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PubMed2004

Clinical significance of vascular endothelial growth factor (VEGF) in sera of patients with pediatric malignancies.

BACKGROUND: Angiogenesis is essential for solid tumor growth. It is induced by tumor cells through stimulatory angiogenic peptides, one such peptide is vascular endothelial growth factor (VEGF). PURPOSE: The ultimate aim of the work is to investigate the possible role of VEGF as an early biomolecule involved in the progression of pediatric malignant tumors with high metastatic potential. PATIENTS AND METHODS: Forty-five pediatric patients were studied. They included four groups with malignant solid tumors suffering from Ewing's sarcoma, osteosarcoma, neuroblastoma and rhabdomyosarcoma. In addition, a healthy control group including fifteen age and sex matched children was included in the study. Serum VEGF levels were determined by ELISA technique. RESULTS: The level of VEGF was significantly higher in all types of solid tumors compared to normal healthy children. The mean values obtained for patients and controls were 429.44 +/- 258.55 pg/ml and 79.36 +/- 63.81 pg/ml, respectively. No significant difference was detected in the level of VEGF among males and females. Also, no statistically significant difference was detected among the different types of malignant tumors. However, a marked significant difference was elucidated between metastatic and non-metastatic cancer patients, the values recorded were 753.33 +/- 173.64 pg/ml and 267.5 +/- 75.54 pg/ml, respectively (p < 0.001). Furthermore the results showed that 207 pg/ml of serum level of VEGF is the optimal cut-off value (mean +/- 2 SD of control) with sensitivity of 87% and specificity of 100%. Using the receiver operating characteristic (ROC) curve analysis,the area under the curve (0.917) indicated the validity of using serum VEGF level in the diagnosis of all different types of pediatric malignant solid tumors with high potentiality to metastasis. CONCLUSION: VEGF is an angiogenic stimulatory peptide. Its serum level could be a reliable marker in assessing pediatric malignancies with high metastatic potentials.

Journal Article↗
PubMed1979

Clinical activity of detorubicin: a new anthracycline derivative.

The anthracycline derivatives are intercalating drugs which are of major importance in the treatment of leukemias and in the management of solid tumors. Structural analogs have been prepared by semisynthetic modifications in an attempt to extend the spectrum of antitumor activity and to reduce toxicity (acute myelosuppression and cardiotoxicity). This report concerns our preliminary clinical experience in 111 patients who received detorubicin. Two dose schedules were used in acute leukemia patients. Sequential doses were active in acute leukemia relapses but the mucous membrane toxicity was excessive; more recently, intermittent doses proved active in acute leukemia relapses (one 6-mg/kg dose) and in a patient with resistant Burkitt's lymphoma. In non-Hodgkin's lymphomas, a complete response rate of 71% was achieved with an intermittent schedule (3 mg/kg/day X 3 weeks). A remarkable shrinkage of skin involvement was also observed. Detorubicin showed a high activity in mycosis fungoides (five regressions among six patients) and some activity in soft tissue sarcomas, osteosarcomas, and various solid tumors.

Acute Disease↗
PubMed1983

[Tumor regression following local chemotherapy in carcinomas of the upper respiratory and digestive tracts. The viewpoint of the pathologist].

Few pathologists have given much thought to the problem of post-chemotherapeutic tumoral regression of upper respiratory and digestive tract carcinoma. In other oncological fields (pediatry: nephroblastoma, embryonic sarcoma, osteosarcoma; gynecology: mammary tumors...) pre- and post-chemotherapy tissue studies have led to histological grading of prognostic value (particularly well known is that of Rosen et al). Numerous specimens were examined following operations for cancer, including pelvimandibulectomy, buccopharyngectomy, facial resection... Possible tumoral changes were evaluated using a conventional scale of regression based on 6 histologic degrees, and findings were of prognostic significance when compared with the initial biopsy results. This evaluation scale may require modification in the near future since recently introduced chemotherapy, particularly cisplatinum, appears to have a more potent and more specific effect on histologie features.

Carcinoma↗
PubMed1993

Germline mutations of the p53 tumor-suppressor gene in cancer-prone families: a review.

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder that predisposes individuals to multiple forms of cancer including breast carcinoma, soft tissue sarcoma, osteosarcoma, leukemia and adrenocortical carcinoma. These diverse tumor types develop at unusually early ages. Analysis of the tumor suppressor gene p53 in family members with LFS have demonstrated that germline mutations in the p53 gene were present in most of the LFS family tested so far. Furthermore, germline p53 mutations were also found in cancer-prone individuals which were not indicative of the LFS.

Genes, p53↗
PubMed1996

[MDR (Multiple Drug Resistant) type of resistance to chemotherapy in clinical practice].

Multifactorial resistance is the main mechanism of chemotherapy failure in cancers. Multidrug resistance (MDR) is related to the expression of a 170 kDa membrane glycoprotein, the so-called P-glycoprotein (P-gp). This protein is able to extrude drugs of various structures and mechanisms out of the cytoplasm. P-gp is a pronostic value in hemopathy as well as in child sarcoma, osteosarcoma and neuroblastoma. Modulator agents of different generations are capable of inhibiting P-gp. MDR modulation is obtained in hemopathies and is associated with an eradication of the P-gp (+) cell clones. In solid tumors, clinical trials using verapamil or cyclosporin are not so convincing. It is likely that other mechanisms of resistance are responsible for tumor progression, such as the MRP system, glutathion and topoisomerases. A better knowledge of multifactorial resistance and drug synthesis counteracting these resistance mechanisms will allow to elaborate new therapeutic basis for cancer therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

[Mdm2, p53 and the cell cycle: when well enough is best left alone].

The mdm2 cellular protooncogene is involved in many human tumors where it has been shown to be overexpressed, including sarcomas, osteosarcomas, gliomas and others. The Mdm2 protein is believed to be oncogenic by binding and inactivating the p53 and Rb tumor suppressor gene products and by activating the E2F-1/DP-1 transcription factors, thus promoting the G1 to S phase transition. The mdm2 gene is activated transcriptionally by p53, thus forming an autoregulatory negative feedback loop. This feedback loop is important in normal cells and when cells are exposed to various genotoxic agents. By activating its own negative regulator, p53 would signal the cells to resume proliferation after a p53-mediated G1 arrest in response to DNA damage. The review aims to detail the functions of Mdm2 in normal and tumor cells. We also discuss several recent data suggesting that Mdm2 may exhibit activities unrelated to its well known function as a negative regulator of p53 activities.

Cell Cycle↗
PubMed1998

Simian virus 40 oncogenesis in hamsters.

Simian virus 40 (SV40) is a DNA tumour virus which is highly oncogenic in hamsters. Only specific histologic types of tumours develop in hamsters injected with SV40, and these are influenced by the route of virus inoculation. When SV40 is injected systemically to expose most different cell types to the virus, the animals develop mesotheliomas, osteosarcomas, sarcomas, and lymphomas within six months. When the virus is injected subcutaneously, sarcomas at the site of injection develop. If hamsters are injected intracranially with SV40, they develop ependymomas. These same tumour types have been found to contain SV40.

Animals↗
PubMed1990

Response of osteosarcoma and Ewing sarcoma to preoperative chemotherapy: assessment with dynamic and static MR imaging and skeletal scintigraphy.

In 15 osteosarcomas and six Ewing sarcomas, response to preoperative chemotherapy was assessed with magnetic resonance (MR) imaging without and with gadolinium diethylenetriaminepentaacetic acid (DTPA) enhancement and with dynamic Gd-DTPA studies, and the results were compared with the scintigraphic findings. All studies were obtained prior to and following preoperative chemotherapy. Static MR imaging was of little value for assessment of response; reduction in signal intensity within soft-tissue masses on the T2-weighted spin-echo images indicated response with a sufficient degree of accuracy (71%) but low sensitivity, whereas an increase in signal intensity after Gd-DTPA administration indicated zones of viable tissue with low specificity. With three-phase skeletal scintigraphy, the findings in the perfusion and blood-pool phases were of no value, whereas the findings in the osseous phase allowed the prediction of response with an accuracy of 73.7%. Of all techniques employed, dynamic MR imaging had the highest degree of accuracy (85.7%) and was superior to scintigraphy, particularly in patients who were receiving intraarterial chemotherapy.

Adolescent↗
PubMedDate not supplied

Fat-saturated contrast-enhanced T1-weighted MRI in evaluation of osteosarcoma and Ewing sarcoma.

To assess contrast-enhanced (C+), fat-saturated (FatSat), T1-weighted (T1W) imaging in the characterization of the soft tissue mass associated with primary bone tumors, we compared it with T2-weighted (T2W) imaging in patients with osteosarcoma (n = 36) and Ewing sarcoma family of tumors (Ewing sarcoma; n = 11). Periosseous tumor compared with normal muscle had greater contrast-to-noise ratio (CNR) on the FatSat T1W C+ image than on T2W for 81% (38/47; P < .0001) of patients. The CNR of periosseous tumor compared with subcutaneous fat was greater on FatSat T1W C+ for 98% (46/47; P < .0001). Radiologists found it easier to evaluate neurovascular bundle proximity to tumor with FatSat T1W C+ images than with T2W for 64% of patients (30/47; P < .0001). They judged FatSat T1W C+ superior to T2W for periosseous tumor conspicuity and visualization of soft tissue necrosis in 62% (29/47; P < .0001). In patients with osteosarcoma or Ewing sarcoma, FatSat T1W C+ imaging may replace T2W imaging for soft tissue mass evaluation, especially if contrast is being used for dynamic enhancement.

Adolescent↗
PubMed1995

Massive allografts in the treatment of osteosarcoma and Ewing sarcoma in children and adolescents.

A retrospective review was performed of the results of all allograft reconstructions that had been done after the resection of an osteosarcoma or an Ewing sarcoma in a skeletally immature patient between 1982 and 1989 at The Hospital for Sick Children in Toronto. There were twenty-six patients. Six reconstructions were intercalary, sixteen were resection arthrodeses, three followed resection of a bone segment including the epiphysis (osteoarticular reconstruction), and one was a replacement of the entire humerus. Resection arthrodesis about the knee was performed with a smooth intramedullary rod and with one growth plate left intact. Six procedures were performed in the upper extremity. Excluding the patients who died, the average duration of follow-up was five years and three months. Twenty-one of the twenty-six patients had reached skeletal maturity at the time of follow-up. Eighteen (69 per cent) of the patients had a good or excellent result, four (15 per cent) had a fair result, and four had a failure. Twenty patients (77 per cent) had at least one complication (other than a limb-length discrepancy), and fourteen (54 per cent) sustained at least one fracture of the allograft. Fifteen patients who had had a reconstruction in the lower extremity had survived with survival of the allograft at the time of the latest follow-up. A limb-length discrepancy of at least two centimeters developed in nine of the fifteen patients. Five were managed with a contralateral epiphyseodesis, and one of them had an unsuccessful attempt at limb-lengthening as well. The patients who had a limb-length discrepancy of more than three centimeters at the time of follow-up had been significantly younger (p < 0.05) at the time of the reconstruction than those who had a smaller discrepancy. Three allografts (12 per cent), two of which were implanted early in the series, became infected. Soft-tissue coverage is of paramount importance for the prevention of infection, and we now routinely perform primary muscle (gastrocnemius or latissimus dorsi) transfers when dealing with an inadequate muscle envelope. Twelve patients were followed for more than four years (average, six years and seven months); they had no complications other than increased limb-length discrepancy and one subluxation of the shoulder after the first four years following the reconstruction. Although the rate of complications is higher than in adults, allograft reconstruction remains a useful option for the management of skeletally immature individuals.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1999

Microsatellite alterations in various sarcomas in Japanese patients.

To determine the usefulness of microsatellite analysis in the differential diagnosis of various sarcomas, we investigated microsatellite alterations at 12 microsatellite loci by polymerase chain reaction and electrophoresis in 39 Japanese patients with sarcomas. The sarcomas were: osteosarcoma, Ewing's sarcoma, chondrosarcoma, liposarcoma, leiomyosarcoma, epithelioid leiomyosarcoma, rhabdomyosarcoma, synovial sarcoma, and malignant fibrous histiocytoma. We also examined ten leiomyomas to contrast with leiomyosarcoma. No microsatellite instability (MSI) or loss of heterozygosity (LOH) were found in Ewing's sarcoma, chondrosarcoma, epithelioid leiomyosarcoma, malignant fibrous histiocytoma, and leiomyoma. Only three patients, one each with liposarcoma, leiomyosarcoma, and synovial sarcoma, manifested MSI, whereas, osteosarcoma, liposarcoma, leiomyosarcoma, rhabdomyosarcoma, and synovial sarcoma manifested LOH, with an incidence of 43%, 14%, 86%, 20%, and 75%, respectively. Interestingly, three patients showed unusual patterns of LOH, probably due to intratumoral heterogeneity. Kaplan-Meier analysis revealed that LOH on 11p was predictive of poor prognosis in osteosarcoma. The low incidence of MSI indicates that MSI is not necessary for neoplastic transformation in sarcomas. However, the very high incidence of LOH in leiomyosarcoma indicates that microsatellite analysis may serve for the differential diagnosis of leiomyosarcoma versus leiomyoma. Microsatellite analysis may also predict prognosis in osteosarcoma.

Adolescent↗
PubMed1997

Expression of interleukin 15 (IL-15) in human rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma.

Interleukin 15 (IL-15) is a recently discovered cytokine that stimulates lymphocyte proliferation and migration via a trimeric receptor sharing the beta and gamma signal transducing chains with the IL-2 receptor. IL-15 is typically produced by normal cells that do not release IL-2, but little information is currently available on human tumors. To assess whether human musculo-skeletal sarcomas produce IL-15, we analyzed surgical specimens and cell lines obtained from rhabdomyosarcoma, osteosarcoma and Ewing's sarcoma. IL-15 mRNA was present in 9/9 surgical specimens (3 Ewing's sarcomas, 5 osteosarcomas and 1 rhabdomyosarcoma). The analysis of a panel of cell lines (7 derived from Ewing's sarcoma, 12 from osteosarcoma and 5 from rhabdomyosarcoma) showed that all rhabdomyosarcoma and osteosarcoma cell lines expressed IL-15 mRNA at levels ranging from low to high, while Ewing's sarcoma cells contained little or no IL-15 message. ELISA assays showed IL-15 release in a subset of rhabdomyosarcomas and osteosarcomas, but not in Ewing's sarcoma. The highest production of IL-15, in the picogram/ml range, was found in rhabdomyosarcoma cell lines RH30 and RD.

Enzyme-Linked Immunosorbent Assay↗
PubMed1989

Antibodies detecting abnormalities of the retinoblastoma susceptibility gene product (pp110RB) in osteosarcomas and synovial sarcomas.

The retinoblastoma (RB) susceptibility gene is one member of a putative "cancer suppressor gene" family in which loss of gene function is associated with tumor formation. Using antibodies generated against a trypE-RB fusion protein, we previously identified a nuclear phosphoprotein, pp110RB, as the RB gene product. Here we describe three additional polyclonal antibodies that were generated to separate epitopes of pp110RB with three synthetic peptides deduced from the RB cDNA sequence. All four antibodies could specifically recognize the same phosphoprotein in human cells. This protein was phosphorylated on serine and threonine, but not tyrosine, residues. RB homologous proteins with molecular masses of 105-128 kD were detected in other vertebrates, such as monkey, rodent, and chicken, by at least two antibodies, indicating evolutionary conservation of the RB gene. These antibodies were specific and sensitive for monitoring RB gene inactivation as demonstrated by screening several osteosarcoma and synovial sarcoma cell lines. Of nine cell lines examined, three expressed no immunoprecipitable normal RB protein. DNA rearrangement and abnormal RB mRNA were detected in two of these three cell lines, whereas RB protein was absent from one synovial sarcoma cell line in which normal-sized RB mRNA was clearly present. Therefore, direct immunoprecipitation of RB protein can reveal RB gene mutations that are undetectable by DNA and mRNA analysis. These results further support a crucial role for the RB gene in the oncogenesis of some mesenchymal tumors.

Amino Acid Sequence↗
PubMed1990

[The effect of CdCl2 and ZnCl2 on Dunn osteosarcoma].

Three murine sarcoma cells (Dunn osteosarcoma, Gunma clone-4, Sarcoma 1509a) were cultured for four days at various concentrations of CdCl2 or ZnCl2 and assayed for their viability. Dunn osteosarcoma was more sensitive to CdCl2 and less sensitive to ZnCl2 than the others. CdCl2 and ZnCl2 were weekly administered to C3H/He mice intraperitoneally from three days after the inoculation of Dunn osteosarcoma. The size of the tumors was measured twice a week for five weeks. CdCl2 suppressed the growth of the tumor, whereas ZnCl2 did not. These results suggest that CdCl2 has antitumor activity, especially against osteosarcoma.

Animals↗
PubMed1987

[Surgical tactics in malignant bone tumors].

In treating bone sarcomas two principles apply: 1) Oncologically radical removal of the tumor. 2) Maximum functional preservation and/or restoration of the extremity. Modern chemotherapy has clearly improved the prognosis for some sarcomas (e.g. osteosarcoma, Ewing's sarcoma), justifying even extensive surgery and lengthy rehabilitation. Primary malignant bone tumors are fairly rare. To optimize therapeutical results, supraregional and interdisciplinary treatment centers have to be established.

Bone Neoplasms↗
PubMed2002

High-dose chemotherapy in the treatment of relapsed osteosarcoma: an Italian sarcoma group study.

PURPOSE: To study the feasibility and activity of two courses of high-dose chemotherapy (HDCT) in patients with osteosarcoma in metastatic relapse. PATIENTS AND METHODS: Patients with high-grade osteosarcoma in metastatic relapse (multiple metastases or solitary metastasis at intervals of less than 30 months) were eligible for study. High-dose chemotherapy consisted of carboplatin and etoposide followed by stem-cell rescue. A second course was planned 4 to 6 weeks after the first. Surgery was performed before or after HDCT. RESULTS: Thirty-two patients were enrolled onto the study. At the end of the treatment, 25 patients were in complete remission (CR), six were alive with disease progression, and one died of toxicity. At present, 14 patients are alive with a median survival time of 23 months from study entry: four are in first CR, three are in second CR, and one is in fourth CR. Six patients are alive with disease. Eighteen patients (56%) died: 17 of disease and one of toxicity. Transplantation-related mortality was 3.1%. The relapse or progression disease rate was 84.4%. The 3-year overall survival rate is 20% and the 3-year disease-free survival rate is 12%. CONCLUSION: HDCT combined with surgery is feasible and can induce CR in a large portion of patients. Two points, however, need to be considered: only patients who are chemosensitive to induction treatment can obtain CR after HDCT, and the length of remission is short, because most patients relapse. Thus novel strategies are needed to maintain the remission status or to treat patients who do not respond to induction treatment.

Adolescent↗