. CONCLUSIONS: In most patients with kaposi's sarcoma and AIDS, seroconversion to positivity for antibodies against KSHV-related nuclear antigens occurs before the clinical appearance of Kaposi's sarcoma. This supports the hypothesis that Kaposi's sarcoma results from infection with KSHV.

Acquired Immunodeficiency Syndrome↗