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Regression of feline sarcoma virus-induced sarcomas in dogs. II. Immunologic investigations.

The serial development of cell-mediated immunity (CMI), cytotoxic antibody activity, serum blocking activity, and virus-neutralizing antibody levels were monitored in vitro for beagle and mongrel puppies inoculated with feline sarcoma virus (FeSV) and were compared to in vivo histologic markers of regression of induced sarcomas. CMI developed rapidly and maintained a high level of in vitro activity throughout the tumor life-span. Cytotoxic antibody levels similarly rose rapidly to peak just before clinically detectable regression and then declined during most of the regression sequence. This suggested antibody fixation at the tumor site, correlating with the histologic finding of focal necrosis and neutrophilic infiltrates. Inactivation of antibody by circulating antigen with subsequent immune complex formation was a possibility. Levels of virus-neutralizing antibody in sera paralleled those of cytotoxic antibody; their relationship in the circulation was not clear, but each related to virus-determined antigenic specificities. Serum blocking activity rose rapidly, leveled off during most of the tumor life-span, and rose slightly during the last stages of regression. This partly explained the lack of in vivo tumor lymphoid infiltrates to correlate with the striking in vitro CMI. Blocking activity was also present, however, when lymphoid infiltrates were seen histologically. Thus in vitro-in vivo correlation was best for cytotoxic antibody, which suggested that antigen-antibody reactions involving neutrophil-mediated regression sequences were important in effecting tumor-cell destruction.

Animals↗

Radiation therapy in the multimodal management of Ewing's sarcoma of bone: report of the Intergroup Ewing's Sarcoma Study.

This paper is a progress report on the role of radiation therapy (RT) in local tumor control and the decreased incidence of pulmonary metastasis in 251 patients entered in the Intergroup Ewing's Sarcoma Study. All were followed for more that 1 year, and their RT records were reviewed. Doses to the primary tumor in the range of 4,500--6,500 rad were administered over approximately 5 to 6 weeks in combination with 4 drugs, i.e., vincristine (VCR), dactinomycin (DAC), cyclophosphamide (CY), and adriamycin, or only the first 3. One group of patients received the 3 drugs and bilateral pulmonary irradiation (approximately 1,500 rad in 2 wk). Preliminary analysis showed a local primary tumor control of approximately 90%. Patients with lesions in the pelvis and humerus had local failure rates of 13% (7 of 54) and 21.4% (6 of 28), respectively. The treatment groups differed significantly in the incidence of pulmonary metastasis. Patients treated with the 4 drugs (regimen 1) had a 14% incidence, whereas 42% of those treated with only 3 drugs (regimen 2) developed pulmonary metastases. Of all patients treated with 3 drugs and pulmonary irradiation (regimen 3), 18% showed lung metastases. The study indicated that intensive chemotherapy and RT significantly improved the local control and survival of patients with localized Ewing's sarcoma. However, the high incidence of metastasis indicated the need for more effective systemic chemotherapy for further improvement of treatment results. More studies are needed so we can define the volume to be treated and the optimal dose of irradiation to determine a therapeutic strategy that will yield optimal survival and tumor control with the fewest sequelae.

Adolescent↗

Intramyofiber skeletal muscle invasion in Ewing's sarcoma of bone: clinicopathologic observations from the intergroup Ewing's sarcoma study.

Skeletal muscle may be infiltrated by a variety of invasive or metastatic malignant tumors. In 14 out of 291 cases of Ewing's sarcoma, we observed diagnostic biopsies in which local skeletal muscle fibers contained intrasarcolemmal aggregates of tumor cells. Cases demonstrating local intramyofiber invasion have a higher mitotic count, an increased rate of developing distant metastases, and a decreased survival when compared to cases not demonstrating this skeletal muscle "parasitism." The usefulness of skeletal muscle intramyofiber invasion in the differential diagnosis of Ewing's sarcoma remains unknown at this time.

Biopsy↗

The use of recombinant human granulocyte-macrophage colony-stimulating factor with combination chemotherapy in the treatment of advanced adult soft-tissue sarcomas: early results from the EORTC Soft-Tissue and Bone Sarcoma Group.

We gave the "optimal" dose of doxorubicin (75 mg/m2) with ifosfamide (5 g/m2), the two most active agents against metastatic soft-tissue sarcomas, in an attempt to determine the feasibility of administration of these doses in combination. To offset complications arising from the myelosuppression associated with this regimen, recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF, 250 micrograms/m2 daily) was given by subcutaneous injection during the intervals between courses of chemotherapy. In all, 111 patients with progressive metastatic soft-tissue sarcoma were entered, 104 of whom were eligible for preliminary analysis. Use of rhGM-CSF allowed full doses of chemotherapy to be given to the majority of patients, although cumulative thrombocytopenia became a dose-limiting toxicity during subsequent courses. Two treatment-related deaths occurred, one from presumed septicemia while the patient was at home and one as a result of cardiac failure. An overall response rate of 45% was achieved. The activity of this high-dose combination (with rhGM-CSF) will be compared with that of standard treatment doses in a future phase III randomized trial.

Adult↗

Kaposi's sarcoma-associated herpesvirus: a lymphotropic human herpesvirus associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease.

Despite extensive epidemiological evidence suggesting that Kaposi's sarcoma (KS) has an infectious origin, a specific viral association with KS had not been documented until recently, when two novel DNA fragments were identified in KS lesional tissue from a patient with the acquired immunodeficiency syndrome (AIDS). These fragments belong to a previously unidentified human herpesvirus, called KS-associated herpesvirus (KSHV), or human herpesvirus 8. Although this virus is generally absent from normal control tissues, inflammatory conditions, and a variety of tumors, it is present in most AIDS- as well as non-AIDS-related KS lesions, suggesting that it is not simply an opportunistic infection in human immunodeficiency virus (HIV)-infected patients. Furthermore, this virus is consistently present in a specific type of non-Hodgkin's lymphoma, frequently although not exclusively occurring in patients with AIDS (namely, the primary effusion lymphomas, previously called body cavity-based lymphomas). KSHV is also present in a significant proportion of cases of AIDS- and non-AIDS-related multicentric Castleman's disease. Sequence analysis has led to the identification of genes in the KSHV genome that may have important pathobiological functions, and experimental approaches have been developed to isolate, grow and transmit KSHV in vitro. An understanding of KSHV is important for evaluating its role in the pathogenesis of Kaposi's sarcoma, primary effusion lymphomas, and multicentric Castleman's disease, and to help develop better methods for the prevention and treatment of these diseases.

Castleman Disease↗

Risk of Kaposi's sarcoma-associated herpes virus transmission from donor allografts among Italian posttransplant Kaposi's sarcoma patients.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a newly discovered herpes virus found in all forms of Kaposi's sarcoma (KS) including KS among immunosuppressed transplant patients. It is unknown whether this virus is transmitted by organ transplantation or is reactivated during immunosuppression among those patients infected before transplantation. To investigate the risk of KSHV transmission during organ transplantation, we conducted a case-control study of transplant recipients with and without KS matched to their respective donors. Sera were collected at time of transplantation and tested in a randomized and blinded fashion using four KSHV serologic assays testing for antibodies to both latent and lytic phase antigens. Ten (91%) of 11 organ recipients who developed KS were seropositive prior to transplantation by one or more of the assays compared with two (12%) of 17 control organ recipients (OR = 75, 95% CI = 4.7, 3500). KS cases were more likely to have been born in southern Italy where KS is endemic than the recipient controls or either donor group. Only four (36%) of 11 donors to case patients and three (18%) of 17 donors to control patients were seropositive (P = .38, two-tailed Fisher's exact test). KSHV transmission could not be ruled out for the single KS patient seronegative at transplantation and clear evidence for organ-related transmission was found for another KS patient outside of the case-control study. Antibodies to KSHV are detectable in the sera from most transplant recipients before initiation of immunosuppressive treatment suggesting that KS among immunosuppressed transplant patients is primarily due to virus reactivation. KSHV transmission, however, from an infected allograft can occur, and our study reports the first documented case of person-to-person transmission of KSHV.

Adult↗

Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data. Sarcoma Meta-analysis Collaboration.

BACKGROUND: Individually, randomised trials have not shown conclusively whether adjuvant chemotherapy benefits adult patients with localised resectable soft-tissue sarcoma. METHODS: A quantitative meta-analysis of updated data from individual patients from all available randomised trials was carried out to assess whether adjuvant chemotherapy improves overall survival, recurrence-free survival, and local and distant recurrence-free intervals (RFI) and whether chemotherapy is differentially effective in patients defined by age, sex, disease status at randomisation, disease site, histology, grade, tumour size, extent of resection, and use of radiotherapy. FINDINGS: 1568 patients from 14 trials of doxorubicin-based adjuvant chemotherapy were included (median follow-up 9.4 years). Hazard ratios of 0.73 (95% CI 0.56-0.94, p = 0.016) for local RFI, 0.70 (0.57-0.85, p = 0.0003) for distant RFI, and 0.75 (0.64-0.87, p = 0.0001) for overall recurrence-free survival, correspond to absolute benefits from adjuvant chemotherapy of 6% (95% CI 1-10), 10% (5-15), and 10% (5-15), respectively, at 10 years. For overall survival the hazard ratio of 0.89 (0.76-1.03) was not significant (p = 0.12), but represents an absolute benefit of 4% (1-9) at 10 years. These results were not affected by prespecified changes in the groups of patients analysed. There was no consistent evidence that the relative effect of adjuvant chemotherapy differed for any subgroup of patients for any endpoint. However, the best evidence of an effect of adjuvant chemotherapy for survival was seen in patients with sarcomas of the extremities. INTERPRETATION: The meta-analysis provides evidence that adjuvant doxorubicin-based chemotherapy significantly improves the time to local and distant recurrence and overall recurrence-free survival. There is a trend towards improved overall survival.

Adolescent↗

A phase II trial of paclitaxel in the treatment of recurrent or metastatic soft tissue sarcomas or bone sarcomas.

The study aimed to determine the activity and toxicity of taxol in the treatment of recurrent or metastatic soft tissue sarcomas or osteosarcomas. The major findings are that five patients had stable disease after two cycles of chemotherapy but two of these patients were subsequently removed from the study at their own request. The other three patients progressed after an additional two cycles of chemotherapy. Seven patients progressed during the first two cycles and were removed from the study. One patient completed only one cycle of therapy and was deemed inevaluable for study response. There were eight episodes of grade 3 or 4 neutropenia and two episodes of grade 3 thrombocytopenia. One patient experienced grade 3 neurological toxicity and one patient grade 3 mucositis. Two patients are currently alive with progressing disease and one patient is alive with no evidence of disease after undergoing surgery and radiotherapy. The principal conclusions are that Paclitaxel is ineffective in treating recurrent or metastatic soft tissue sarcoma and osteosarcoma. Treatment at this dose is quite myelosuppressive, but toxicity is generally manageable. Further study of this agent is not justified in this setting.

Adult↗

Demonstration of Kaposi's sarcoma-associated herpes virus cyclin D homolog in cutaneous Kaposi's sarcoma by colorimetric in situ hybridization using a catalyzed signal amplification system.

Kaposi's sarcoma-associated herpes virus (KSHV)/human herpes virus 8 (HHV8) DNA sequences have been demonstrated in Kaposi's sarcoma (KS), as well as in some acquired immunodeficiency syndrome (AIDS)-related non-Hodgkin's lymphomas (NHL) and in multicentric Castleman's disease. Although KSHV DNA generally is abundant in KSHV-associated lymphomas, few copies of the virus are present in KS, a property that confounds detection by in situ methods. Previous in situ studies, which identified KSHV in lesions of KS, relied on the use of polymerase chain reaction (PCR) to amplify target DNA sequences before in situ hybridization (ISH) for localization or used ISH with radioactively-labeled probes to obtain adequate levels of detection sensitivity. In this study, a novel nonisotopic nucleic acid ISH method using catalyzed signal amplification and colorimetric detection without PCR-dependent target amplification was used to identify KSHV-specific sequences. The level of sensitivity was increased further by using a probe that detects viral cyclin D homolog transcripts, which are expressed at significant levels during latent viral infection. Thirty cutaneous lesions of KS (25 AIDS-related and five classical European type) were evaluated. AIDS-related NHL and cell lines derived from patients with AIDS-related NHL, all of which were known to harbor KSHV by Southern blot analysis, were used as positive controls. NHL and benign cutaneous vascular lesions not associated with AIDS were used as negative controls. For each of the 30 KS lesions studied, hybridization signals were detected in most of the spindle cells surrounding the atypical slit-like vascular channels and also were detected in some endothelial cells in well-formed blood vessels in the perilesional dermis. Plaque and nodular lesions generally contained more labeled cells than did early patch lesions. All AIDS-related NHL and cell lines contained KSHV-specific sequences; however, the non-AIDS-related NHLs and benign vascular lesions were negative. These results confirm the presence of KSHV sequences in cutaneous KS and provide in situ evidence of infection by this virus in early patch-stage lesions. This study also defines the in situ expression of the KSHV cyclin D homolog viral oncogene in cutaneous KS. The use of this sensitive nonisotopic ISH method should allow detection of other KSHV-specific gene products, further defining the pathobiology of this virus.

3,3'-Diaminobenzidine↗

Localization of anti-osteogenic sarcoma monoclonal antibody 791T/36 in a primary human osteogenic sarcoma and its subsequent xenograft in immunodeprived mice.

A primary human osteogenic sarcoma was visualized in situ by external gamma-camera imaging following administration of 131I-labelled anti-osteogenic sarcoma monoclonal antibody 791T/36. A xenograft of the tumour established in immunodeprived mice also showed localization of 131I-791T/36 determined by both gamma-camera imaging and organ distribution studies. Radiolabelled normal immunoglobulin showed no tumour localization. Expression of the 791T/36-defined antigen on xenografted tissue was further confirmed by reaction of its in vitro-cultured cells with fluorescein-labelled 791T/36 antibody.

Animals↗

Ophthalmologic manifestations of granulocytic sarcoma (myeloid sarcoma or chloroma). The third Pan American Association of Ophthalmology and American Journal of Ophthalmology Lecture.

The clinicopathologic review of 33 well-documented cases of granulocytic sarcoma on file in the Registry of Ophthalmic Pathology confirmed the facts that this tumor is encountered mainly in children, that boys are affected more frequently than girls, and that white Americans appear to be less vulnerable than other ethnic groups. While granulocytic sarcoma is a variant of granulocytic leukemia, the tumor may appear before, after, or concomitantly with hematologic evidence of leukemia. In the present series only four of the 33 patients were already known to have leukemia when they were first seen by an ophthalmologist for their orbital, ocular, or adnexal lessions. The Leder stain has proved extremely helpful in arriving at a definitive histopathologic diagnosis. Accurate diagnosis is important to prevent inappropriate medical or surgical treatment and to indicate the need for vigorous antileukemic chemotherapy. Prognosis at best is poor.

Adolescent↗

Granulocytic sarcoma of the uterine cervix--literature review of granulocytic sarcoma of the female genital tract.

Granulocytic sarcoma is an extramedullary tumor of malignant granulocytic progenitor cells that accompanies, heralds, or signals relapse of acute myelogenous leukemia (AML), or indicates blastic transformation of a chronic myeloproliferative disorder. We describe a case involving the uterine cervix of a 51-year-old woman that led to the diagnosis of AML. Granulocytic sarcoma can occur in the female genital tract and may be the first clinically significant manifestation of a hematologic malignancy. The salient findings in 28 reported cases from 12 different countries are reviewed. Awareness of this lesion is important for all medical personnel involved in the health care of women.

Diagnostic Errors↗

Avian sarcoma virus Y73 genome sequence and structural similarity of its transforming gene product to that of Rous sarcoma virus.

From the complete nucleotide sequence of the genome of the avian sarcoma virus Y73, we have predicted amino acid sequence of p90 gag-yes, the product of the transforming gene. Contrary to previous evidence from molecular hybridization studies p90 gag-yes was found to have much homology with the transforming gene product p60 src of Rous sarcoma virus, suggesting that the cellular counterparts of the two (c-yes and c-src) originated from a common prototype sequence.

Alpharetrovirus↗

[Immunoblastic sarcoma (reticulum-cell sarcoma) of the gastro-intestinal tract in a case of dermatitis herpetiformis Duhring (author's transl)].

In a 43-year-old man who for 20 years was known to have dermatitis herpetiformis there co-existed, since 1974, a "dermatogenic enteropathy" with gastro-intestional symptoms. Several small-intestine biopsies demonstrated severe partial to subtotal villous atrophy with crypt hyperplasia, as seen in gluten-sensitive enteropathy. At post-mortem there was an immunoblastic sarcoma - so-called reticulum-cell sarcoma - in the upper jejunum and abdominal lymph-nodes, which was presumably the immediate complication of the sprue-like lesions of the small intestines.

Adult↗

[Sarcoma botryoides in the pediatric vagina--a soft tissue sarcoma with good prognosis].

Although rare, sarcoma botryoides of the vagina in infants is a highly aggressive soft tissue tumour. Former opinions suggesting exenterative surgery and radiation to improve the dismal outcome in these young children, are outdated. Due to balanced therapies (topical tumourectomy, chemotherapy and radiation adjusted to tumour stage) cure of these sarcomas may be expected dependent on tumour stage, localisation and response to chemotherapy. The rate of complete remissions has increased in recent years. We report on an eighteen-month old girl with complete remission of tumour stage IIA who had been treated according to the CWS 91 protocol. Diagnosis and treatment were performed in March 1994 at the age of six months. We observed the patient in complete remission for 8 months (till September 1995).

Biomarkers, Tumor↗

Elimination of the sarcoma genome from murine sarcoma virus transformed cat cells.

Cat cells transformed by Moloney murine sarcoma virus contain virus-specific sequences in their RNA and DNA. Cloned, spontaneous revertant cell lines derived from clones of these cells had no evidence of the sarcoma genome in the cell RNA or DNA as judged by RNA-complementary DNA or DNA-complementary DNA hybridizations. ?This is apparently the first report of loss of a transforming genome in a revertant cell line.

Cell Line↗

Restriction endonuclease mapping of unintegrated proviral DNA of Snyder-Theilen feline sarcoma virus: localization of sarcoma-specific sequences.

Extrachromosomal DNA purified from mink cells acutely infected with the Snyder-Theilen strain of feline sarcoma virus (FeSV) was digested with restriction endonucleases, and the DNA fragments were electrophoretically separated, transferred to a solid substrate, and hybridized with radiolabeled DNA transcripts complementary to different portions of the FeSV RNA genome. Major DNA species 8.4 and 5.0 kilobase pairs (kbp) long represent the linear, unintegrated proviruses of Snyder-Theilen feline leukemia virus and FeSV, respectively. Transfection experiments performed with electroeluted DNAs showed that the 8.4-kbp form led to the production of replicating nontransforming virus in mink and cat cells; in contrast, the 5.0-kbp DNA produced helper virus-independent foci of transformation in mouse NIH/3T3 cells and helper virus-dependent foci in mink cells at an efficiency comparable to that obtained with unfractionated extrachromosomal DNA. Sites of restriction endonuclease cleavage for six enzymes were oriented with respect to one another within the FeSV provirus. EcoRI recognized cleavage sites at 0.3 to 0.4 kbp from each terminus of FeSV DNA, reducing the 5.0-kbp DNA to molecules 4.3 kbp long; this enzyme excised a large internal proviral DNA fragment of corresponding size from the DNA of FeSV-transformed mink nonproducer cells. By using DNA transcripts complementary to different portions of the FeSV genome, sarcoma-specific sequences (the FeSV src gene) were positioned within 2.1 and 3.4 kbp from the 5' end of the proviral DNA with respect to the viral RNA genome. The src gene is flanked at both ends by sequences shared in common with feline leukemia virus. The localization of src sequences to this region suggests that a portion of an FeSV polyprotein which contains feline oncornavirus-associated cell membrane antigen (FOCMA-S) is the major product of this gene.

Animals↗