Pulmonary function tests after whole-lung irradiation and doxorubicin in patients with osteogenic sarcoma.

PURPOSE: Because of the scarcity of information regarding long-term follow-up of pulmonary function after whole-lung irradiation, a prospective study was started at the University of Florida in 1979 to evaluate pulmonary function after treatment with whole-lung irradiation and doxorubicin in patients with osteogenic sarcoma. PATIENTS AND METHODS: Between 1979 and 1984, 57 osteogenic sarcoma patients with no evidence of metastatic disease at diagnosis received adjuvant therapy consisting of whole-lung irradiation (with the heart shielded) followed by Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH). The whole-lung irradiation schema was 1,600 cGy in 10 fractions with 8-MV x-rays via anterior and posterior fields. This was followed by five cycles of Adriamycin for a total dose of 450 mg/m2. Pulmonary function tests (PFTs) consisting of spirometry, lung volumes, and diffusing capacity were obtained before the whole-lung irradiation, at 6 and 12 months after irradiation, and at yearly intervals thereafter. RESULTS: At the time of analysis, 28 of the 57 patients were available for study, with a mean follow-up of 42 months (range, 6 to 77 months). Follow-up pulmonary function testing revealed decreased forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV1) during the first 6 to 12 months after whole-lung irradiation. These values returned to baseline during the second-year posttherapy and remained at baseline throughout the remainder of the follow-up period. Changes in lung volumes demonstrated a similar early trend, with significant decreases in total lung capacity (TLC) and functional residual capacity (FRC) at 6 to 12 months. These changes, however, did not improve significantly during the remainder of the follow-up period. Diffusing capacity of the lungs for carbon monoxide (DLCO) also reached a nadir at 6 to 12 months after whole-lung irradiation, with resolution by 2 years and maintenance of at least baseline values for the remainder of the follow-up period. CONCLUSIONS: Treatment with whole-lung irradiation and Adriamycin, as given in this study, caused no significant sequelae, as demonstrated by pulmonary function testing during the mean follow-up period of 42 months, although a mild, transient restrictive ventilatory defect occurred at 6 to 12 months after treatment.

Suramin inhibits growth and transforming growth factor-beta 1 (TGF-beta 1) binding in osteosarcoma cell lines.

Autocrine production of growth factors has been shown to be involved in the multistep process of tumorigenesis. The ability of suramin, a polyanionic anti-parasitic drug, to block growth factor-induced cell proliferation makes it a potential antineoplastic drug. We studied the effects of suramin on seven osteosarcoma cell lines. Using clinically achievable concentrations of suramin (50-400 micrograms/ml), we found a time- and dose-dependent inhibition of [3H]thymidine incorporation. We also showed that suramin is able, dose-dependently, to prevent binding of transforming growth factor (TGF)-beta 1 to its receptors. DNA synthesis inhibition by suramin was attenuated by TGF-beta 1 in some cell lines. Two cell lines that were inhibited by TGF-beta 1 were affected similarly by suramin as cell lines that were stimulated by TGF-beta 1. In conclusion, in five out of seven osteosarcoma cell lines, we showed a correlation between inhibition of growth factor-stimulated mitogenesis and binding of TGF-beta 1 to its receptor. Similar effects in TGF-beta 1-inhibited osteosarcoma cell lines suggest involvement of other mechanisms and/or growth factors. However, suramin proves to be a potent inhibitor of osteosarcoma cell proliferation in vitro.

High-risk Ewing's sarcoma: end-intensification using autologous bone marrow transplantation.

Because of retrospective analysis showing survival to be related to primary tumor size, in February 1982 a study to test this hypothesis prospectively was begun at the University of Florida. Patients with primary tumors 8 cm or less in maximum diameter and no metastases received adjuvant chemotherapy consisting of vincristine, cyclophosphamide, doxorubicin, and dactinomycin plus radiotherapy or surgery (standard-risk protocol). All others received a similar regimen followed by end-intensification with high-dose melphalan and autologous bone marrow transplantation (Protocol HR-2). Because of poor results of HR-2, another high-risk protocol (HR-3) was initiated in January 1985. Patients on HR-3 received 2 cycles of chemotherapy containing vincristine, cyclophosphamide, and doxorubicin followed by local radiation therapy and maintenance chemotherapy. At the end of this therapy, autologous bone marrow transplantation (ABMT) was performed, using a preparatory regimen of total body irradiation and intensive chemotherapy. The 2-year disease-free survival rate was 70% for the standard-risk protocol, 20% for HR-2, and 80% for HR-3. The follow-up on HR-3 is still short, but the results are promising enough to warrant further clinical trials.

Individualizing management of aggressive fibromatoses.

PURPOSE: To examine prognostic indicators in aggressive fibromatoses that may be used to optimize case-specific management strategy. METHODS AND MATERIALS: One hundred and seven fibromatoses presenting between 1971 and 1992 were analyzed. The following treatment modalities were utilized: (a) surgery alone for 51 tumors; (b) radiation alone for 15 tumors; and (c) radiation and surgery (combined modality) for 41 tumors. Outcome analysis was based on 5-year actuarial local control rates. RESULTS: Control rates among surgery, radiation therapy, and combined modality groups were 69%, 93%, and 72%. Multivariate analysis identified age < 18 years, recurrent disease, positive surgical margins, and treatment with surgery alone as predictors for failure. Patients treated with surgery alone had control rates of 50% (3 of 6) for gross residual, 56% for microscopically positive margins, and 77% for negative margins. Radiation and surgery resulted in rates of 59% for gross residual, 78% for microscopically positive margins, and 100% (6 of 6) for negative margins. For recurrent vs. primary tumors, control was achieved in 48% vs. 77%, 90% vs. 100% (5 of 5), and 67% vs. 79% in the Surgery, Radiation, and Combined modality Groups, respectively. Patients presenting with multiple disease sites tended to have aggressive disease. A radiation dose-control relation to > 60 Gy was seen in patients with unresected or gross residual disease. Of the patients, 23 with disease involving the plantar region had a control rate of 62%, with significantly worse outcomes in children. CONCLUSIONS: These results are consistent with those found in the relevant literature. They support primary resection with negative margins when feasible. Radiation is a highly effective alternative in situations where surgery would result in major functional or cosmetic defects. When negative surgical margins are not achieved in recurrent tumors, radiation is recommended. Perioperative radiation should be considered in other high-risk groups (recurrent disease, positive margins, and plantar tumors in young patients). Doses of 60-65 Gy for gross disease and 50-60 Gy for microscopic residual are recommended. Observation may be considered for primary tumors with disease remaining in situ when they are located such that progression would not cause significant morbidity. Although plantar lesions in children may represent a group at high risk for recurrence or aggressive behavior, the greater potential for radiation-induced morbidity in this group must also temper its use. Given the inconsistent nature and treatment response of this tumor, it is fundamental that treatment recommendations should be made based on the risk:benefit analysis for the individual patient, dependent on tumor characteristics and location, as well as patient characteristics and preferences.

An assay to measure adriamycin binding in osteosarcoma cells.

Adjuvant chemotherapy is currently employed in the treatment of patients with osteosarcoma, but the drug regimens, although effective in improving disease-free survival, are unsuccessful in 20-40% of patients and very toxic. It would be useful to know whether tumor cells are sensitive to a given drug prior to its use. To this end, we developed a method of assessing Adriamycin (doxorubicin) binding to tumor nuclei as a possible means of detecting sensitivity to the drug. Adriamycin-sensitive murine osteosarcoma cells were used to develop the assay. The in vitro conditions (drug concentration, duration of incubation, and temperature) were optimized with use of the murine osteosarcoma cells in culture. After the cells had been incubated with Adriamycin, cell viability was determined and Adriamycin fluorescence intensity was measured with a cytofluorometer. The optimal parameters for Adriamycin binding were found to be a 30-minute incubation in a 10 micrograms/ml concentration of Adriamycin at 37 degrees C; the frequency of cells that emitted Adriamycin fluorescence from the nucleus compared with the total number of living cells reached 100% under these conditions. In a murine leukemia cell line with known sensitivity to Adriamycin, the cells emitted red fluorescence from the nucleus and cytoplasm, whereas in a resistant line the cells emitted Adriamycin fluorescence from only the cytoplasm. We demonstrated that it is possible to differentiate nuclear from cytoplasmic concentration of Adriamycin in a tumor cell with use of a fluorescent microscope and that resistant cell lines can be distinguished from sensitive cell lines by this method.(ABSTRACT TRUNCATED AT 250 WORDS)

Surgical wound healing.

It is clear that the alterations in wound healing caused by irradiation and chemotherapy are due to reduced rates of collagen production, probably from adverse effects of irradiation and chemotherapy on fibroblasts. The effect is to slow the process of wound healing so much that there is significantly more time for a complication to occur. If no complication occurs in the first 3-4 weeks after wound production, healing seems to proceed reasonably normally. The specific mechanisms by which irradiation and chemotherapy cause their damage is not known and additional research is needed.

Polyploidization induced by acridine orange in mouse osteosarcoma cells.

This study was undertaken to clarify the in vitro effect of acridine orange (AO) on the cell kinetics of mouse osteosarcoma cells, as well as the mechanism of cell growth inhibition induced by AO. A mouse osteosarcoma cell line (MOS), established from a radiation-induced mouse osteosarcoma, was cultured under exposure to 0.05, 0.5, 5, and 50 micrograms/ml of AO, either continuously or for 10 minutes. The cell kinetic analysis was performed using the following parameters: tumor cell growth by trypan blue exclusion test, mitotic activity, DNA synthetic activity by BrdU labeling and DNA ploidy by cytofluorometry. The results showed that continuous exposure to 5 and 50 micrograms/ml of AO or 10 minute exposure to 50 micrograms/ml of AO quickly killed the tumor cells within 12 hours, whereas continuous exposure to 0.5 microgram/ml of AO or 10 minute exposure to 5 micrograms/ml of AO gradually inhibited tumor cell growth. Under the latter conditions, mitotic activity was rapidly and completely inhibited within 48 hours but DNA synthetic activity was not completely inhibited even after 96 hours. DNA ploidy analysis demonstrated that most of the tumor cells arrested at the S-G2 phase after 12 hours, followed by G2 phase arrest after 24 hours and progressive DNA synthesis to a higher DNA ploidy class after 48 to 96 hours. We therefore concluded that a high concentration of AO has a strong cytocidal effect due to cytotoxicity whilst a moderate concentration of AO induces progressive and synchronous polyploidization by mitotic inhibition without DNA damage in MOS cells. We presume that this in vitro effect on MOS cells may be caused by protein synthetic inhibition after transfer RNA inactivation caused by AO binding.

Relationship between histologic grade and cytofluorometric cellular DNA and RNA content in primary bone tumors.

The diagnosis and grading of bone tumors remains a challenging problem. We studied the relationship between histologic grade and cytofluorometric cellular DNA and RNA content in 108 primary bone tumors. The data included DNA ploidy, mean DNA content (MDC), S-phase fraction (SPF), mean RNA content (MRC) and RNA/DNA ratio (RDR; MRC/MDC) which represents the RNA content normalized for the DNA content. Benign tumors had a diploid stem line with low MDC (mean; 1.04), low SPF (0.9), high MRC (2.41) and high RDR (2.31). Giant cell tumors of bone, which are locally aggressive benign tumors, showed diploidy with relatively higher MDC (1.07, p < 0.01) and SPF (2.6, p < 0.01) and lower MRC (1.81, p < 0.01) and RDR (1.69, p < 0.01). Similar results were obtained in low-grade sarcomas. In high-grade sarcomas, the data depended on the histologic findings. Pleomorphic sarcomas such as osteosarcomas revealed aneuploidy with remarkably higher MDC (1.70 in osteosarcomas, p < 0.01) and SPF (6.5, p < 0.01), but lower RDR (1.70, p < 0.01). In contrast, small cell sarcomas, such as Ewing's sarcomas, showed diploidy with low MDC (1.11 in Ewing's sarcomas, N.S.) and SPF (2.5, p < 0.01) and extremely low RDR (1.34, p < 0.01). The RDR value was higher in well-differentiated tumors than in primitive tumors, rendering it useful in grading bone tumors with a diploid stem line. By combining the RDR value with the MDC value, 96% of diploid sarcomas could be distinguished from benign tumors. These results indicate that cellular DNA and RNA content analysis may be of value in assessing the malignant potential of diploid as well as aneuploid bone sarcomas.

Fractures of long bones previously treated for Ewing's sarcoma.

Patients with Ewing's sarcoma of a long bone who survive for two years from the time of diagnosis and have been treated with irradiation and chemotherapy have a significant risk of fracture of the involved segment of bone. In our experience, this risk is especially high when the humerus or femur is involved. Healing of these fractures is not normal, and our data suggest that early or even prophylactic internal fixation and bone-grafting may be indicated.

Chondroblastoma. A review of seventy cases.

We reviewed the cases of seventy patients with chondroblastoma who were treated at the Istituto Ortopedico Rizzoli between 1949 and 1983 and found that the proximal end of the humerus was the most common location (eighteen), with the proximal end of the femur (fifteen), distal end of the femur (fifteen), and proximal end of the tibia (twelve) being the other frequently involved sites. Sixty-three of the patients were between eleven and thirty years old. Fifty-eight patients sought medical attention because of an aching pain, usually referred to the adjacent joint. Fifty patients were followed for two years or longer after treatment. Seven patients had a local recurrence: four were successfully treated with a repeat curettage and one, by two subsequent marginal excisions; one was advised to have a repeat curettage; and the seventh was advised to have a resection and arthrodesis of the knee. The final functional results were considered to be excellent in forty-seven of the fifty patients who were followed for two years or more.

Parosteal osteosarcoma of the posterior aspect of the distal part of the femur. Oncological and functional results following a new resection technique.

BACKGROUND: Parosteal osteosarcoma is a low-grade malignant bone tumor that arises from the surface of the metaphysis of long bones. Parosteal osteosarcoma is usually well differentiated and displays a low propensity to metastasize. Wide resection of a parosteal osteosarcoma has been shown to provide a relatively risk-free method of preventing local recurrence. We propose a new method of resection of parosteal osteosarcomas located in the popliteal paraosseous space of the distal part of the femur. This method involves resection of the mass through separate medial and lateral incisions, which allows for wide margins yet limits the amount of dissection of the soft tissues and the neurovascular bundle. METHODS: Six patients with parosteal osteosarcoma located on the posterior aspect of the distal part of the femur underwent resection of the lesion and reconstruction with a posterior hemicortical allograft through dual medial and lateral incisions. The patients were evaluated with regard to pain, postoperative function, union of the allograft (osteosynthesis), and the prevalence of local recurrence. RESULTS: The average time until the last follow-up assessment was 4.3 years. No metastases developed, and there were no local recurrences. All patients were free of disease at the last follow-up evaluation. Postoperatively, the average range of motion of the knee was 0 to 122 degrees. Five of the six patients were free of pain at the time of the latest follow-up. Five of the six patients returned to their preoperative active functional status. CONCLUSIONS: We recommend resection of a parosteal osteosarcoma located on the posterior surface of the femur through separate medial and lateral incisions. This approach provides minimal dissection of the neurovascular bundle but ample exposure for reconstruction with a hemicortical allograft.

The comparative value of bone scintigraphy and computed tomography in determining bone involvement by soft-tissue sarcomas.

In seventeen patients with a soft-tissue sarcoma, bone scintigrams were found to be more useful than computed tomograms for evaluating bone involvement. The scintigrams had higher predictive value and higher sensitivity, as there were no false-negative or false-positive scintigrams, while there were three false-positive computed tomograms. Accurate scintigraphy requires the use of high-resolution static gamma-camera images that show the tangential relationship between tumor and bone. The images that are usually made in surveying the skeleton for metastatic disease--routine whole-body bone scans, or even gamma-camera images that provide only anterior and posterior views--are inadequate. They did not demonstrate the true relationship of the tumor to bone in the patients in this study when activity within the tumor itself was superimposed over bone. In such patients, properly selected oblique views sometimes showed that the tumor was clearly separate from normal bone activity. Determination of the relationship of the soft-tissue tumor to bone is an important part of the accurate anatomical staging that is required to select appropriate surgical management.

The results of transplantation of intercalary allografts after resection of tumors. A long-term follow-up study.

We reviewed the results of 104 intercalary allograft procedures that had been performed, between April 1974 and August 1992, in 100 patients, usually after resection of a segment of bone because of an osseous neoplasm. The median duration of follow-up was 5.6 years. Retention of the graft and return to essentially normal function were the measures of success and, on that basis, eighty-seven (84 per cent) of the 104 reconstructions were successful. Of the fifteen limbs in which the reconstruction failed, four were salvaged with insertion of a second allograft and three, with use of some other technique. Of the 104 allograft procedures, eight (including two in patients who had a recurrent tumor) were followed by an amputation; thus, the ultimate rate of salvage was 92 per cent for the entire series. Thirty-one grafts failed to unite at one junction with the host or both, within one year after the operation, and this necessitated eighty-one additional operative procedures to achieve a good result. Life-table regression analysis showed that age, gender, anatomical site, and length of the graft were not associated with significant differences in the over-all outcome. Infection (p = 0.0001); fracture (p = 0.002); stage of the lesion (p = 0.007); and use of adjuvant chemotherapy or radiation, or both (p = 0.008), all had an adverse effect on the survival of the allograft. Despite the relatively high rate of non-union that necessitated additional operations, these data indicate that transplantation of allografts for the treatment of intercalary defects has a high rate of success and usually results in a functional limb.

The role of radionuclide bone-scanning in determining the resectability of soft-tissue sarcomas.

In sixty patients with soft-tissue sarcoma, radionuclide bone scans were 92 per cent accurate in evaluating the presence or absence of involvement of contiguous bone by the tumor itself, by the tumor's reactive pseudocapsule, or by tissue contaminated during inadequate excision. The scans were most helpful when the relationship of the tumor to the bone was crucial in determining the resectability of the tumor. Meticulous imaging technique is essential to a complete and accurate radionuclide study. High-resolution, high-count gamma-camera scans in multiple projections are required for precise localization of tumor.

Aneurysmal bone cyst of the spine.

The cases of twenty-two patients with an aneurysmal bone cyst of the spine above the sacrum were analyzed with regard to sex, age, site, symptoms, and radiographic findings. Four patients had extension of the lesion to the adjacent vertebra or rib, and twelve patients had neurological deficits. The primary treatment was either radiotherapy or surgery alone, or surgery and radiotherapy combined. No recurrences were found in patients who were treated with surgery alone or with surgery and radiotherapy, while three of the six patients who were treated with radiotherapy had a local recurrence, two of which were fatal. The patients with neurological deficits recovered after healing of the cyst.

Operative treatment of sacrococcygeal chordoma. A review of twenty-one cases.

Between 1972 and 1992, twenty-one patients had a primary operation for the treatment of a sacrococcygeal chordoma; seventeen had had a diagnostic biopsy elsewhere. The average age at the time of the operation was fifty-five years (range, six to seventy-eight years); fourteen patients were male and seven were female. In all patients, a posterior approach was used, even for resections at the cephalic levels of the sacrum. In addition, sixteen of the twenty-one patients were treated with adjuvant radiation therapy. Four patients died; three died of metastatic chordoma. Of the remaining seventeen patients, fifteen were apparently free of disease and had not had a local recurrence at the time of the latest follow-up examination. The average duration of follow-up for these fifteen patients was four and one-half years. Of the nine patients who were followed for at least five years, seven were disease-free at the latest follow-up evaluation. Of the seven patients in whom both second sacral roots were the most caudad nerve-roots spared, four had normal bladder control and five had normal bowel control. Of the four patients in whom the most caudad nerve-roots spared were the first sacral or more cephalic roots, all had impaired bladder control, one had impaired bowel control, and three had a colostomy.

Experimental models for the study of drug resistance in osteosarcoma: P-glycoprotein-positive, murine osteosarcoma cell lines.

P-glycoprotein is an adenosine triphosphate-dependent drug-efflux pump that extrudes drugs from cells and causes drug-resistance. P-glycoprotein is believed to mediate drug-resistance in a wide variety of tumors. In this study, we developed two P-glycoprotein-positive, murine osteosarcoma cell lines that were resistant to Adriamycin (doxorubicin) (MOS/ADR1 and MOS/ADR2). We created the cell lines by short-term pulse exposures of the parent cell line to Adriamycin followed by single-cell cloning. The MOS/ADR1 and MOS/ADR2 cells were sevenfold and eighteenfold more resistant to Adriamycin than the cells from the parent line. Expression of P-glycoprotein, as examined with an immunofluorescence method, was detected in most of the MOS/ADR1 and MOS/ADR2 cells but not in the parent cells. After the cells had been incubated with Adriamycin for one hour, there was less accumulation of the drug in the resistant cell lines than in the parent cell line. The reduced accumulation was due to the increased efflux of Adriamycin. The Adriamycin-resistant cell lines demonstrated greater alkaline phosphatase activity than the parent cell line and produced more differentiated osteoblastic sarcomas in mice. Dose survival studies with use of a tetrazolium colorimetric assay showed that the MOS/ADR1 cells were cross-resistant to vincristine, vinblastine, etoposide, bleomycin, mitomycin C, and actinomycin D but not to dacarbazine, cisplatin, carboplatin, cytosine arabinoside, carmustine, cyclophosphamide, ifosfamide, methotrexate, and 5-fluorouracil. Although the MOS/ADR2 cells exhibited a similar spectrum of cross-resistance, they were more resistant than the MOS/ADR1 cells. We also tested the effect of three different resistance-modifying agents on the reversal of resistance to Adriamycin. We found that verapamil and trifluoperazine substantially reversed resistance to Adriamycin in the P-glycoprotein positive cell lines, whereas cyclosporin A was relatively ineffective. Because these cell lines retain the histological and biochemical features of bone-producing sarcomas and display the multidrug-resistant phenotype, they may be useful models for additional investigations of drug resistance in osteosarcoma.

Surgical treatment for osteosarcoma.

Fifty-three patients who had a high-grade osteosarcoma had either a limb-salvage resection or an amputation. They all received adjuvant therapy that consisted of administration of Adriamycin (doxorubicin) and whole-lung irradiation. At the time of follow-up, the surgical margin was assessed by examination of the surgical specimen. Each patient was followed for at least three years or until death. The data suggested that a wide surgical margin is adequate to control a primary osteosarcoma. When a wide surgical margin can be used and a functional limb can be salvaged, an amputation probably is not required.

Recurrence of giant-cell tumors of the long bones after curettage and packing with cement.

The nine-year experience with sixty patients who had had a giant-cell tumor of a long bone was reviewed to determine the rate of recurrence after treatment with curettage and packing with polymethylmethacrylate cement. The demographic characteristics, including the age and sex of the patient and the site of the tumor, were similar to those that have been reported for other large series. An average of four years (range, two to ten years) after the operation, the over-all rate of initial local recurrence was 25 per cent (fifteen of sixty patients). Patients who had had a tumor of the distal aspect of the radius had a higher rate of recurrence (five of ten) than those who had had a tumor of the proximal aspect of the tibia (seven [28 per cent] of twenty-five) or of the distal part of the femur (three [13 per cent] of twenty-three). Higher rates of recurrence were also noted for patients who had had a pathological fracture (three of six), those who had had a Stage-III tumor according to the classification of Campanacci et al. (six of sixteen), and those who had not had adjuvant treatment with either a high-speed burr or phenol (eight of nineteen). Patients who had had an initial recurrence after packing with cement had a low rate of secondary recurrence when the initial recurrence had been treated with a wide resection or a second intralesional procedure (zero of ten and one of five patients, respectively), after an average of three years (range, ten months to eight years). No patient had a multicentric tumor or metastasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Chondrosarcoma of bone: an assessment of outcome.

BACKGROUND: The data on 227 patients who had been managed for a chondrosarcoma at one institution were reviewed to determine the nature of the lesions, the predictors of outcome, and whether there were any ways to change the treatment approaches to improve the results. METHODS: The patients were followed for a mean duration of six years (range, three to twenty-five years). The mean age of the patients was forty-seven years (range, nine to eighty-four years). The most prevalent sites of the tumors were the femur (seventy-eight), the pelvis (fifty-one), and the humerus (thirty-nine). The tumors were divided into two groups according to histological grade. Eighty-six tumors (sixteen atypical enchondromas and seventy grade-1 chondrosarcomas) that were locally destructive but were associated with a low likelihood of metastasis were considered to be low-grade. The remaining 141 lesions, which were locally destructive, potentially metastatic, and capable of causing death, were thought to be high-grade. One hundred and three of these 141 lesions were grade 2, and thirty-eight were grade 3 (eighteen of the thirty-eight were grade 3 only, and twenty were both grade 3 and dedifferentiated). Two hundred and twenty-four patients were managed with resection and a limb-sparing procedure; the remaining three patients had an amputation. Postoperative adjuvant radiation was used for fifty-six patients; chemotherapy, for thirty-five; and both radiation and chemotherapy, for nineteen. Flow cytometric patterns were analyzed for 105 patients. RESULTS: The patients who had a high-grade tumor were older than those who had a low-grade tumor (mean age [and standard deviation], 50+/-17.0 years compared with 40+/-15.9 years; p < 0.001). Pathological fracture, metastasis, local recurrence, and death were more prevalent in the group that had a high-grade lesion (p < 0.001). Predictors of metastasis and death in that group of patients included local recurrence, a pelvic location of the tumor, a tumor that was more than 100 cubic centimeters in size, a ploidic abnormality (aneuploidy coupled with a high mean DNA index), a histological grade of 3, and a dedifferentiated type of tumor (p < 0.001). CONCLUSIONS: Although the data are suggestive, with the numbers available for study we could not detect a significant difference in the rates of pulmonary metastasis and death between the patients who had a grade-3 lesion and those who had a grade-3 lesion that was also dedifferentiated. However, the interval between diagnosis and death was 32+/-22.8 months for the patients who had a grade-3 lesion compared with 5+/-3.7 months for those who had a grade-3 lesion that was also dedifferentiated (p < 0.001). Overall, patients who had had a resection with wide margins (margins extending outside the reactive zone) had a longer duration of survival than did those who had had a so-called marginal resection (margins extending outside the tumor but within the reactive zone) or an intralesional resection (margins within the lesion) (p < 0.04). Adjunctive chemotherapy or radiation, or both (which, it must be noted, was used, without a protocol, in a relatively small number of patients), after an intralesional resection, for recurrent disease, or for distant metastasis did not appear to alter the outcome.