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PubMed2006

Involvement of P-glycoprotein and MRP1 in resistance to cyclic tetrapeptide subfamily of histone deacetylase inhibitors in the drug-resistant osteosarcoma and Ewing's sarcoma cells.

Despite recent improvements in multimodal therapies for osteosarcoma (OS) and Ewing's family of tumors (EFTs), the prognosis of relapsed cases remains very poor because of the resistance to chemotherapy. Histone deacetylase inhibitors (HDACIs), including members of the cyclic tetrapeptide family such as FK228 and apicidin, are novel antitumor agents that can induce cell cycle arrest and apoptosis in various cancer cells. HDACIs also exhibit potent antitumor effects on OS and EFTs. However, to date there have been no studies to our knowledge reporting the effects of HDACIs on drug-resistant OS and EFTs. Here, we demonstrated that FK228 and apicidin exhibited strong resistance in doxorubicin-resistant clones of OS and EFTs expressing P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1) and that P-gp and MRP1 might play a crucial role in the resistance mechanism to FK228 and apicidin. A P-gp inhibitor (verapamil) and an MRP1 inhibitor (MK571) could independently reverse the resistance to FK228 and apicidin in the drug-resistant clones. Moreover, the combination of verapamil and MK571 could enhance HDACI-induced cell number reduction in drug-resistant clones to a similar extent as that in their parental clones. Although these findings suggest the difficulty in treating drug-resistant tumors expressing P-gp and/or MRP1 with these HDACIs, the combination of P-gp and MRP1 inhibitors might reverse the resistance to the HDACIs in the treatment of those tumors. Because HDACIs are potent and promising antitumor drugs and seem to be close to clinical use, it is necessary to pay attention to the resistance mechanisms against HDACIs.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Prognostic and therapeutic relevance of HER2 expression in osteosarcoma and Ewing's sarcoma.

Expression of HER2 was evaluated by immunohistochemical techniques in 84 osteosarcoma (OS) and 113 Ewing's sarcoma (ES) paraffin-embedded tumour biopsies. HER2 gene status was also assessed in a panel of cell lines as well as in vitro efficacy of trastuzumab (a humanised antibody directed against HER2) as single agent or in combination with the insulin-like growth factor I receptor (IGF-IR) IR3 antibody. Overexpression of HER2 was present in 32% of OS and 16% of ES and was significantly associated with the increased expression of P-glycoprotein, a surface molecule responsible for multidrug resistance. Event-free survival analyses revealed a prognostic value for HER2 and/or P-glycoprotein expression in OS, but not in ES. However, despite its prognostic relevance, no therapeutic effectiveness was observed pre-clinically for trastuzumab-driven therapy, in both OS or ES cell lines, unless the antibody was associated with anti-IGF-IR targeting strategies. Therefore, the therapeutic potential of trastuzumab in these neoplasms may be better exploited in combined treatments with anti-IGF-IR approaches.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Expression of functional CD40 on human osteosarcoma and Ewing's sarcoma cells.

CD40, a membrane glycoprotein of the tumor necrosis factor receptor family, is expressed by several tumor types, including B-cell lymphomas, carcinomas, and melanoma, but little is known concerning its expression by sarcoma. We used flow cytometry to analyze the expression of CD40 in human cell lines derived from 12 osteosarcomas, 6 Ewing's sarcomas, and 5 rhabdomyosarcomas. Detectable CD40 levels ranging from low to very high were found in one-third of osteosarcomas, whereas five of six Ewing's sarcomas expressed intermediate levels of CD40; all rhabdomyosarcomas were CD40-negative. At the tissue level, two of eight primary high-grade osteosarcomas showed CD40-positive immunostaining. Osteosarcoma cells and Ewing's sarcoma cells expressing CD40 were treated with recombinant soluble CD40 ligand to analyze CD40 function. Treatment with soluble CD40 ligand increased the level of apoptotic cells and stimulated the transcription of matrix metalloproteinase 9 gene, enhancing matrix metalloproteinase 9 enzyme secretion. The results indicate that in human osteosarcoma and Ewing's sarcoma, CD40 is a functional receptor whose engagement can have opposite effects on tumor cell survival and malignancy.

Apoptosis↗
PubMed2005

Interleukin-12 up-regulates Fas expression in human osteosarcoma and Ewing's sarcoma cells by enhancing its promoter activity.

Interleukin-12 (IL-12) has shown significant antitumor activity in several preclinical animal tumor models. Our previous studies showed that IL-12 inhibited tumor growth in human osteosarcoma and Ewing's sarcoma animal model. Decreased Fas expression in osteosarcoma increased the lung metastatic potential. In this study, we further examined the mechanism of IL-12 antitumor activity and showed that IL-12 significantly increased Fas expression in both human osteosarcoma cells LM7 and Ewing's sarcoma cells TC71. Up-regulation of Fas expression increased their sensitivity to Fas-induced cell apoptosis. Constructs of the Fas promoter linked to a luciferase reporter gene were used to determine the promoter activity. IL-12 increased Fas promoter activity 4.2- and 4.9-fold in TC71 and LM7 cells, respectively. Time course studies have shown that recombinant IL-12 stimulated Fas promoter activity at 2 hours, reached the peak level at 4 hours, and then declined at 24 hours. To investigate whether IL-12 specifically enhanced Fas promoter activity, we determined whether another gene (E1A) was able to stimulate Fas promoter activity. We also evaluated effect of IL-12 on the topoisomerase IIalpha promoter. The results indicated that E1A but not IL-12 stimulated topoisomerase IIalpha promoter activity. E1A failed to increase Fas promoter activity. We also found that kappaB-Sp1 element at position -295 to -286 in Fas promoter was essential for IL-12-induced activation, and nuclear factor-kappaB transcription factor was activated after IL-12 treatment in TC71 cells. These results indicate that IL-12 up-regulates Fas expression in human osteosarcoma and Ewing's sarcoma by enhancing Fas promoter activity. Understanding this mechanism may lead to new therapeutic approaches for the treatment of sarcoma involving the use of IL-12.

Animals↗
PubMed2006

Comparative analysis between osteosarcoma and Ewing's sarcoma: evaluation of the time from onset of signs and symptoms until diagnosis.

OBJECTIVE: The purposes of this study were to describe the early signs and symptoms of osteosarcoma and Ewing's sarcoma, identify symptoms that could be used to help differentiate the two types of tumors, and determine the time elapsed between the onset of signs and symptoms and the definitive diagnosis in our service, providing information and imputus for earlier diagnosis of these tumors. METHODS: A retrospective analysis of the medical dossiers of 365 patients under 30 years of age diagnosed with osteosarcoma or Ewing's sarcoma was performed, and the aspects of the clinical diagnosis were statistically analyzed and compared. RESULTS: The time between the onset of signs and the symptoms was 5.25 months for osteosarcoma and 8.1 months for Ewing's sarcoma, and the most frequent (89.5%) early symptom of osteosarcoma and Ewing's sarcoma was local pain. Symptoms that might aid diagnosis included early local volume increase and the presence of fever. CONCLUSION: The time until diagnosis of both neoplasias was higher than that reported for North America and Europe. Education of the lay public and medical professionals regarding suspicious early signs and symptoms might shorten the delay of diagnosis.

Adolescent↗
PubMed1985

Osteosarcomas and Ewing's sarcomas. Comparative immunocytochemical investigation of filamentous proteins and cell membrane determinants.

Primary malignant bone tumors, osteosarcomas (9 cases), and Ewing's sarcomas (10 cases) were examined for their reactivities with monoclonal and polyclonal antibodies against filamentous proteins and cell membrane determinants of the lymphoid and macrophage marker series. The reactivity of antibodies was studied on snap-frozen tissue probes by using a triple layer immunoperoxidase method. Osteosarcomas were positive for vimentin and, in part, for HLA-DR. Other types of intermediate-sized filaments were not detected in tumour cells. In a small number of cases (2/9) tumour cells were reactive with antibodies of the macrophage series (Leu M2). In Ewing's sarcomas, vimentin and HLA-DR was also demonstrated. It was particularly interesting that Leu M2 staining was found in the majority of cases (8/10). The staining pattern supports the assumption that this peculiar tumour is of mesenchymal (monocyte/macrophage) histogenesis. It was evident from the present study that, in primary osteogenic tumors, none of the examined tumour "markers" were as distinctive as they are for bone metastases. Nevertheless, the reactivity of Ewing's sarcoma cells with monoclonal antibodies of the Leu M2 type throws some highlights on the, as yet, obscure histogenesis of the neoplasm and may be of diagnostic value in conjunction with the known light and electron microscope features of the tumour.

Adolescent↗
PubMed2006

[Expression of MDR1 and GST-pi in osteosarcoma and soft tissue sarcoma and their correlation with chemotherapy resistance].

OBJECTIVE: To explore the expression of multidrug resistance gene 1 ( MDR1), glutathione-S-transferases-pi (GST-pi) in osteosarcoma and soft tissue sarcoma tissues from 34 patients and their correlation with chemotherapy resistance. METHODS: MDR1 and GST-pi expressions were analyzed by real-time fluorescence quantitative polymerase chain reaction (FQ-PCR) and flow cytometry (FCM) at mRNA and protein levels, respectively. Chemotherapy sensitivity on adriamycin, cisplatinum, fluorouracil, mitomycin C, dacarbazine, vincristine, methotrexate in tumor tissues were detected by MTT assay. RESULTS: The nonsensitive rates on adriamycin, cisplatinum, fluorouracil, mitomycin C, dacarbazine, vincristine, methotrexate in tumor tissues were 41.18%, 17.7%, 47.1%, 50.0%, 76.5%, 61.8% and 52.9%, respectively. The expression of P-glycoprotein (P-gp) and GST-pi in tumor tissues was 1.54 and 2.58 (relative fluorescence intensity). Chi2 analysis showed that there was a positive correlation between P-gp expression and drug resistance on ADM, GST-pi expression and resistance on ADM, DDP and MMC (P < 0.05). There was not seen obvious correlation between expression of MDR1, GST-pi and age, gender, pathological type, tumor size in osteosarcoma and soft tissue sarcoma patients (P > 0.05). The expression of GST-pi was increased in patients receiving preoperative chemotherapy. The rate of postoperative recurrence was higher in patients with higher GST-pi expression level than those with lower GST-pi expression level before operation (P < 0.05). CONCLUSION: Individual differences exist in chemotherapy sensitivity and expression of MDR1 and GST-pi in osteosarcoma and soft tissue sarcomas patients. Chemotherapy can induce up-regulation of GST-pi protein expression. Primary high expression of GST-pi is the main mechanism of resistance of osteosarcoma and soft tissue sarcomas to chemotherapy and is related to poor prognosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Late effects of therapy in adult survivors of osteosarcoma and Ewing's sarcoma.

To study the late consequences of primary bone cancer, we interviewed 82 osteosarcoma and 29 Ewing's sarcoma survivors regarding their health, fertility and offspring, employment, annual income, and activities of daily living. All subjects had been diagnosed before age 20 (mean age, 14.6 years), had survived at least 5 years from diagnosis, and were at least 21 years of age. On average, they were 32.5 years of age at interview. As controls, 151 siblings were interviewed. During the follow-up period, eight survivors had died, and eight survivors had been diagnosed with a second malignancy (7.2%; P = .002). No other health condition distinguished survivors from controls. Although the survivors were more likely than controls to have some difficulty climbing stairs and to have had employment disability, employment status and annual income at follow-up were similar. Deficits in marriage and fertility were not significant. Adult survivors of primary bone tumors diagnosed during childhood or adolescence are at high risk for second malignancies and premature death, making continued medical follow-up of utmost importance. Despite the physical impairment following limb amputation for many, the majority of outcomes we measured did not differ from controls, suggesting few adverse psychosocial outcomes in this group of cancer survivors.

Adult↗
PubMed2001

Extracorporeal irradiation for malignant bone tumors.

PURPOSE: Extracorporeal irradiation (ECI) has been used selectively in the management of primary malignant bone tumors since 1996. We report our techniques for ECI and the short-term oncologic and orthopedic outcomes. METHODS AND MATERIALS: Sixteen patients with primary malignant bone tumors were treated with ECI from 1996 to 2000. The median age was 14 years. The histologic diagnoses were Ewing's sarcoma (11), osteosarcoma (4) and chondrosarcoma (1). The treated sites were femur (7), tibia (4), humerus (2), ilium (2), and sacrum (1). Following induction chemotherapy in Ewing's sarcomas and osteosarcoma, en bloc resection of the tumor and tumor-bearing bone was performed. A single dose of 50 Gy was delivered to the bone extracorporeally using either a linear accelerator (9 cases) or a blood product irradiator (7 cases). The orthopedic outcome was recorded using a standard functional scale. RESULTS: At a median follow-up of 19.5 months, there were no cases of local recurrence or graft failure. One patient required amputation due to chronic osteomyelitis. For the 10 patients with follow-up greater than 18 months, the functional outcomes were graded good to excellent. CONCLUSION: The short-term oncologic and orthopedic results are encouraging and suggest that ECI provides a good alternative for reconstruction in limb conservative surgery in selected patients. This technique should only be used in a multidisciplinary setting, where careful follow-up is available to assess the long-term outcomes.

Adolescent↗
PubMed2006

Characterization of receptors for growth hormone-releasing hormone in human osteosarcomas and Ewing's sarcomas.

Antagonists of growth hormone-releasing hormone (GH-RH) inhibit growth of various human cancers including osteosarcomas and Ewing's sarcomas, xenografted into nude mice or cultured in vitro. The antiproliferative effect of GH-RH antagonists could be mediated, in part, through the splice variants (SVs) of receptors for GH-RH which have been found in several human cancers and cancer cell lines. In this study we investigated the expression of SVs of GH-RH receptors and the binding characteristics of these receptor isoforms in MNNG/HOS human osteosarcoma and SK-ES-1 human Ewing's sarcoma grown in nude mice. RT-PCR revealed the presence of mRNA for SVs of GH-RH receptors in both human malignant bone cancer models. Using ligand competition assays with 125I-labeled GH-RH antagonist JV-1-42, we demonstrated in MNNG/HOS and SK-ES-1 tumors the presence of specific high affinity binding sites for GH-RH (Kd=5.83 nM and Kd=2.76 nM) with a maximal binding capacity (Bmax) of 552.1 fmol/mg protein and 371.9 fmol/mg protein, respectively. We also investigated the effect of GH-RH antagonist JV-1-38, administered s.c. at a dose of 20 microg twice daily for 4 weeks on the gene expression, affinity and concentration of receptors for GH-RH in MNNG/HOS human osteosarcomas xenografted into nude mice. Treatment with JV-1-38 did not affect the expression and binding characteristics of GH-RH receptors. High affinity binding of JV-1-38 to GH-RH receptors on MNNG/HOS tumors was characterized by an IC50 value of 1.04 nM. The presence of GH-RH receptors in human bone tumors provides a rationale for new approaches to the therapy of this malignancy based on GH-RH antagonists.

Animals↗
PubMed1995

Osteosarcoma and Ewing's sarcoma after neoadjuvant chemotherapy: value of dynamic MR imaging in detecting viable tumor before surgery.

OBJECTIVE: This study analyzed the value of dynamic contrast-enhanced and subtraction MR images in detecting residual viable tumor before surgery, with emphasis on timing of enhancement, in patients with high-grade osteosarcoma and Ewing's sarcoma after neoadjuvant chemotherapy. SUBJECTS AND METHODS: Twenty-one patients with proved osteosarcoma or Ewing's sarcoma were treated with neoadjuvant chemotherapy followed by surgery. After IV administration of gadopentetate dimeglumine, dynamic enhancement patterns on preoperative MR images were compared with corresponding areas on histologic sections of the resected specimens. On dynamic subtraction images obtained with high temporal resolution (1.5-3 sec), the interval between arrival of the bolus of contrast agent in an artery and start of tumoral enhancement was used to distinguish residual viable tumor. Early enhancing foci (interval artery-tumor < 6 sec) and late or nonenhancing areas seen on MR images were correlated with the histopathologic findings in these areas of the resected specimens. RESULTS: Early and progressively enhancing structures seen on MR images corresponded to feeding arteries, physeal vessels, or residual viable tumor at specific preferential sites on corresponding histologic sections of the resected specimens. Tumor foci as small as 3-5 mm2 could be detected on dynamic MR images. Remnant viable tumor was often located subperiosteally and at the margins of the tumor. Occasionally, active periosteal reaction without presence of viable tumor contributed to early enhancement. Late and gradually enhancing or nonenhancing areas corresponded histopathologically to regions of chemotherapy-induced necrosis, mucomyxoid degeneration, or fibrosis. Alternatively, late or nonenhancing areas were associated with reactive changes such as edema, hemorrhage, or osteomyelitis or with tumor-related extracellular matrices such as abundant osteoid or chondroid. Viable tumor areas with scarce formation of matrix on microscopy, such as small cell osteosarcoma areas or Ewing's sarcoma, showed early enhancement with rapid washout of contrast agent on the dynamic MR images. CONCLUSION: Fast dynamic contrast-enhanced sequences are essential for identifying residual tumor before surgery. A short time interval of less than 6 sec between arterial enhancement and tumoral enhancement strongly correlates with presence of viable tumor. Both therapy-related alterations of tissue and tumor-related matrices must be considered when late or lack of enhancement is noted on dynamic MR images.

Adolescent↗
PubMed1980

In vivo utilization of substrate by human sarcoma-bearing limbs.

Human sarcoma-bearing limb substrate utilization was characterized by studying 10 otherwise healthy patients with extremity sarcomas (five osteosarcomas, five soft tissue sarcomas). All patients were studied in the postabsorptive state. Extremity blood flow was measured using a non-invasive capacitance plethysmograph. Percutaneous arterial and venous effluent blood samples from the tumor-bearing (TB) and control extremity were obtained and flux was calculated for free fatty acids (FFA), glucose, and amino acids. The control limb showed a release of amino acids similar to that reported previously. There was a dramatic difference in the TB extremity, which consistently released fewer amino acids. Both the TB and control limbs released FFA at the same rate. A significant difference in glucose uptake between TB and control limbs was noted for soft tissue sarcoma patients but not osteogenic sarcoma patients. The amount extracted correlated with excised tumor size and gluconeogenic amino acid release from the contralateral normal limb. This study suggests that the tumor-bearing limb ignores the inherent conservation mechanisms in the postabsorptive state and continues to utilize substrate, apparently at the expense of host tissues.

Adolescent↗
PubMedDate not supplied

[Follow-up of patients with osteosarcoma and Ewing's sarcoma: a retrospective cost-benefit analysis].

PURPOSE: Determination of the respective roles of clinical investigation, laboratory tests and various imaging techniques in the follow up of children and adolescents with osteosarcoma and Ewing's sarcoma. METHODS: In a retrospective monocenter analysis, charts of 72 patients with osteosarcoma and 47 patients with Ewing's sarcoma were reviewed with respect to ability of different diagnostic methods to detect the relapse, and correlated outcome. RESULTS: In about 25% of relapses, a second remission could be achieved. The most sensitive methods to detect a potentially curable relapse were clinical investigations and chest x-ray in the case of osteosarcoma and chest x-ray and whole body scintigraphy in the case of Ewing's sarcoma. CONCLUSIONS: The different value of diagnostic methods in the follow-up of the two illnesses may be explained by the different tumor biologies and by distinct therapeutic strategies for the treatment of relapses in the two tumor entities. However, an ongoing evaluation of current follow-up strategies is necessary to take into account new therapeutic developments which may shift the importance of certain imaging techniques.

Adolescent↗
PubMed1998

Expanding prostheses in conservative surgery for lower limb sarcoma.

Conservative resection of bone sarcoma in the lower limbs in children is very likely to be followed by a progressive problem of leg length inequality resulting from removal of the growth cartilage. To overcome this we have been using an expanding prosthesis and we report our experiences during the period 1985-1996. The prostheses are made of titanium and comprise 3 parts: an articular component, an expanding mechanism, and tibial and femoral stems. The degree of possible lengthening of the prostheses is virtually unlimited, and they can be inserted in children of 5 or more years of age. We report the use of 28 prostheses in patients aged from 5 to 18 years, of which 4 were tibial, 5 total femur, and 16 distal femur. There were 6 Ewing's sarcoma, 21 osteosarcoma, and 1 synovial sarcoma. The average follow-up was for 5 years. Five patients died from their disease, and 21 benefited from an average lengthening of 2.6 cm (range: 2 mm-120 mm). Using the Société Européenne des Tumeurs Osseouses (EMSOS) criteria, the functional results were excellent or very good in 16, fair in 7 and bad in 5. Five patients developed an infection; one required amputation and the others received a new expanding prosthesis. We conclude that an expanding prosthesis is an excellent alternative to amputation in young children. However, the risk of infection associated with repeat surgery has led us to develop a prosthesis which can be lengthened externally, without the need for reopening the wound.

Adolescent↗
PubMedDate not supplied

Primary thoracic sarcomas.

Primary sarcomas of the thorax are rare. The diagnosis is established only after sarcomalike primary lung malignancies and metastatic disease have been excluded. Primary sarcomas of the thorax are classified according to their histologic features and constitute a large group of tumors that occur in the lung, mediastinum, pleura, and chest wall. Angiosarcoma, leiomyosarcoma, rhabdomyosarcoma, and mesothelioma (sarcomatoid variant) are the most common primary intrathoracic sarcomas. Ewing sarcoma, primitive neuroectodermal tumor, chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, synovial sarcoma, and fibrosarcoma usually arise in the chest wall. Although primary thoracic sarcomas commonly manifest as large, heterogeneous masses, they have a wide spectrum of radiologic manifestations, including solitary pulmonary nodules, central endobronchial tumors, and intraluminal masses within the pulmonary arteries. The different histologic types of sarcomas are frequently indistinguishable at radiologic analysis. However, differences in clinical presentation and the location of the tumor, as well as morphologic features such as calcification within the mass and rib involvement, can be useful in suggesting the appropriate diagnosis. For example, a large rib mass in a child with fever and malaise indicates a Ewing sarcoma, a mass with a calcified matrix is likely a chondrosarcoma or osteosarcoma, and a pulmonary artery mass is likely a leiomyosarcoma.

Adult↗