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PubMed1995

Inhibition of growth of human osteosarcomas by antagonists of growth hormone-releasing hormone.

BACKGROUND: Insulin-like growth factor I (IGF-I) may be involved in the proliferation of human osteosarcomas. Most of the IGF-I found in blood is produced in the liver, where transcription of the IGF-I gene is regulated by growth hormone (GH). Recently, we synthesized various potent antagonists of GH-releasing hormone (GH-RH), including [Ibu0, D-Arg2, Phe(4-Cl)6, Abu15, Nle27]hGH-RH(1-28)Agm, which is also called MZ-4-71. PURPOSE: We investigated the effects of this antagonist on the growth of the human osteosarcoma cell lines SK-ES-1 and MNNG/HOS, transplanted into nude mice or cultured in vitro. METHODS: Nude male mice bearing SK-ES-1 and MNNG/HOS tumors were treated for 4 and 3 weeks, respectively, with MZ-4-71 administered from osmotic minipumps at a dose of 40 micrograms per animal per day. Tumor volume, tumor weight, and levels of receptors for IGF-I were determined. IGF-I levels in serum, tumor, and liver tissue were measured by radioimmunoassay. In other experiments, tumor-bearing nude mice were treated subcutaneously for 3 weeks with the GH-RH agonist hGH-RH(1-29)NH2 or with MZ-4-71 for 13 days at doses of 50 micrograms per animal per day. Effects of MZ-4-71, hGH-RH(1-29)NH2, and human GH (hGH) on cell proliferation and on the production of IGF-I and cyclic adenosine monophosphate were also evaluated in SK-ES-1 and MNNG/HOS cells in vitro. RESULTS: The growth of SK-ES-1 and MNNG/HOS tumors in nude mice was significantly inhibited by MZ-4-71, as measured by a reduction in tumor volume and weight (all P values < .05). MZ-4-71 treatment of either SK-ES-1 or MNNG/HOS tumor-bearing animals decreased tumor tissue IGF-I levels. The growth of MNNG/HOS xenografts was stimulated by hGH-RH(1-29)NH2 (P < .01). IGF-I levels in serum of tumor-bearing nude mice treated subcutaneously for 13 days with MZ-4-71 were decreased (both P values < .01). High-affinity binding sites for IGF-I were demonstrated on cell membranes of SK-ES-1 and MNNG/HOS tumors. In cell cultures of both osteosarcomas, IGF-I production was stimulated by 25 ng/mL hGH but was not changed by 10 ng/mL hGH-RH(1-29)NH2 or 5 microM MZ-4-71. Incorporation of [3H]thymidine into DNA in SK-ES-1 (but not MNNG/HOS) cells was increased by 25 ng/mL IGF-I (P < .01). The proliferation rate of the two cell lines was not affected by 5-50 ng/mL hGH-RH(1-29)NH2 or 1-80 ng/mL hGH but was suppressed by 10(-6)-10(-5) M MZ-4-71. CONCLUSIONS: Our findings demonstrate that the GH-RH antagonist MZ-4-71 can significantly inhibit the growth of SK-ES-1 and MNNG/HOS osteosarcomas in mice.

Animals↗
PubMed2003

Role of the MET/HGF receptor in proliferation and invasive behavior of osteosarcoma.

Signal transduction downstream HGF receptor (MET) activation involves multiple pathways that account for mitogenesis, motility and morphogenesis in a cell type-dependent fashion. MET receptor is aberrantly expressed in almost 100% of human osteosarcomas. We analyzed the effect of the MET receptor activation in five human osteosarcoma cell lines evaluating the levels of HGF-dependent activation of MAPK and PKB/AKT as biochemical readouts of mitogenic and invasive responses, respectively. All the cell lines tested expressed high levels of the MET proto-oncogene. Four cell lines showed activation of the MAPK cascade upon HGF stimulation, suggesting that this growth factor serves a common proliferative function in osteosarcomas. Two lines showed activation of PKB/AKT that is known to be involved in migration mediated by HGF receptor. Accordingly, cell lines where MAPK cascade was activated responded to HGF with increased proliferation, while induction and inhibition of PKB/AKT activity corresponded to acquisition or block of the invasive-motile response to HGF, respectively. Both the HGF dependent responses were reverted by the specific MET inhibitor K252a. These data show that HGF activates both the mitogen and motogen machinery in osteosarcoma cells and suggest that HGF might promote their malignant behavior by concomitant activation of different pathways and biological functions.

Bone Neoplasms↗
PubMed1995

Efficacy of liposomal muramyl tripeptide (CGP 19835A) in the treatment of relapsed osteosarcoma.

Muramyl tripeptide phosphatidylethanolamine (MTP-PE) is a synthesized lipophilic analogue of muramyl dipeptide. MTP-PE encapsulated in liposomes (L-MTP-PE) allows selective delivery to pulmonary macrophages and circulating monocytes. In vivo administration has resulted in tumor regression in mice with B16 melanoma lung and lymph node metastases and a 40% long-term disease-free survival in dogs with osteosarcoma. Phase I studies have demonstrated that the drug is well tolerated. A Phase II trial using L-MTP-PE was undertaken in relapsed osteosarcoma patients to determine whether L-MTP-PE therapy could improve the progression-free interval in this high-risk group of patients. Patients had histologically proven osteosarcoma and pulmonary metastases that had developed during adjuvant chemotherapy or that were present at diagnosis and had persisted despite chemotherapy. Patients were rendered disease free by surgery. L-MTP-PE, 2 mg/m2, was infused over a 1-hour period twice a week for 12 weeks in 12 patients (Group 1). Sixteen patients (Group 2) received 2 mg/m2 L-MTP-PE twice a week for 12 weeks, then once a week for 12 weeks, for a total of 24 weeks of therapy. Progression-free intervals in each group were calculated from the day of surgery to the day of relapse and compared with the progression-free interval of a historical control group (Group 3) treated postoperatively with chemotherapy at M. D. Anderson Cancer Center between 1980 and 1990. Patients who received 24 weeks of L-MTP-PE therapy had a significant prolongation in time to relapse but those who received 12 weeks of therapy did not. The median time to relapse for group 2 patients was 9.0 months compared with 4.5 months for the control group (Group 3). These data suggest that L-MTP-PE deserves further investigation in a more appropriate adjuvant setting. A nationwide randomized Phase III trial is now underway in newly diagnosed osteosarcoma patients in conjunction with the Children's Cancer Study Group and the Pediatric Oncology Group.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2002

Rare complication of breast cancer irradiation: postirradiation osteosarcoma.

Radiation-induced osteosarcoma is a rare complication of radiation therapy for breast cancer. The authors present a 60-year-old patient in whom osteosarcoma of the chest wall developed 5 years after modified radical mastectomy and radiation therapy for breast cancer. One year after resection of the chest osteosarcoma, metastasis to the contralateral axillary lymph nodes developed and these were removed. Radiation-induced osteosarcoma is difficult to treat and has a poor prognosis, thus early diagnosis is necessary for optimal treatment.

Breast Neoplasms↗
PubMed1998

Osteosarcoma of the orbit associated with Paget disease.

Osteosarcoma is a common primary bone malignancy most often involving the long bones and occurring in the second decade of life. Orbital involvement in this disease process is rare and is usually due to extension of the tumor from an adjacent sinus cavity. Orbital osteosarcoma arising from preexisting Paget disease is exceedingly rare. We report the case of a 78-year-old female patient with Paget disease of the forehead who presented with rapidly increasing bilateral proptosis and visual loss for several months. Examination showed bilateral aphakia, decreased motility, proptosis with resistance to retropulsion, and tumorous infiltration of the eyelids and periorbital soft tissue. Fundus examination showed marked bilateral scleral indentation without overlying serous retinal detachment. A computed tomographic (CT) evaluation of the orbits demonstrated extensive soft tissue involvement of the paranasal sinuses, nasal cavity, periorbital soft tissue, and orbits, with compression of the optic nerve and globe bilaterally. Biopsy of the periorbital soft tissue demonstrated osteosarcoma. Radiation therapy failed to stem the progression of the disease process, and the patient died approximately 4 months later. Although osteosarcoma of the orbit associated with Paget disease is unusual, it should be considered in the differential diagnosis of older patients with a rapidly progressive orbital mass.

Aged↗
PubMed2000

Osteosarcoma in preadolescent patients.

The medical records of boys younger than 11 years and girls younger than 10 years of age with osteosarcoma of the pelvis or extremity were reviewed. Thirty patients were identified who were newly diagnosed but untreated for osteosarcoma. None of these patients had pulmonary metastases. The same four protocols were used to treat the patients in the current study as were used to treat adolescents. The event-free and overall survival was calculated and prognostic factors were assessed. The median followup time was 8 years (range, 6-14 years). The results were compared with the results of older patients treated with the same protocols and with published results. Fourteen patients had pulmonary metastases (47%); among these patients, four also had skeletal metastases (in two of the latter, skeletal metastases appeared before the pulmonary metastases). Event-free survival was 53% and overall survival was 57%. This result is comparable with current survival results in adolescent and older patients. Serum alkaline phosphatase and serum lactic dehydrogenase levels before treatment, height percentile greater than 50%, chemotherapy-induced tumor necrosis, surgical procedure, tumor site, tumor histologic features, and patient gender were not prognostic indicators. The prognosis for prepubertal patients with osteosarcoma is similar to the prognosis of their adolescent and older counterparts. There does not seem to be any indication to treat preadolescent patients with osteosarcoma using alternate therapies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Development of acute myeloid leukemia after chemotherapy for osteosarcoma.

The current study describes two patients with osteosarcoma who had acute myeloid leukemia develop after treatment with multiagent chemotherapy. The incidence density for the chemotherapy protocol was 129.8 per 10,000 person-year of followup. Karyotype analysis of 16 reported patients (including the current two patients) indicated that most leukemias after treatment of osteosarcoma correlated with the use of topoisomerase II inhibitors, such as doxorubicin. The deoxyribonucleic acid-damaging activity of doxorubicin reinforced by the use of alkylating agents is highly suspected as a causative event in the development of leukemia after treatment of osteosarcoma. As the next step in the development of treatment for patients with osteosarcoma, the type and intensity of treatment must be evaluated to minimize possible leukemogenic effects without compromising the potential for cure.

Acute Disease↗
PubMed2003

Postoperative progression of pulmonary metastasis in osteosarcoma.

Early relapse with distant metastasis often is observed in patients with cancer after resection of the primary tumor. It is considered that resection of the primary tumor induces activation of systemic angiogenesis and enhances progression of remote metastasis. The authors show that resection of the primary osteosarcoma tumor enhances progression of pulmonary metastasis in animal osteosarcoma models. Matrigel plug neovascularization assay revealed that systemic angiogenic activity was elevated after primary tumor removal (tumor intact group, 1.61 +/- 0.21 g/dL; tumor removed group, 4.92 +/- 0.35 g/dL). In addition, serum concentration of the angiogenesis inhibitor, endostatin, decreased significantly after primary tumor removal. Treatment with the antiangiogenic reagent TNP-470 suppressed postoperative progression of pulmonary metastasis. These results indicate the possibility that activation of angiogenic activity after resection of osteosarcoma tumors enhances progression of pulmonary metastasis. The current data also suggest that administration of antiangiogenic reagents can prevent progression of pulmonary metastasis in osteosarcoma postoperatively.

Angiogenesis Inhibitors↗
PubMed1998

Mechanisms of accumulation of small particles of iron oxide in experimentally induced osteosarcomas of rats: a correlation of magnetic resonance imaging and histology. Preliminary results.

RATIONALE AND OBJECTIVES: This study was conducted to investigate the distribution and kinetics of small particles of iron oxide in osteosarcoma-like tumors. METHODS: Magnetic resonance (MR) imaging was performed in eight athymic nude rats with an experimentally induced osteosarcoma of the right hind leg immediately after intravenous injection of a superparamagnetic iron oxide preparation. Five animals received 150 mumol iron oxide/ kg and three received 50 mumol iron oxide/kg. The iron oxide preparation consisted of polythylenglycol-coated particles with a core diameter of 6 to 8 nm. The MR images were correlated with histologic slices of the tumors. RESULTS: The tumors accumulated iron oxide rapidly. A marked decrease in signal intensity, preferentially along the periphery of the tumor, was followed by a partial return of the signal intensity within the first minute. The maximum signal decrement throughout the entire tumor exceeded 41% and 21% with one dose each of 150 mumol iron/kg and 50 mumol iron/kg, respectively. The rate of return depended on the injected dose and tumor area, with the signal intensity approaching the initial value before the injection of iron oxide after 45 minutes. Histologic correlation only showed deposition of contrast medium in the proliferative areas of the tumors, mainly confined to the tumor margin. In addition to a predominantly extracellular deposition, intracellular storage could be detected. CONCLUSIONS: The findings help to advance the understanding of the distribution and kinetics of intravenous-injected small particles of iron oxide in osteosarcoma-like tumors. A first-pass accumulation of iron oxide could be documented by MR imaging in the periphery of osteosarcomas. Due to sieving of iron oxide particles by liver, spleen, and bone marrow, the signal intensity at 45 minutes after the injection of iron oxide returned to 89% (150 mumol iron oxide/kg) and 95% (50 mumol iron oxide/kg) of the preinjection intensity.

Animals↗
PubMed1997

Osteosarcoma of the head and neck: meta-analysis of nonrandomized studies.

To assess the role of adjuvant therapy in the treatment of osteogenic sarcoma of the head and neck, treatment and survival information from 173 patients with osteosarcoma of the head and neck was entered into a database. A meta-analysis of the data was attempted with primary emphasis on the effect of adjuvant therapy on disease outcome. The overall 5-year survival was 37%. Patients with mandibular and maxillary tumors had similar survival rates; both groups fared significantly better than patients with extragnathic tumors (P<0.001). Treatment with surgery alone was associated with significantly longer survival rates (P<0.03) than surgery with adjuvant therapy. In the majority of patients reported, information about surgical margins was not available. For this reason, the differences may not adequately represent the effect of adjuvant therapy. While there have been encouraging results with adjuvant treatment protocols for long bone osteosarcoma, the ultimate role of radiation and chemotherapy in the management of osteosarcoma of the head and neck remains unproven. Nevertheless, we recommend that adjuvant therapy be considered due to the poor prognosis in osteosarcoma of the head and neck.

Adolescent↗
PubMed1995

Correlation of p-glycoprotein detection by immunohistochemistry with mdr-1 mRNA levels in osteosarcomas. Pilot study.

All the factors that influence prognosis in patients with osteosarcomas have not been fully determined. One reported predictor of poor outcome is increased multi-drug resistant gene (mdr-1) expression, as measured by reverse transcription and polymerase chain reaction (RT-PCR). We examined whether immunostaining for p-glycoprotein, the protein product of mdr-1, could be used instead of RT-PCR to indicate the presence of the multidrug-resistant phenotype. The sensitivity of the immunostaining was determined using KB cell sublines. For 13 cases of osteosarcoma, samples were immunostained for p-glycoprotein and the levels of mdr-1 expression quantitated with use of RT-PCR. Three osteosarcomas with undetectable levels of mdr-1 expression by RT-PCR were negative immunohistochemically. Ten cases showed mdr-1 expression ranging from approximately 1 to 32 copies of mdr-1 mRNA/cell. Of these cases, five cases contained occasional tumour cells with positive immunostaining. There was no correlation between levels of expression and the presence or number of immunoreactive cells. These results indicate that the presence of p-glycoprotein immunostaining does not reliably correlate with the level of mdr-1 expression. However it may be useful in conjunction with RT-PCR to further define different subgroups of osteosarcomas that may have different prognoses, and this is currently under investigation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Molecular alterations of the RB1, TP53, and MDM2 genes in primary and xenografted human osteosarcomas.

We report the status of the RB1, TP53, and MDM2 genes in human osteosarcomas and cell lines established from surgical specimens and transplanted into athymic naked mice. By using reverse transcriptase-polymerase chain reaction (RT-PCR) as a prescreening technique and posterior sequencing, we observe new mutations in the RB1 gene, notably a duplication in tandem of exons 3 through 6. TP53 mutations appear in codons most frequently mutated in osteosarcomas. We have not seen MDM2 gene amplification in any reported case. These molecular alterations appear in different osteosarcomas not simultaneously present in the same tumor sample. A link has been described between these three genes in the pathways that control the cell cycle and the tumoral progression, but their functions are probably independent in the development of osteosarcomas. TP53 mutations appear in adult patients, whereas RB1 alterations occur mostly in younger patients.

Adolescent↗
PubMedDate not supplied

Multicentric osteosarcoma, Rothmund-Thomson syndrome, and secondary nasopharyngeal non-Hodgkin's lymphoma: a case report and review of the literature.

PURPOSE: Rothmund-Thomson syndrome (RTS) is an autosomal recessive disease characterized by poikiloderma, photosensitivity, skeletal deformities, and other changes. It is also associated with an increased risk of malignancies, including osteosarcoma. Sixteen previous cases of RTS and osteosarcoma have been reported. PATIENT: A patient with RTS in whom multicentric osteosarcoma developed is described. After surgery and chemotherapy, a secondary malignant neoplasm (SMN) developed consistent with nasopharyngeal non-Hodgkin's lymphoma. RESULTS: The patient was treated with anti-CD20 monoclonal antibody and is in complete remission. CONCLUSION: This is the first report of a patient with RTS treated for osteosarcoma in whom a SMN developed. Potential factors involved in this SMN include genetic predisposition and previous chemotherapy.

Adult↗
PubMedDate not supplied

Presurgical window of carboplatin and surgery and multidrug chemotherapy for the treatment of newly diagnosed metastatic or unresectable osteosarcoma: Pediatric Oncology Group Trial.

PURPOSE: Relapse remains a significant problem in patients with metastatic osteosarcoma. The response to carboplatin of patients with newly diagnosed metastatic or unresectable osteosarcoma was assessed in an upfront phase II window, which was followed-up by surgery and intensive multiagent chemotherapy. PATIENTS AND METHODS: Thirty-seven patients, ages 3 to 23 years with histologically confirmed diagnoses of osteosarcoma, were treated between January 1992 and November 1994 with carboplatin 1,000 mg/m2 per dose administered as a 48-hour continuous infusion. Two courses were administered in 3-week intervals, depending on marrow recovery. After radiographic reevaluation, patients underwent surgical removal of tumor (if feasible) and then 40 weeks of chemotherapy with high-dose methotrexate, ifosfamide, doxorubicin, and cisplatin. RESULTS: One of the 37 evaluable patients demonstrated a partial response to carboplatin; there were no complete responses. Patients were additionally analyzed by the response of pulmonary metastases to therapy and the extent of tumor necrosis of the primary lesion. By these criteria, 8 of 37 (22%) of patients showed a response at one or more sites, whereas 20 of 37 (54%) had unequivocal disease progression. Severe myelosuppression was the major toxicity. The projected 3-year event-free and overall survival rates were 23.9% and 31.9%, respectively. Only 1 of 17 patients with unresectable disease or distant bone metastases remains alive, in contrast to 6 of 17 patients with the lung as their only metastatic site and two of three patients with resected regional bone metastases. CONCLUSIONS: Continuous-infusion carboplatin demonstrated limited activity as an upfront agent in patients with metastatic osteosarcoma at diagnosis, even at doses that result in severe and prolonged myelosuppression. Patients with isolated pulmonary metastases or resectable bone metastases have a longer median survival time and greater chance of long-term survival than do patients with unresectable bone disease, for whom the prognosis remains dismal.

Adolescent↗
PubMed2002

Treatment of refractory osteosarcoma with fractionated cyclophosphamide and etoposide.

PURPOSE: Standard multiagent chemotherapy for osteosarcoma may include platinum compounds, doxorubicin, and high-dose methotrexate. By identifying new chemotherapeutic strategies, the outcome of these patients can be improved and the toxicity of treatment regimens decreased. PATIENTS AND METHODS: The authors evaluated the activity of the combination of cyclophosphamide (500 mg/m2 per day for 5 days) and etoposide (100 mg/m2 per day for 5 days) given with granulocyte colony-stimulating factor (G-CSF) to children with osteosarcoma unresponsive to conventional treatment. RESULTS: Fourteen patients with refractory osteosarcoma were treated with this combination. Twelve patients had been previously treated with a multiagent regimen that included carboplatin, ifosfamide, methotrexate, and doxorubicin. Seven of 11 evaluable patients had a poor histologic response in their primary tumor at the time of definitive surgery (Huvos grade 1 or 2). Sites of relapse included lung, bone, and brain. A total of 47 courses were given. An overall response rate of 28.5% was achieved. A complete response was obtained in one patient (7.1%), a partial response was obtained in three patients (21.4%), and stable disease for 1 to 4 months was achieved in five patients (35.7%). Five patients (35.7%) had progressive disease. Grade 4 neutropenia was the primary form of toxicity observed; the median duration of absolute neurophil count less than 500/microL was 4 days. CONCLUSIONS: The combination of cyclophosphamide and etoposide resulted in a response rate of 28.5% in patients with refractory or relapsed osteosarcoma, and its incorporation into front-line therapies deserves further evaluation.

Adolescent↗
PubMed2002

Existence of acute lymphoblastic leukemia and osteosarcoma in a child.

The existence of acute lymphoblastic leukemia (ALL) and osteosarcoma is described. An 8-year-old girl had osteosarcoma diagnosed on radiologic and pathologic examination during ALL maintenance treatment. Cytogenetic analyses in primary cell culture of osteosarcoma tissue from the patient showed complex chromosomal abnormalities including t(1;19), usually seen in B precursor cell ALL, and del 13, found in a great majority of primary osteosarcomas. To show the possibility of the existence of the genetic susceptibility caused by gene rearrangements, we used molecular technique. But we could not determine any association between gene and genetic susceptibility.

Child↗
PubMed2003

Cyclooxygenase-2 expression does not correlate with outcome in osteosarcoma or rhabdomyosarcoma.

PURPOSE: To determine if expression of cyclooxygenase (COX)-2, an inducible enzyme with known tumor-promoting activity, correlates with outcome in pediatric sarcomas. COX-2 overexpression correlates with more aggressive disease in a variety of adult solid tumors. METHODS: Archived human osteosarcoma, rhabdomyosarcoma, and Ewing sarcoma tumors were retrospectively evaluated, blinded to outcome, for COX-2 expression by immunohistochemistry and correlated with patient characteristics and survival. RESULTS: COX-2 expression was detected in 94 of 142 (66%) tumors (osteosarcoma, 66/99 [67%]; rhabdomyosarcoma, 21/35 [60%]; Ewing sarcoma, 7/8 [88%]) and 51 of 85 (60%) diagnostic biopsies (osteosarcoma, 26/45 [58%]; rhabdomyosarcoma, 21/35 [60%]; Ewing sarcoma, 4/5 [80%]). COX-2 expression did not vary with clinicopathologic features and was not predictive of prognosis in these cases. CONCLUSIONS: This study does not support the use of COX-2 expression as an upfront prognostic variable in patients with osteosarcoma or rhabdomyosarcoma. Results from the small number of patients studied with Ewing sarcoma suggest a similar lack of predictive value for COX-2 expression. However, COX-2 inhibitors are not entirely dependent upon enzyme expression for their antitumor effects; this study does not necessarily preclude the use of COX-2 inhibitors for the treatment of pediatric sarcomas.

Adult↗
PubMed2003

Genetic and epigenetic alterations of the cell cycle regulators and tumor suppressor genes in pediatric osteosarcomas.

PURPOSE: To analyze the genetic and epigenetic alterations affecting the RB1, TP53, p16INK4, and p21WAF1 tumor suppressor genes, loss of heterozygosity (LOH) at 3q and 18q, and the clinical variables of a series of Spanish children with osteosarcoma. These genetic changes were tested for an association with prognosis. METHODS: Peripheral blood samples and clinical data were available from 76 patients with osteosarcoma. Paired tissue was available from 41 of them. The mutation and methylation status of p16INK4, p21WAF1, TP53, and RB1 was screened as well as LOH at 3q and 18q. RESULTS: Loss of heterozygosity affecting RB1 (37.2%), TP53 (42.3%), and 18q (30.8%) and TP53 mutation (39%) were frequently encountered. TP53 mutation was associated with diagnosis at a later age. RB1 alteration was associated with reduced survival and event-free survival. The clinical variables associated with poor prognosis were the presence of metastasis at diagnosis (P = 0.035) or during treatment (P = 0.016) and the chondroblastic histologic subtype (P = 0.007); the response to induction chemotherapy (<90% necrosis) also tended to be related to poor prognosis (P = 0.08). CONCLUSIONS: RB1, TP53, and possibly other tumor suppressor genes located at 18q and other localizations are involved in pediatric osteosarcoma carcinogenesis, together with other genetic alterations not fully understood to date. Based on these results, the presence of an altered RB1 gene should be regarded as a poor prognostic factor for pediatric osteosarcoma.

Adolescent↗