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PubMed1999

DNA sequence copy number increase at 8q: a potential new prognostic marker in high-grade osteosarcoma.

Histologic response to chemotherapy is currently the best prognostic parameter in high-grade osteosarcoma but it can be evaluated only after several weeks of chemotherapy. Thus a prognostic parameter known at the time of diagnosis would be of great clinical benefit. In the present study, we present the results of 31 primary high-grade osteosarcomas analyzed by comparative genomic hybridization (CGH). CGH allows for genome-wide screening of a tumor by detecting alterations in DNA sequence copy number. The most frequent aberrations were copy number increases at 1q21 in 58% of the tumors and at 8q (8q21.3-q22 in 52% and 8cen-q13 in 45%), followed by copy number increases at 14q24-qter (35%) and Xp11.2-p21 (35%). The most common losses were detected at 6q16 (32%) and 6q21-q22 (32%). Patients with a copy number increase at 8q21.3-q22 and/or at 8cen-q13 had a statistically significant poor distant disease-free survival (p = 0.003) and showed a trend toward short overall survival (p = 0.04). Patients with a copy number increase at 1q21 showed a trend toward short overall survival (p = 0.04). Thus, specific genetic aberrations detected at the time of the diagnosis could be used in prognostic evaluation of high-grade osteosarcoma.

Adolescent↗
PubMed1999

Establishment, characterisation and partial cytokine expression profile of a new human osteosarcoma cell line (CAL 72).

Permanent human osteosarcoma cell lines are important tools for the study of bone cancer. As representative of an osteoblastic phenotype, they partly reflect their normal osteoblastic counterparts and, thus, may represent appropriate models to investigate the mechanisms involved in bone remodelling and in haematopoietic differentiation. In the present work, we describe a new human cell line, CAL 72, obtained from an osteosarcoma of the knee of a 10-year-old boy. These cells grow in continuous culture, and karyotypic analysis has revealed clonal abnormalities in number and structure, especially loss of chromosome Y. These cells exhibit morphological, immuno-histochemical and molecular characteristics of the osteoblastic lineage. Using RT-PCR, we have shown that the CAL 72 cell line expresses high levels of mRNA coding for several cytokines, such as G-CSF, GM-CSF, IL-1beta and IL-6. In view of this expression profile, the CAL 72 phenotype appears to be closer to normal primary osteoblasts than other reported osteosarcomas. Moreover, these cells express mRNA for both HGF and its receptor c-MET, suggesting that this autocrine loop might contribute to the invasiveness of the tumour from which CAL 72 originated.

Alkaline Phosphatase↗
PubMed1998

Control of cell cycle gene expression in bone development and during c-Fos-induced osteosarcoma formation.

We have used c-Fos transgenic mice which develop osteosarcomas to determine the expression patterns of cyclins, cyclin-dependent kinases (CDKs), and cyclin-dependent kinase inhibitors (CKIs) in different bone cell populations in order to define the potential mechanisms of c-Fos transformation. Immunohistochemical analysis in embryonic and early postnatal bone demonstrated that cyclin E and its kinase partner CDK2 were expressed specifically in bone-forming osteoblasts. Cyclin D1 expression was absent despite high levels of CDK4 and CDK6, and the CKI p27 was expressed in chondrocytes, osteoclasts, and at lower levels in osteoblasts. Following activation of the c-fos transgene in vivo and before overt tumor formation, cyclin D1 expression increased dramatically and was colocalized with exogenous c-Fos protein specifically in osteoblasts and chondrocytes, but not in osteoclasts. Prolonged activation of c-Fos resulted in osteosarcoma formation wherein the levels of cyclin D1, cyclin E, and CDKs 2, 4, and 6 were high in a wide spectrum of malignant cell types, especially in transformed osteoblasts. The CKI p27 was expressed at very high levels in bone-resorbing osteoclasts, and to a lesser extent in chondrocytes and osteoblasts. These in vivo observations suggest that cyclin D1 may be a target for c-Fos action and that elevation of cyclin D1 in osteoblasts which already express cyclin E/CDK2 and the cyclin D1 partners CDKs-4 and 6, may predispose cells to uncontrolled cell growth leading to osteosarcoma development. This study implicates altered cell cycle control as a potential mechanism through which c-Fos causes osteoblast transformation and bone tumor formation.

Animals↗
PubMed1999

Correlation between pulsed electromagnetic fields exposure time and cell proliferation increase in human osteosarcoma cell lines and human normal osteoblast cells in vitro.

We have exposed cultured bone cells to a pulsed electromagnetic field (PEMF) for different times to find the minimal exposure time necessary to stimulate an increase of DNA synthesis. We used two different human osteosarcoma cell lines, TE-85 and MG-63, and human normal osteoblast cell (NHOC) obtained from surgical bone specimens. The cells were placed in multiwell plates and set in a tissue culture incubator between a pair of Helmoltz coils powered by a pulse generator (1.3-ms pulse, repeated at 75 Hz) for different periods of time. [3H]Thymidine incorporation was used to evaluate cell proliferation. The two osteosarcoma cell lines increase their thymidine incorporation when exposed to a PEMF for at least 30 min, both in a medium containing 10% fetal calf serum and in a serum-free medium. NHOC are known to increase their cell proliferation when exposed to PEMF but only if cultured in the presence of 10% fetal calf serum. In this experimental condition, three of the four cell lineages studied required at least 9 h of PEMF exposure to increase their DNA synthesis, whereas one cell lineage increased its cell proliferation after 6 h of PEMF exposure. Our observations confirm the hypothesis that the proliferative responses of NHOC and human osteosarcoma cell lines to PEMF exposure are quite different. Moreover, NHOC required minimal exposure times to PEMF to increase their cell proliferation, similar to that needed to stimulate bone formation in vivo.

Adult↗
PubMed1977

Adjuvant multiple drug chemotherapy for osteosarcoma of the extremity.

Results of treatment for osteosarcoma of the extremity have been poor with metastases usually causing death within 2 years following diagnosis. Because of the great risk of development of metastases, 20 patients have received adjuvant chemotherapy with Adriamycin, cyclophosphamide and high-dose methotrexate-leucovorin rescue for up to 12 months following amputation for osteosarcoma. Sixteen of these patients are surviving; 11 are free of evident tumor from 6 to 34 months following amputation. Five patients were found to have pulmonary metastases while receiving chemotherapy and three patients developed metastases following completion of chemotherapy. One patient died following her third treatment with high-dose methotrexate-leucorovin rescue. Other toxicity included nausea, vomiting, mucosal ulcerations, infections, hematologic abnormalities, changes in kidney and liver functions tests, and minor coagulation abnormalities. The natural history of osteosarcoma may have been modified by the use of these agents for periods exceeding the median time to predicted detection of pulmonary metastases. Microscopic metastases of some patients were eradicated by this adjuvant chemotherapy. For patients who developed metastases, these metastases were delayed in their time of detection and in their number at the time of detection.

Adolescent↗
PubMed1977

Metastatic osteosarcoma to lung: a clinicopathologic study of surgical biopsies and resections.

Metastatic tumor to the lungs is one of the most important factors in the poor prognosis of primary osteosarcoma of bone. Until recently, pulmonary resection alone was the only therapeutic method available to salvage these patients. Previous investigators have reviewed a number of clinical and pathologic parameters which may possibly relate to the prognosis of osteosarcoma and the occurrence of pulmonary metastases. The pathologic features of these latter lesions have received little attention other than to state that they generally are less differentiated than the primary tumor. A review of multiple pulmonary nodules resected from 15 patients has demonstrated that 66% of all lesions were essentially identical to the primary tumor. The 5-year survival from the original amputation was 33% in this series; however, it was not possible to prognosticate a favorable outcome from the metastasis, a similar type of observation which has been made by others in relation to the primary osteosarcoma.

Adolescent↗
PubMed1983

Osteosarcoma: intra-arterial treatment of the primary tumor with cis-diammine-dichloroplatinum II (CDP). Angiographic, pathologic, and pharmacologic studies.

Intra-arterial CDP was utilized to treat the primary tumor in 11 pediatric patients with osteosarcoma and in one with malignant fibrous histiocytoma. The investigation commenced with a phase I-II pilot study in four osteosarcoma patients. A dose of 150 mg/m2 was found to be safe and effective in producing a clinical response. This was followed by a definitive study in the remaining seven osteosarcoma patients and in the one malignant fibrous histiocytoma patient. The results were assessed by specific clinical, pharmacologic, radiographic and pathologic criteria. The overall response in the definitive study was 50% with two patients exhibiting total tumor destruction. The success of intra-arterial CDP was attributed to its ability to achieve high local drug concentration and tumor penetration. This was demonstrated by pharmacologic studies.

Adolescent↗
PubMed1987

Thoracotomy for pulmonary metastatic osteosarcoma. An analysis of prognostic indicators of survival.

Removal of pulmonary metastases of osteosarcoma by thoracotomy is an accepted treatment; however, few investigators have analyzed the value of various prognostic factors in estimating survival. A review of all patients undergoing thoracotomy for recurrent osteosarcoma with pulmonary metastases treated at St. Jude Children's Research Hospital is reported. Since 1968, two thirds (39/59) of all patients who developed pulmonary metastases have had a total of 66 thoracotomies. Nine patients are alive with no evidence of disease, and six additional patients are alive with disease. Analyzed in 39 evaluable patients, the prognostic factors that correlate with survival by univariate analysis are: sex, number of nodules detected radiographically and resected, completeness of resection, and tumor location (bilateral versus unilateral). By Cox regression analysis, only sex and the number of nodules detected either radiographically or during surgery, and resected, had statistically significant correlation with survival. Thoracotomy is curative for some patients with pulmonary metastatic osteosarcoma and Prognostic factors predictive for survival are defined.

Child↗
PubMed1987

Extraskeletal osteosarcoma.

A retrospective study of 88 cases of extraskeletal osteosarcoma revealed that this tumor affects adults almost exclusively, with a high incidence in patients older than 50 years, and is slightly more common in males (58%) than in female patients. The tumor occurred principally as a soft tissue mass in an extremity, with a predilection for the thighs (lower extremity, 46.6%; upper extremity, 20.5%) and the retroperitoneum (17%). Most were deep-seated and were firmly attached to the fascia, but occasionally they were freely movable and confined to the subcutis or dermis. Nearly all presented as an insidiously growing mass rarely causing pain or tenderness. The preoperative duration of symptoms ranged from 2 weeks to 25 years (median, 6 months). In 17 cases, it exceeded 2 years. A history of prior trauma to the site of the tumor was stated in 11 of the 88 cases (12.5%) and of radiation in five cases (5.7%). Microscopically, the tumors contained varying amounts of neoplastic osteoid and bone, sometimes together with islands of malignant-appearing cartilage. Like osteosarcoma of bone, extraskeletal osteosarcoma showed a striking variation in histologic appearance and focally resembled malignant fibrous histiocytoma, fibrosarcoma, and malignant schwannoma. Follow-up information was available for 65 patients. Eight (12.3%) patients were alive with no evidence of recurrence; 12 (18.5%) patients were alive with one or more recurrences; and five (7.6%) were alive with metastases. Twenty-eight of the tumors (43%) recurred and 39 (63%) metastasized. Forty (61.5%) of the patients with follow-up information had died, 36 from the tumor and four from miscellaneous causes. The prevailing sites of metastases were the lung, the regional lymph nodes, and bone.

Adolescent↗
PubMed1989

Systemic doxorubicin and intraarterial cisplatin preoperative chemotherapy plus postoperative adjuvant chemotherapy in patients with osteosarcoma.

The role of adjuvant chemotherapy for osteosarcoma has been well defined. Recently, the use of preoperative chemotherapy has been further enhanced by the use of intraarterial cisplatin. The authors describe the use and results of systemic doxorubicin and intraarterial cisplatin as a preoperative regimen for eight pediatric patients with nonmetastatic osteosarcoma of an extremity. The therapy was well tolerated. Six patients achieved satisfactory local tumor control and were able to receive the surgical procedure to permit limb salvage. Two of these six patients subsequently developed metastatic disease. Of the two patients who did not achieve satisfactory local tumor control to permit a limb salvage procedure, both underwent amputation and one later developed metastatic disease. Five patients have remained continuously free of disease for a median of 18 months (range, 12-21 months). This report confirms the observations that intraarterial cisplatin and doxorubicin can be used as a safe and effective regimen preoperatively for pediatric patients with osteosarcoma of an extremity.

Adolescent↗
PubMed1991

Percent tumor necrosis as a predictor of treatment response in canine osteosarcoma.

The percent tumor necrosis was determined in 200 dogs with spontaneously occurring osteosarcoma. One hundred dogs had no treatment before amputation or death. One hundred other dogs were treated with either radiation therapy alone (n = 23), intraarterial (IA) cisplatin alone (n = 16), intravenous (IV) cisplatin alone (n = 6), radiation therapy plus IA cisplatin (n = 47), or radiation therapy plus IV cisplatin (n = 8). Eighty-nine of these 100 dogs had their tumors resected 3 weeks after the end of therapy (6 weeks after the initiation of therapy) and replaced with a cortical bone allograft. Dogs with preoperative treatment were evaluated for local tumor control and time to metastasis. The mean percent tumor necrosis in untreated osteosarcoma was 26.8%. The mean percent tumor necrosis for dogs receiving radiation only, IA cisplatin only, and IV cisplatin only was 81.6%, 49.1% and 23.8%, respectively. The mean percent tumor necrosis for dogs receiving radiation therapy plus IA cisplatin or radiation therapy plus IV cisplatin was 83.7% and 78.2%, respectively. There was no significant difference between percent tumor necrosis in untreated osteosarcoma compared with those receiving IV cisplatin, but there was a significant increase in percent tumor necrosis with all other treatments. A mathematic model for the effect of cisplatin and radiation dose was developed using multiple regression analysis. The radiation dose calculated to cause at least 80% tumor necrosis was 42.2 Gy (95% confidence interval [CI], 38.0 to 47.6 Gy) when radiation was given alone and 28.1 Gy (95% CI, 21.3 to 36.6 Gy) when radiation was combined with IA cisplatin. Areas of viable tumor tended to be most frequent adjacent to the articular cartilage and in the joint capsule. Percent tumor necrosis was strongly predictive for local tumor control; 28 of 32 dogs with greater than 80% tumor necrosis had local control, and only eight of 29 dogs with less than 79% tumor necrosis had local control (P = 0.0047). There was no correlation between percent tumor necrosis and time to metastasis.

Animals↗
PubMed1991

Etoposide, cyclophosphamide, cisplatin, and doxorubicin as neoadjuvant chemotherapy for osteosarcoma.

The authors evaluated the combination of etoposide/cyclophosphamide (VP/CY) as initial, presurgical therapy for patients with osteosarcoma and found an 88% response rate for the primary tumor and any metastases. After definitive, limb-salvage surgery and adjuvant chemotherapy with etoposide, cyclophosphamide, cisplatin, and doxorubicin, patients without metastases at diagnosis whose cases were followed for a median of 2 years from diagnosis achieved a relapse-free survival (RFS) probability of 78% +/- 9%. This result is equivalent to the best adjuvant chemotherapy results reported to date. Patients without metastases at diagnosis had significantly better RFS probability (78% +/- 9%) than those with metastases at diagnosis (0%). Transient, severe myelosuppression has been the only major toxicity of the VP/CY courses. No irreversible organ damage or toxic deaths have been seen in patients enrolled in this study. The authors conclude that the combination of VP/CY is effective treatment for osteosarcoma, and when combined with cisplatin/doxorubicin (CIS/DOX), is as effective as any previously reported chemotherapy for osteosarcoma.

Adolescent↗
PubMed1992

Bone infarct-associated osteosarcoma.

Reported is a patient with an osteosarcoma arising in a medullary infarct of the humerus. Infarct-associated sarcoma (IAS) of bone is rare. In a collective review of 50 cases reported in the medical literature, only 37 were fully documented. Including our patient, 26 men and 12 women, ranging in age from 18 to 82 years (mean, 53.4 years) have been reported. Black patients appeared to be disproportionately represented, accounting for 36% of the group. In most patients, there was no known cause for the infarct, whereas in the remainder, the most common underlying condition was a prior dysbaric event or alcoholism. Approximately 75% of the patients had multiple bone infarcts. The femur was involved in 21 patients, the tibia in 14, the humerus in 2, and the radius in 1. Among 40 sarcomas in these patients, 7 (18.4%) were osteosarcomas, and 29 (72.5%) were malignant fibrous histiocytomas. The survival rate in patients with IAS is poor: 5 of the 7 patients with osteosarcoma (71%) and 20 of the 31 other patients (65%) died of tumor. Eight patients are alive and well, all for longer than 5 years.

Aged↗
PubMed1992

Improved prognosis of children with osteosarcoma metastatic to the lung(s) at the time of diagnosis.

BACKGROUND: A poor outcome is traditionally ascribed to osteosarcoma metastatic to the lungs, but data have been unavailable regarding the outcome of such patients after systematic treatment on clinical trials. METHODS: The clinical course and outcome of 31 patients who had osteosarcoma metastatic to the lungs diagnosed between 1962 and 1990 at St. Jude Children's Research Hospital were reviewed to determine whether the use of increasingly aggressive multimodality therapy has improved their outcome. The patients were grouped by treatment eras, based on major changes in therapy (i.e., single-agent or two-agent era, 1962-1972; standard multiagent era, 1972-1982; and intensive multiagent era, 1982-1990). RESULTS: With increasingly intensive chemotherapy, more aggressive efforts to resect metastatic disease, and earlier detection of pulmonary metastases by computed tomography, the survival of these patients has improved significantly over the 28-year study period. Those treated since 1982 have a 50% estimated probability of survival at 3 years, whereas there were no survivors at 3 years in the two earlier eras. Survival for the former group reached a plateau of 30% at 4 years. CONCLUSIONS: The use of aggressive multimodality therapy, coupled with modern pediatric imaging techniques to detect pulmonary disease, has improved the traditionally dismal outlook in pediatric patients with osteosarcoma and synchronous pulmonary metastases.

Adolescent↗
PubMed1993

Prognostic significance of serum alkaline phosphatase measurements in patients with osteosarcoma treated with adjuvant or neoadjuvant chemotherapy.

BACKGROUND: It is known that many patients with osteosarcoma have high serum alkaline phosphatase (SAP) levels. The prognostic significance of this finding, however, is still controversial. METHODS: The pretreatment SAP levels of 656 patients with osteosarcoma of the extremities (107 metastatic and 549 localized at presentation) were examined to evaluate whether the enzyme levels had a clinical value in predicting the course of the disease. RESULTS: The percentage of patients with increased SAP levels was significantly higher in the metastatic group than in the group of patients with localized disease (91.5% versus 61.3%; P < 0.001). In the latter group, treated with adjuvant and neoadjuvant chemotherapy, the relapse rate was significantly higher in patients with elevated pretreatment SAP levels than in those with normal levels (55.1% versus 26.4%; P < 0.001). Among patients with elevated SAP levels, the percentage of relapses was higher in patients with high levels of the enzyme in comparison with patients with moderately elevated values (66.4% versus 47%; P < 0.05). After treatment, SAP levels almost always return to normal values, and a correlation between postoperative levels of the enzyme and prognosis could not be made. CONCLUSIONS: These data demonstrate that in osteosarcoma of the extremities, pretreatment SAP levels have a prognostic value and they should be considered when comparing the results achieved with different therapeutic protocols and in planning new randomized clinical trials.

Adult↗
PubMed1993

Brain metastases in osteosarcoma. Report of a long-term survivor and review of the St. Jude Children's Research Hospital experience.

BACKGROUND: Brain metastasis has been considered a rare event in osteosarcoma, although with prolonged survival an increasing incidence has been suggested. There have been no prior reports of long-term survivors among patients with this complication. METHODS: The authors describe a child treated for osteosarcoma who is alive and free of disease 8 years after the detection of brain metastases. Of 254 patients with primary osteosarcoma referred to St. Jude Children's Hospital between 1962 and 1989, 13 developed brain metastases, all after relapse or recurrence in another site. Concomitant active lung metastases were present in all of the patients except the one long-term survivor, whose pulmonary disease had responded to treatment with cisplatin and doxorubicin. Log-rank analyses were used to compare survival duration and the frequency of brain metastases among patients treated before and after 1982, when effective multiagent therapy was initiated. RESULTS: Log-rank analyses comparing patients treated before and after 1982 showed that the introduction of effective modern therapy improved survival among patients at risk for brain metastases (i.e., those with recurrent and progressive disease, P = 0.007) but was not associated with a statistically significant increase in the frequency of brain metastases (15.5% versus 4.5%, P = 0.125). CONCLUSIONS: Although the outlook for patients with this complication remains bleak, the resolution of brain metastases after eight courses of ifosfamide in the patient described in this article suggests that enrollment of selected patients in Phase II trials is merited.

Adolescent↗
PubMed1993

Long-term survival after central nervous system relapse in a patient with osteosarcoma.

BACKGROUND: Since the advent of multiagent adjuvant chemotherapy, survival among patients with localized osteosarcoma has improved to 60% or more. Pulmonary relapse, the most common cause of treatment failure, is associated with less than 25% long-term survival; central nervous system (CNS) metastasis, when it occurs, often presents as a catastrophic clinical event in preterminal patients. METHODS: The authors report a patient with osteosarcoma who had an isolated pulmonary relapse and a subsequent isolated CNS relapse. Complete surgical resection was accomplished on both occasions and followed in the initial instance by adjuvant chemotherapy and in the latter instance by adjuvant whole-brain irradiation. RESULTS: An isolated CNS metastasis was resected and adjuvant whole brain irradiation was administered; the patient is alive and relapse free more than 5 years later. CONCLUSIONS: Patients with osteosarcoma in whom isolated, resectable metastases develop can derive benefit from gross total resection followed by adjuvant chemotherapy or radiation therapy for microscopic residual disease.

Brain Neoplasms↗
PubMed1993

Primary chemotherapy and delayed surgery for nonmetastatic osteosarcoma of the extremities. Results in 164 patients preoperatively treated with high doses of methotrexate followed by cisplatin and doxorubicin.

BACKGROUND: Neoadjuvant chemotherapy is the most accepted treatment for localized osteosarcoma. This has led to a great improvement in limb-sparing surgery and in disease-free survival. Patients with a good response to preoperative chemotherapy showed a higher disease-free survival rate. Current studies examine the possibility of patients whose limbs could be rescued with a poor necrosis and a reduction of the side effects related to aggressive treatments. METHODS: Between September 1986 and December 1989, 164 patients entered the second neoadjuvant study conducted at the Rizzoli Institute, Bologna, Italy, for non-metastatic osteosarcoma of the extremities. Preoperative chemotherapy consisted of two cycles of high-dose methotrexate intravenously (i.v.) followed by cisplatin intraarterially and doxorubicin i.v. After surgery, patients classified as good responders (> 90% tumor necrosis) received three more cycles of these drugs, whereas poor responders (< 90% tumor necrosis) had more chemotherapy, which included ifosfamide and etoposide in addition to the other three drugs. RESULTS: Limb salvage was performed in 83% of cases. At an average follow-up of 54 months (36-76), 109 patients (66%) were continuously disease-free, 2 died from doxorubicin cardiotoxicity, and 52 experienced metastases and 3 had local recurrence. In two of these three patients, metastases followed local recurrence. The 5-year actuarial continuously disease-free survival rate was 63%, with no differences between good and poor responders. Excluding 20 patients who had major protocol violations, the projected continuous disease-free survival rate was 71%. CONCLUSIONS: With an aggressive neoadjuvant chemotherapy, it is possible to cure more than 60% of nonmetastatic osteosarcoma of the extremities, avoiding amputation in most cases. Ifosfamide and etoposide seem to be effective in patients who did not respond to preoperative chemotherapy.

Adolescent↗