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PubMed2005

Phenotypic and functional analysis of lymphocytes infiltrating osteolytic tumors: use as a possible therapeutic approach of osteosarcoma.

BACKGROUND: Osteosarcoma is the most common type of primary bone tumor. The use of aggressive chemotherapy has drastically improved the prognosis of the patients with non-metastatic osteosarcomas, however the prognosis of the patients with metastasis is still very poor. Then, new and more effective treatments for curing osteosarcoma, such as immunotherapy are needed. Tumor-infiltrating lymphocytes (TIL) have been involved in the control of tumor development and already assessed with success for the treatment of several cancers including melanoma. While TIL represent a fascinating therapeutic approach in numerous malignant pathologies, there is few report concerning adult bone-associated tumors including osteosarcoma. METHODS: Human TIL were isolated and characterized (phenotype, lytic activity) from twenty-seven patients with bone-associated tumors (osteosarcoma, Ewing's sarcoma, giant cell tumor, chondrosarcoma, plasmocytoma and bone metastases). Similar experiments were performed using rat osteosarcoma model. RESULTS: While TIL with a main CD4+ profile were easily isolated from most of the tumor samples, only TIL extracted from osteosarcoma were cytotoxic against allogeneic tumor cells. In all cases, TIL lytic activity was significantly higher compared to autologous peripheral blood leukocytes. Similar data were observed in rat osteosarcoma model where TIL were characterized by a main CD4+ profile and high lytic activity against allogeneic and autologous tumor cells. Moreover, rat TIL expansion was not accompanied by refractoriness to further activation stimulus mainly by tumor antigens. CONCLUSION: These results demonstrated that TIL therapy could be a very efficient strategy for the treatment of adult osteosarcoma.

Adolescent↗
PubMedDate not supplied

SV40 sequences in human osteosarcoma of German origin.

Simian virus 40 (SV40) is a dsDNA polyomavirus that induces osteosarcomas and mesotheliomas in hamsters and transforms many types of cells in tissue culture, including human cells. Osteosarcoma is a bone malignancy with multiple molecular lesions underlining progression from normal bone to osteosarcoma. Recent investigations have identified SV40 DNA sequences in osteosarcomas, suggesting that SV40 may contribute to tumor development. However, these studies also demonstrated that geographical differences exist between SV40 and tumor association. Our study analyzed 46 frozen German tumor specimens (42 osteosarcomas and 4 sarcomas initially suspected to be osteosarcomas) for the presence of SV40 DNA sequences by using PCR. Two different primer sets amplifying a 573 bp region of SV40 Tag gene with the complete intron sequence (SV.for 2/SV.rev) and a 172 bp region with no intron sequence (SV.5/SV.6) were used. DNA sequencing analysis verified the results. No SV40 sequences could be detected using the primer set SV.for 2/SV.rev, while 2 out of 42 osteosarcoma specimens and 1 out of 4 poorly-differentiated tumor specimens contained SV40 sequences, using the primer set SV.5/SV.6. From one of these two positive osteosarcomas, multiple tumor biopsies taken at different times during the dissection, including metastasis, tested positive for SV40. These results indicated that in Germany, only rare osteosarcomas can be linked to SV40. These results support previous findings involving geographical differences in the presence of SV40. Finally, the specific detection of SV40 sequences with multiple specimens from one of the two patients and the absence of SV40 sequences in all other samples underscores the specificity and reproducibility of this investigation and ruled out PCR contamination.

Adolescent↗
PubMed2006

Osteosarcoma: current status of immunotherapy and future trends (Review).

Osteosarcoma is the most common primary bone tumor and represents a major therapeutic challenge in medical oncology. While the use of aggressive chemotherapy has drastically improved the prognosis of the patients with non-metastatic osteosarcomas, the very poor prognosis of patients with metastasis have led to the exploration of new, more effective and less toxic treatments, such as immunotherapy for curing osteosarcoma. Compared to the numerous reports describing successful immunotherapy for other solid tumors, the number of reports concerning immunotherapy for osteosarcoma is low. However, this therapeutic strategy opens new areas for the treatment of osteosarcoma. In this review, the reasons for delay and all elements essential to develop immunotherapy concerning osteosarcoma are defined. Several pieces of evidence strongly support the potential capability of new therapies such as cellular therapy and gene therapy to eradicate osteosarcoma. Thus, clinical human trials using peptides, cytokines and dendritic cells have been performed. Tumor-infiltrating lymphocytes and some tumor antigens have been identified in osteosarcoma and resulted in an important breakthrough in cellular immunotherapy. Also, RANKL/RANK/OPG, the key regulator of bone metabolism, is a hot spot in this field as therapeutic tools. Immunotherapy for osteosarcomas has great potential, promising improvement in the survival rate and better quality of life for the patients.

Bone Neoplasms↗
PubMed2006

[Biochemical bone turnover markers in patients with conventional and nonconventional osteosarcoma].

UNLABELLED: Biochemical bone turnover markers which reflect bone formation as well as bone resorption processes are sensitive indicators of early bone metabolism disturbances. They are considered to be useful in diagnosis and treatment of many metastatic bone diseases and primary osseous tumours. THE AIM: of the study was to assess bone turnover markers in patients with conventional and nonconventional osteosarcoma during treatment. MATERIAL AND METHODS: We examined 55 patients (5-20 years) with osteosarcoma. Among them 91% had conventional and 9% had nonconventional histology. Among patients with most frequent conventional osteosarcoma distinguished histological subtypes. Bone turnover markers were determined in serum by immunoenzymatic assay at diagnosis, during preoperative- and postoperative chemotherapy and then after treatment. RESULTS: We found different values of bone turnover markers in serum of patients with conventional osteosarcoma. At the moment of biopsy the highest value of osteocalcin in patients with fibroblastic subtype was observed. The highest activity of bone alkaline phosphatase and collagen type I crosslinked C-telopeptide in children with osteoblastic subtype of osteosarcoma were obtained. The levels of tested parameters decreased about 20-40% during preoperative and postoperative chemotherapy, then they increased after treatment first of all in patients with chondroblastic subtype (p < 0.05). Next we found that the osteocalcin concentration was 4-fold lower, in nonconventional osteosarcoma in comparison to the conventional. This marker is stable during treatment and remains unchanged after it. Moreover we showed that the changes of the bone alkaline phosphatase activity and the collagen type I crosslinked C-telopeptide concentration during and after treatment were less dynamic in children with nonconventional osteosarcoma. CONCLUSIONS: Observed changes of markers in various histological subtypes of osteosarcoma can indicate different rate of their bone turnover. Changes observed during treatment are more dynamic in conventional than in nonconventional type of osteosarcoma.

Adolescent↗
PubMed1989

Characterization of osteosarcoma cells from two sibling large-breed dogs.

Neoplastic cells were isolated from 2 sibling Great Dane/Labrador Retriever mixed-breed dogs in which telangiectatic type osteosarcomas arose concurrently. Cells from various sites in the same osteosarcoma appeared similar in culture, but there were differences between the 2 osteosarcomas in growth characteristics and appearance of cells. Cells from 1 osteosarcoma had a small, but significant (P less than 0.05), cyclic adenosine monophosphate response to parathyroid hormone stimulation, indicating a low order of osteoblastic differentiation. Cells from the other osteosarcoma had no response to parathyroid hormone stimulation. Cells from both osteosarcomas and a concentrated cell-free filtrate from the osteosarcoma with osteoblastic differentiation were injected into nude mice, but osteosarcomas were not induced. Results of ultrastructural examination of osteosarcoma samples for viral particles were negative and supernatant fluids from cultured cells were considered negative for viral reverse transcriptase activity.

Animals↗
PubMed1993

Increased expression of nucleoside diphosphate kinase/nm23 and c-Ha-ras mRNA is associated with spontaneous lung metastasis in rat-transplantable osteosarcomas.

The relationship between expression of nucleoside diphosphate kinase (NDP kinase)/nm23, c-Ha-ras, and c-myc genes and metastatic potential was assessed in rat-transplantable osteosarcoma lines, derived from spontaneous and chemical carcinogen (4-hydroxyamino quinoline 1-oxide)-induced osteosarcomas in Fischer 344/NS1c rats. These osteosarcomas possess metastatic potential and highly metastatic lines spontaneous osteosarcoma-selected lung metastatic lesions and 4-hydroxyamino-quinoline 1-oxide-induced osteosarcoma-selected lung metastatic lesions were respectively established by selectively transplanting lung metastatic lesions. Northern blot analysis revealed that the levels of NDP kinase/nm23 and c-Ha-ras gene expression were increased in line with metastatic ability; thus transcript levels were remarkably greater in both spontaneous osteosarcoma-selected lung metastatic lesions and 4-hydroxyamino-quinoline 1-oxide-induced osteosarcoma-selected lung metastatic lesions highly metastatic lines than in their respective low metastatic spontaneous and chemical carcinogen (4-hydroxyamino quinoline 1-oxide)-induced osteosarcoma counterparts. c-myc mRNA expression was observed in all tumor lines, without any correlation with metastatic ability. Southern blot analysis did not show evidence of gross rearrangement or amplification of NDP kinase/nm23, c-Ha-ras, or c-myc genes suggesting regulation of their gene expression at the transcriptional and/or posttranscriptional level. These results indicate that NDP kinase/nm23 and c-Ha-ras might be cooperatively involved in a positive manner in signal transduction processes, especially involving G-protein reactions, responsible for metastasis of rat-transplantable osteosarcomas.

Animals↗
PubMed1998

Comparative genomic hybridization of low-grade central osteosarcoma.

Very little is known concerning the cytogenetic and molecular genetic changes of low-grade central osteosarcoma, a rare form of osteosarcoma. In the present study, we used comparative genomic hybridization (CGH) to screen for DNA sequence copy number aberrations in 10 samples from 6 patients: 7 typical low-grade central osteosarcomas, one low-grade (Grade II) central osteosarcoma, and two high-grade (III and IV) local recurrences of a low-grade central osteosarcoma Nine samples had aberrations. Six typical low-grade central osteosarcoma samples had a single DNA sequence copy number change per tumor. Three samples from more advanced tumors (a Grade II low-grade central osteosarcoma and local recurrences of Grade III and IV) had a mean of five changes per tumor. Recurrent changes affected these minimal common regions: +12q13-q14 (three tumors), +12p (two tumors), and +6p21.1-p21.3 (two tumors). Nine samples were analyzed for CDK4 and MDM2 expression and SAS amplification. One sample with a gain of chromosome 12 had a very strong expression of MDM2, strong expression of CDK4, and amplification of SAS. One sample with a gain of 12q13-q14 had strong expression of CDK4 and MDM2. Strong expression of CDK4 was found in two additional tumors; one had a gain of 12q13-q21, and the other had no changes in chromosome 12 by CGH. No alterations were detected in the CDK4, MDM2, and SAS panel in three other samples with no changes in chromosome 12 by CGH. In conclusion, the low number of DNA sequence copy number alterations reflects the relatively low malignancy of low-grade central osteosarcoma. This simplicity differs from the complex aberrations seen in conventional high-grade osteosarcomas.

Adolescent↗
PubMed1999

Marginal excision for osteosarcoma with caffeine assisted chemotherapy.

The authors report on intentional marginal excision for osteosarcoma in conjunction with caffeine assisted chemotherapy for the purpose of preservation of good limb function. Twenty-seven patients with osteosarcoma (22 patients with Stage IIB and five with Stage IIIB) preoperatively were given three-to-five courses of intraarterial cisplatin and caffeine without or with doxorubicin. For 26 (96%) responders to the chemotherapy, limb salvage surgery was conducted by means of an intentional marginal procedure, which led to the preservation of important structures such as major neurovascular bundles, tendons, ligaments, muscles, and the epiphysis. Tumors were located in the distal femur in 11 patients, the proximal tibia in eight, the proximal fibula in four, the proximal humerus in two, and the proximal femur in one patient. The histologic response of these 26 patients to the preoperative chemotherapy showed no viable cells in 19 patients with Stage IIB osteosarcoma and only scattered foci of viable cells in two patients with Stage IIB and five patients with Stage IIIB osteosarcoma. As for reconstruction, distraction osteogenesis was performed in eight patients, allograft or autoclaved bone and prosthesis composite in four, autoclaved bone in two, osteochondral allograft in two, megaprosthesis in six, and resection alone in four patients. The average functional evaluation of the 26 patients was 91% of normal. Local tumor recurrence was seen in one patient, whereas 18 patients with Stage IIB osteosarcoma remain diseasefree with a mean followup of 61 months. Two patients with Stage IIB osteosarcoma and four patients with osteosarcoma Stage IIIB died of the disease. Intentional marginal excision for osteosarcoma in conjunction with caffeine assisted chemotherapy is advantageous because it results in the preservation of healthy important structures, with joint preservation possible in selected cases. This approach should help to improve the success rate of limb salvage surgery for osteosarcoma and to preserve the function of the affected limb.

Adolescent↗
PubMed2003

Telomerase activity in juxtacortical and conventional high-grade osteosarcomas: correlation with grade, proliferative activity and clinical response to chemotherapy.

Seven samples from seven patients with juxtacortical osteosarcomas, and 27 samples from 19 patients with conventional high-grade osteosarcomas were investigated for a possible correlation between telomerase activity and clinicopathological features such as age, sex, and response to chemotherapy. Of seven juxtacortical osteosarcomas, telomerase activity was weakly positive in three parosteal osteosarcomas, and highly positive in one parosteal osteosarcoma. In contrast, of 27 conventional high-grade osteosarcomas, telomerase activity was weakly positive in eight tumors and highly positive in three. Of all samples, 44.1% of the osteosarcomas showed telomerase activity (57.1% of juxtacortical and 40.7% of conventional osteosarcomas). The majority of poor responders to chemotherapy showed no telomerase activity (nine of 11), whereas five of seven good responders showed strong or weak telomerase activity. There was a significant correlation between telomerase activity and the response to chemotherapy (P<0.05). Telomerase activity was not correlated with MIB-1 proliferation index, age at the time of surgery, or sex. These findings suggest that telomerase activation occurs early in the oncogenesis of osteoblastic tumors without having an effect on the progression of these tumors. In malignant osteoblastic tumors, the biological significance of telomerase activation is different from that described for most epithelial cancers.

Adolescent↗
PubMed1996

Nucleolar organizer regions in parosteal and central osteosarcomas.

Silver stained nucleolar organizer regions (AgNOR) have revealed differences in the biological behavior of certain entities. This study involves a morphometric analysis of AgNOR in 6 central, classic osteosarcomas and 6 parosteal osteosarcomas. There was a statistically significant difference in the number of AgNOR per nucleus between central and parosteal osteosarcomas. Single AgNOR volume was smaller in central osteosarcomas as compared to parosteal osteosarcomas. However, this difference did not reach statistical significance. The parameter AgNOR number per nucleus revealed a cut off value such that 100% of central osteosarcoma cases lay above this value and 100% of parosteal osteosarcoma cases lay below this value. AgNOR demonstration involves a simple technique which can be performed on formalin fixed, paraffin embedded file material. Thus, it may be prudent to routinely assess AgNOR as a contributor to the determination of the pathophysiology of osteosarcomas.

Bone Neoplasms↗
PubMed1983

Demonstration of specific serologic reactivity in human osteosarcoma.

Cultured cell lines of osteosarcoma and normal skin fibroblasts were derived from tissues of five patients with localized osteosarcoma. Testing of pretreatment patient sera in an indirect immunofluorescence assay against both autologous normal fibroblasts and autologous osteosarcoma cells showed cytoplasmic staining. Quantitative absorption of patient sera with human fetal cells removed all reactivity against autologous fibroblasts, but fetal-absorbed sera showed cytoplasmic, membrane, and nuclear fluorescence when tested against autologous osteosarcoma. Testing the five patient sera against all five cell lines showed staining of allogeneic fibroblasts and osteosarcoma by nonabsorbed sera. Following fetal absorption, all reactivity against fibroblasts was removed, with the retention of specific staining of all osteosarcoma cell lines by all five patient sera. Additional testing of sera from normal patients, patients with soft tissue sarcomas, and patients with melanoma showed staining of allogeneic cultured fibroblasts and tumor cells derived from a patient with osteosarcoma. All staining against fibroblasts and tumor cells was eliminated by fetal absorption of the allogeneic sera. Results suggested that fetal neoantigens are expressed in cultured normal and malignant cell lines and that such fetal antigens are recognized by natural antibodies. Absorption of antifetal reactivity allowed demonstration of specific serum reactivity against osteosarcoma cells.

Antibodies, Neoplasm↗
PubMed1987

Tumor heterogeneity in osteosarcoma as identified by flow cytometry.

Measurements of the cellular DNA content by flow cytometry were carried out in 25 untreated osteosarcomas to identify the frequency of DNA aneuploidies and heterogeneous DNA stemlines in relation to histopathology. Analyzing multiple specimens from each single tumor (2-16; median, 4), highly malignant osteosarcomas were found to express DNA aneuploidies in 18 of 21 cases (86%) with multiple aneuploid DNA stemlines in 10 cases (48%). In three paraosteal osteosarcomas, no DNA aneuploidy was detected and a significantly lower proportion of cells in S-phase was observed as compared to the highly malignant osteosarcomas (mean 8.6% vs. 18.8%; P less than 0.05). Like in the paraosteal osteosarcomas, no DNA aneuploidy and a low fraction of cells in S-phase was found in the predominant cell population of one of the very rare sclerosing small cell osteosarcomas, which also revealed a second DNA stemline with a DNA index of 2.0. These results demonstrate a high degree of DNA stemline heterogeneity in highly malignant osteosarcomas. The data emphasize the usefulness of DNA measurements for the characterization of bone tumors and indicate the possibility of discriminating highly malignant from low-grade osteosarcomas.

Aneuploidy↗
PubMed2005

Dedifferentiated parosteal osteosarcoma: the experience of the Rizzoli Institute.

BACKGROUND: Dedifferentiated parosteal osteosarcoma (DPOS) is a variant of osteosarcoma in which a high-grade sarcoma coexists with a conventional parosteal osteosarcoma (c-POS), either at presentation (synchronous type) or at the time of recurrence (metachronous type). Only approximately 60 patients have been reported in the literature. The objective of this study was to analyze the clinicopathologic and radiographic features of a relatively large number of patients with DPOS in an attempt to define further the histologic and biologic behavior of this rare entity. METHODS: In a series of 120 patients with parosteal osteosarcoma who were seen at the Rizzoli Institute from 1958 to 2000, the authors identified 29 patients who were diagnosed with DPOS. The authors reviewed the clinical and radiologic features, histologic sections, treatments, and outcomes in this group of patients with DPOS. RESULTS: Twelve patients were male, and 17 patients were female. The patients ranged in age from 15 years to 65 yrs (average, 36 years; median, 32 years). One tumor involved the scapula, one involved the ilium, and another involved the skull. All 26 of the other tumors were located in the long bones (14 in the femur, 5 in the humerus, 3 in the tibia, 3 in the fibula, and 1 in the ulna). In 18 patients, radiographic areas of lucency were seen within an otherwise sclerotic lesion. Histologically, the dedifferentiated component was high-grade osteoblastic osteosarcoma in 14 patients, fibroblastic osteosarcoma in 10 patients, giant cell-rich osteosarcoma in 3 patients, and chondroblastic osteosarcoma in 2 patients. All tumors were Stage IIB, and invasion of the medullary canal was detected in 19 patients (65%). Twenty-eight patients underwent surgery, and 18 of those patients received chemotherapy (5 patients received neoadjuvant chemotherapy, and 13 patients received adjuvant). Nine patients were dead and 20 patients were alive (average follow-up, 107 months; range, from 3 months to 36 years) at the last follow-up. Of the nine patients who died, one patient received no treatment, five patients underwent surgery (with three patients achieving adequate margins) in combination with chemotherapy, and three patients underwent surgery only (with adequate margins achieved). Of the 20 patients who remained alive, 13 patients underwent surgery (with 10 patients achieving adequate margins) in combination with chemotherapy, whereas 7 patients underwent surgery only (all with adequate margins). Seven of the nine patients who died had widespread metastases. One patient died of causes unrelated to the tumor, and another patient died shortly after undergoing resection of a lesion in the skull. CONCLUSIONS: Dedifferentiation occurred in approximately 24% of patients with c-POS. The prognosis for patients with DPOS was better than the prognosis for patients with dedifferentiated central and dedifferentiated peripheral chondrosarcoma.

Adolescent↗
PubMed2002

Genetic imbalances revealed by comparative genomic hybridization in osteosarcomas.

Osteosarcomas are the most frequent bone sarcomas. The molecular chromosomal aberrations in osteosarcomas were analyzed by comparative genomic hybridization (CGH). We studied 47 frozen tumors (41 primary samples, 6 relapses) in osteosarcoma patients registered in the Cooperative Osteosarcoma Study (COSS) protocol. Genomic imbalances were detected in 40 of 41 primary tumors and 6 of 6 relapsed tumors. Gains were more frequent than losses (ratio of 1.3:1). The median number of changes was 16 and 12 in primary and relapsed osteosarcomas, respectively. The median number of aberrations in primary high-grade osteosarcomas (17.0) was significantly higher than in low- or intermediate-grade osteosarcoma subtypes (3.0) (p = 0.038). The most frequent gains included 8q, 1p21-p31 and 1q21-q24, and the most frequent losses were 10q, 5q and 13q. High-level gains were observed on 8q23-q24, 17p13 and 1q21-q24. A gain of 19p (p < 0.001) or loss of 9p (p = 0.027) was more frequent in poor responders than in good responders. Univariate analysis revealed that patients with primary metastases (p = 0.002), poor histologic responses (p = 0.005), high-level gains of 19p (p = 0.012) or losses of 13q14 (p = 0.042) had significantly lower event-free survival (EFS), whereas patients with a loss of 5q (p = 0.007) or a loss of 10q21-22 (p = 0.017) had significantly higher EFS than patients without these aberrations. Multivariate analysis demonstrated that primary metastasis, loss of 13q14 and loss of 5q were independent prognostic factors. The findings of our study seem to be useful for evaluating the prognosis of patients and may finally lead to treatment strategies based on genetic background of osteosarcoma.

Adolescent↗
PubMed2001

Cellular and molecular properties associated with osteosarcoma cells.

Osteosarcoma cells are recognized by abnormal function that causes a primary bone tumor. Osteosarcoma cells U(2)OS and SAOS-2 were analyzed for the expression of cell surface markers. High expression was quantified for hyaloronidase receptor (CD-44) > moderate for integrins (CD-51 and -61), > and lower for selectins (CD-62). High mitotic capacity were demonstrated by gene expression (measured by RT-PCR) and the protein level (measured by FACS) for cFOS, cMYC, and cJUN. The basic definition of osteosarcoma is excessive production of pathological osteoid. Expression of mRNA for matrix genes osteocalcin, osteonectin, and biglycan was studied. Osteocalcin and osteonectin were detected in RNA from primary cultured marrow stromal, trabecular bone cells, and osteosarcoma cell lines (U(2)OS, SAOS-2). mRNA for biglycan was detected only in primary cells and MG-63 cell line and was undetectable in RNA from U(2)OS, SAOS-2 osteosarcoma cell lines and by RNA extracted from bone biopsies of osteosarcoma patients. The absence of biglycan message observed in osteosarcoma samples provides evidence for the alterations in the extra cellular matrix which result with non-mineralized osteoid produced by the osteosarcoma cells.

Adolescent↗
PubMed2006

Essential erbB family phosphorylation in osteosarcoma as a target for CI-1033 inhibition.

BACKGROUND: The role of erbB tyrosine kinases, especially Her-2, in osteosarcoma has engendered intense debate. Some investigators identified an association between low-level Her-2 expression, compared to none, and poor patient outcome. Others questioned the importance of apparent cytoplasmic expression of Her-2, since membranous overexpression is associated with poor outcome in carcinomas. We previously demonstrated that primary osteosarcoma cells express cell-surface EGFR and Her-2, with the p80 isoform of Her-4 localized to the nucleus. We wished to determine if erbB kinases in osteosarcoma were phosphorylated, and if this was required for growth. PROCEDURES: We cultured early passage osteosarcoma cell lines in the presence or absence of the pan-erbB inhibitor CI-1033 and examined the phosphorylation status of EGFR, Her-2, and Her-4 by immunohistochemistry, cell-based ELISA, flow cytometry and two dimensional Western blot. We also assessed the impact of CI-1033 upon osteosarcoma growth and survival in vitro. RESULTS: EGFR, Her-2, and Her-4 were constitutively phosphorylated in early passage osteosarcoma cells cultured in vitro. CI-1033 abrogated erbB receptor phosphorylation and caused growth inhibition and apoptosis in a titratible fashion with concentrations of 1 muM or more. CONCLUSIONS: EGFR, Her-2, and Her-4 are constitutively phosphorylated in early passage osteosarcoma cells in tissue culture, and erbB signaling provides essential growth and anti-apoptotic signals to osteosarcoma cells. This suggests that erbB overexpression is not required for erbB to promote malignancy, but rather that overexpression is one of several mechanisms that generate unregulated erbB signaling.

Apoptosis↗
PubMed1985

Juxtacortical osteosarcoma: a radiologic and histologic spectrum.

Radiologic and pathologic findings were analyzed in four patients with parosteal osteosarcomas, three with periosteal osteosarcomas and one with a high-grade surface osteosarcoma. Plain film and histologic findings considered together are usually distinctive and permit differentiation of these tumors from each other and from other lesions with which they are frequently confused. Prognosis and management are determined by tumor extent and histologic grade. Computed tomography is more accurate than conventional tomography, angiography, and bone scintigraphy for preoperative determination of tumor extent and for assessing tumor relationships to the bone cortex and medullary cavity. Histologically, parosteal osteosarcomas are usually low-grade, while periosteal and high-grade surface osteosarcomas are generally high-grade tumors and have worse prognoses. High-grade surface osteosarcoma, which is indistinguishable in behavior and histology from classical medullary osteosarcoma, requires more aggressive surgical management than parosteal and periosteal osteosarcomas.

Adolescent↗
PubMed1996

Alterations of the p53, Rb and MDM2 genes in osteosarcoma.

Molecular defects affecting tumor-suppressor genes are an important step in the genesis of sarcomas. For example, inheritance of a defective Rb or p53 gene predisposes the carrier to develop osteosarcoma, among other malignancies. In this study, we have assessed the occurrence of p53, Rb and MDM2 alterations in the same samples of osteosarcomas, along with representative samples of various other sarcomas. Point mutations of the p53 gene were found in 13 of 42 osteosarcomas and 1 of 8 leiomyosarcomas, and gross rearrangement of the p53 gene was demonstrated in 5 of 37 osteosarcomas. The retinoblastoma susceptibility gene (Rb) was either rearranged or deleted in 7 of 37 osteosarcomas, 1 of 7 soft-tissue sarcomas and 1 of 4 Ewing sarcomas. Remarkably, 5 of the osteosarcomas having Rb alterations also had p53 mutations. Amplification and overexpression of the MDM2 oncogene may lead to increased MDM2-p53 binding resulting in inactivation of p53 function. A two- to threefold increase in the copy number of MDM2 was detected in 7 of 37 samples, 5 of which were osteosarcomas. Amplification of the MDM2 gene occurred independently of p53 mutation; one sample having threefold amplification of MDM2 also had a p53 mutation. In summary, 34 alterations of the p53, Rb and MDM2 genes were found in 26 of 42 (62%) osteosarcomas.

Base Sequence↗