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PubMed1982

Phase II evaluation of dibromodulcitol, ICRF-159, and maytansine for sarcomas.

Patients with objectively measurable soft tissue sarcomas, osteosarcomas, chondrosarcomas, and mesotheliomas were treated with dibromodulcitol (DBD) (180 mg/m2 p.o. days 1-10 q4 wks.). ICRF-159 (300 mg/m2 p.o. tid days 1-3 q4 wks), or maytansine (MAYT) (1.5 mg/m2 I.V. q3 wks.). Forty-five evaluable patients received DBD, 47 MAYT, and 37 ICRF-159. Only patients who had had their histopathologic diagnoses confirmed by a pathology reference panel were included in the final analysis. Two patients had objective partial responses: a patient with osteosarcoma who responded to DBD and a patient with fibrosarcoma who had a partial response of brief duration to ICRF-159. Approximately 70% of the patients treated with each drug were of ECOG performance status 0 or 1, and over half had moderate or worse toxicity. It seems unlikely that these drugs have significant therapeutic activity for common mesenchymal malignancies.

Adolescent↗

PubMed2004

Osteosarcoma and Ewing's sarcoma in children and adolescents: retrospective clinicopathological study.

AIM: Almost 20 different prognostic factors have so far been investigated in childhood bone tumors, but apart from clinical stage the results have been inconclusive. We evaluated possible prognostic factors of malignant bone tumors in children and adolescents. METHODS: Seventy children and adolescents, who have been treated for bone sarcomas (36 with osteosarcoma and 34 with Ewing's sarcoma) at the Children's Hospital in Zagreb and the Orthopedic Clinic of the Zagreb University School of Medicine were included in the study. We analyzed 9 variables: clinical stage, patient age and sex, tumor size and location, location of metastases, chemotherapy response, concentration of lactate dehydrogenase (LDH) and erythrocyte sedimentation rate (ESR), and chondroid differentiation in osteosarcoma. RESULTS: The clinical stage was the most important prognostic factor for both type of tumors. Lactate dehydrogenase in patients with Ewing's sarcoma (p=0.033) and in patients with osteosarcoma (p=0.015) as well as erythrocyte sedimentation rate (p<0.001 and p=0.014, respectively) may also be of predictive value. CONCLUSION: Elevated erythrocyte sedimentation rate and high LDH concentration seem to be of importance in both Ewing's sarcoma and osteosarcoma, regardless of their different pathogenesis or pathohistology.

Adolescent↗

PubMed2005

Antitumor activity of the insulin-like growth factor-I receptor kinase inhibitor NVP-AEW541 in musculoskeletal tumors.

Identification of new drugs is strongly needed for sarcomas. Insulin-like growth factor-I receptor (IGF-IR) was found to provide a major contribution to the malignant behavior of these tumors, therefore representing a very promising therapeutic target. In this study, we analyzed the therapeutic potential of a novel kinase inhibitor of IGF-IR, NVP-AEW541, in Ewing's sarcoma, osteosarcoma, and rhabdomyosarcoma, the three most frequent solid tumors in children and adolescents. NVP-AEW541 inhibits IGF-I-mediated receptor activation and downstream signaling. Ewing's sarcoma cells were generally found to be more sensitive to the effects of this drug compared with rhabdomyosarcoma and osteosarcoma, in agreement with the high dependency of this neoplasm to IGF-IR signaling. NVP-AEW541 induced a G1 cell cycle block in all cells tested, whereas apoptosis was observed only in those cells that show a high level of sensitivity. Concurrent exposure of cells to NVP-AEW541 and other chemotherapeutic agents resulted in positive interactions with vincristine, actinomycin D, and ifosfamide and subadditive effects with doxorubicin and cisplatin. Accordingly, combined treatment with NVP-AEW541 and vincristine significantly inhibited tumor growth of Ewing's sarcoma xenografts in nude mice. Therefore, results encourage inclusion of this drug especially in the treatment of patients with Ewing's sarcoma. For the broadest applicability and best efficacy in sarcomas, NVP-AEW541 may be combined with vincristine, actinomycin D, and ifosfamide, three major drugs in the treatment of sarcomas.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1990

Detailed investigation of the diagnostic value in tumour histopathology of ICR.2, a new monoclonal antibody to epithelial membrane antigen.

The production and detailed immunostaining properties of a new rat monoclonal antibody (ICR.2) to epithelial membrane antigen are reported. The antibody was selected for its ability to compete with the polyclonal antiserum (M7), used in the original immunohistological studies, in order that it might serve as a direct replacement in diagnosing epithelial tumours. Most of the staining reactions on normal tissues were identical to those previously reported with M7 but there were some important differences. They included: positivity of renal and adrenal capsular fibroblasts, perineurium, some myoepithelial and smooth muscle cells, occasional osteoblasts and squamous and thyroid follicular epithelium in the normal state. The intercellular canaliculi of sweat glands and secretory canaliculi of gastric oxyntic cells were clearly demonstrated. These staining reactions could be obtained with M7 when a sensitive detection system was used although the results were usually weak and inconsistent. Nearly all adenosquamous and transitional carcinomas were positive. The remaining tumours fell into three major groups: (1) those which were consistently or nearly consistently negative--melanoma, seminoma, rhabdomyosarcoma, alveolar soft part sarcoma, adrenal cortical carcinoma, granulocytic sarcoma, paraganglioma, non-Hodgkin's lymphoma. Hodgkin's disease and embryonal carcinoma: (2) those which were either negative or positive with distinctive patterns of staining--basal cell carcinoma, embryonal tumours: and (3) non-epithelial tumours that were consistently positive--epithelioid sarcoma, synovial sarcoma, osteosarcoma, chordoma and myeloma--or positive in a significant minority of cases--leiomyosarcoma, malignant fibrous histiocytoma, clear cell sarcoma of tendon sheath, various neuroectodermal tumours.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

Imaging evaluation of the response of high-grade osteosarcoma and Ewing sarcoma to chemotherapy with emphasis on dynamic contrast-enhanced magnetic resonance imaging.

Response of high-grade osteosarcoma and Ewing sarcoma to preoperative chemotherapy can significantly affect the surgical approach to patients with these tumors and their disease-free survival. This article presents the findings and limitations of different imaging modalities (radiography, angiography, sonography, scintigraphy, and magnetic resonance [MR] imaging and spectroscopy) for evaluating this chemotherapeutic response. Particular emphasis is given to the currently most effective modality--dynamic contrast-enhanced MR imaging.

Antineoplastic Agents↗

PubMed1988

Malignant disease in the mothers of children with Ewing's tumour.

Previous research has shown that mothers of children with soft tissue sarcoma, osteosarcoma, and chondrosarcoma are at excess risk of developing breast cancer. The occurrence of malignant disease in the mothers of a population-based series of children with Ewing's sarcoma was investigated in order to determine whether these mothers were at excess risk of cancer and of breast cancer in particular. Sixty-one mothers were traced; there were two cases of breast cancer and two other registrable neoplasms. Risk of malignancy in the mothers was not in excess of expectation.

Adult↗

PubMed2000

Osteogenic sarcoma and phthisis bulbi: a case report.

PURPOSE: To describe a case of osteogenic sarcoma (osteosarcoma) that developed within a phthisical eye. METHOD: Case report. RESULTS: An 86-year-old woman with a 20-year history of phthisis bulbi developed pain and proptosis. Tumor was identified by computed tomography. An exenteration was performed, and osteogenic sarcoma was identified. CONCLUSION: Osteogenic sarcoma is the most common primary malignant tumor of bone. In the orbit it frequently is associated with prior irradiation for retinoblastoma. We describe the first case of osteogenic sarcoma that developed de novo from bone within a phthisical eye.

Aged↗

PubMed2001

Relative frequency and morphology of cancers in carriers of germline TP53 mutations.

The spectrum and frequency of cancers associated with germline TP53 mutations are uncertain. To address this issue a cohort of individuals from 28 families with Li-Fraumeni syndrome, segregating germline TP53 mutations was established. Predicted cancers were estimated by applying age, morphology, site and sex-specific UK cancer statistics to person-years at risk. Observed and predicted cancers were compared and two-sided P-values calculated. Cancer types occurring to excess and showing P-values <0.02, were designated strongly associated with germline TP53 mutations. These were removed from the data and a second round of analyses performed. Cancer types with P-values <0.02 and 0.02-0.05 in the second round analyses were considered moderately and weakly associated respectively. Strongly associated cancers were: breast carcinoma, soft tissue sarcomas, osteosarcoma, brain tumours, adrenocortical carcinoma, Wilms' tumour and phyllodes tumour. Carcinoma of pancreas was moderately associated. Leukaemia and neuroblastoma were weakly associated. Other common carcinomas including lung, colon, bladder, prostate, cervix and ovary did not occur to excess. Although breast carcinoma and sarcomas were numerically most frequent, the greatest increases relative to general population rates were in adrenocortical carcinoma and phyllodes tumour. We conclude that germline TP53 mutations do not simply increase general cancer risk. There are tissue-specific effects.

Adolescent↗

PubMed2004

High-level expression of the coxsackievirus and adenovirus receptor messenger RNA in osteosarcoma, Ewing's sarcoma, and benign neurogenic tumors among musculoskeletal tumors.

PURPOSE: The sensitivity of human tumor tissues to infection with recombinant adenoviruses correlates with the expression of the coxsackievirus and adenovirus receptor (CAR). CAR has been shown to function as the primary receptor for adenoviruses and to play a critical role in adenovirus entry into host cells. It is important for clinical gene therapy to determine the expression level of CAR in tumor tissues. EXPERIMENTAL DESIGN: We analyzed the expression of CAR mRNA in 154 musculoskeletal tumor tissues from 154 patients and 10 normal mesenchymal tissues from 3 patients using reverse transcription-PCR and real-time quantitative PCR. An adenovirus infection assay was performed in two cell lines that were established from CAR-positive osteosarcoma tissue and CAR-negative malignant fibrous histiocytoma tissue. RESULTS: Ninety-nine of 154 tumors were detected as CAR positive by reverse transcription-PCR. We found that the expression levels of CAR mRNA varied markedly between different tumors as determined by real-time quantitative PCR. CAR mRNA was expressed at high levels in osteosarcoma, Ewing's sarcoma, neurofibroma, and schwannoma; at intermediate levels in exostosis, giant cell tumor, liposarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, and hemangioma; and at low levels in alveolar soft part sarcoma and desmoid. Whereas the osteosarcoma cell line that expressed a high level of CAR mRNA, like its parent tumor, had a high efficiency of adenovirus infection, the malignant fibrous histiocytoma cell line with almost undetectable expression of CAR mRNA, like its parent tumor, had a low efficiency of infection. CONCLUSIONS: Our data showed the great variations in CAR mRNA expression among human musculoskeletal tumors and mesenchymal tissues and implicated the potential usefulness of adenoviral vectors in gene therapy for osteosarcoma, Ewing's sarcoma, neurofibroma, and schwannoma. Efficient transduction with adenovirus for gene therapy could be realized in appropriate, sensitive tumor types.

Adenoviridae↗

PubMed1976

Evaluation of forequarter amputation in malignant diseases.

Twenty-one forequarter amputations were performed at our institute during a 15 year period for soft tissue sarcoma, osteosarcoma, recurrent malignant melanoma and epidermoid carcinoma. Two patients in this group who have had recurrent carcinoma of the breast with a painful, edematous and ulcerated upper extremity were palliated and had significant relief. The over-all five year survival rate following this procedure for curative intent was 25 per cent. There were no five year survivors of unclassified sarcoma, myosarcoma and recurrent malignant melanoma. Thus, we do not recommend this procedure for recurrent malignant melanoma, although it can be performed as a palliative measure. Since most of the patients with malignant bone tumors, unclassified sarcoma and myosarcoma have systemic metastasis develop within two to eight months after this procedure, new methods should be explored to detect early metastasis before undertaking this psychologically traumatic procedure. Adjuvant chemotherapy and other modalities of adjuvant therapies are recommended in this group with poor prognosis. A local recurrence after this amputation in patients with unclassified lesions and myosarcoma should be considered as an indication of systemic metastasis.

Adolescent↗

PubMed1990

Status report of fast neutron therapy in the Department of Radiotherapy at the University Hospital Hamburg-Eppendorf.

Since 1976 710 patients were treated with fast neutrons at the University Hospital Hamburg-Eppendorf. Since January 1984 154 patients with soft tissue sarcomas (250 patients with soft tissue sarcomas since 1976), 20 patients with advanced and low grade tumors of the paranasal sinuses and 43 patients with adenoid cystic carcinomas were treated with fast neutrons. Our results and reports from several centers indicate a gain from fast neutron therapy for low grade soft tissue sarcomas, osteosarcomas (G1 and G2), for highly differentiated salivary gland tumors, and some other rare low grade tumors as malignant chordomas, chondrosarcomas, pencil gliomas or desmoid tumors.

Adult↗

PubMed1979

Osteogenic sarcoma: the past, present, and future.

The term osteogenic sarcoma (osteosarcoma) is applied to malignant bone-forming tumors, identifiable by the matrix produced, though the histologic pattern may differ greatly. Ths more cellular (osteolytic) forms of the tumor have the poorer prognosis. Other prognostic factors are 1) site of the primary tumor; 2) duration of symptoms; and 3) extent of disease and tumor size. The site of tumor origin is the metaphyseal side of the epiphyseal line. The histogenesis of the tumors accounts for this distribution. Following a diagnostic biopsy, amputation of the extremities remains the treatment of choice. In selected cases, a limb-saving radical en bloc resection may surface. Radiotherapy plays a lesser but important role as adjunctive treatment, and as primary definitive treatment in certain types of bone sarcoma (Ewing sarcoma and primary reticulum cell sarcoma of bone). Until recently, chemotherapeutic agents have been used for late palliation only. Advances in treatment, however, have resulted from the application of innovative postsurgical adjuvant chemotherapy in children. The various chemotherapeutic regimens following amputation in adults and in children are discussed. In most such series of cases following amputation alone, five-year survivals have not exceeded 15-20%, with recurrent disease appearing within 18 months in fatal cases. Current studies reflect more effective regimens of adjuvant chemotherapy, with improved palliative results in metastatic osteogenic sarcoma. Although survival is much prolonged, however, many patients show a recurrence of the disease after long intervals of control, suggesting that five-year survival may not indicate a complete cure. At M.D. Anderson Hospital, th projected overall survival rate at three years is 79% of all patients with nonmetastatic disease. These results have accrued from the use of Compadri-I and Compadri-II regimens of chemotherapy. More intensive therapy may yield higher survival rates. It is known that the immunologic status of a patient definitely relates to prognosis. Although most of the investigations with immunotherapy are preliminary, emphasis is placed on improving the immune system in immunodeficient patients.

Adolescent↗

PubMed1996

SV40-like sequences in human bone tumors.

Simian virus 40 (SV40) is a monkey virus that induces ependymomas, choroid plexus tumors, mesotheliomas, osteosarcomas, sarcomas and true histiocytic lymphomas when injected in hamsters. Recently, approximately 60% of human ependymomas, choroid plexus tumors and mesotheliomas were reported to contain and express SV40-like sequences (N. Engl. J. Med., 1992, 36, 988-993; Oncogene, 1994, 9, 1781-1790). In this study the presence of SV40-like sequences was investigated in additional types of human tumors. Initially, 200 tumor and normal tissue DNA samples were analysed by polymerase chain reaction (PCR) with primers that amplify a 574 base pair region of SV40 large T antigen (Tag), which includes the Rb-pocket binding domain and the intron of Tag. PCR amplification and Southern blot hybridization with a probe specific for SV40 Tag revealed that 18/200 samples contained SV40-like sequences and, unexpectedly, 11/18 were from patients with osteosarcomas. Additional DNA samples from bone tumors were then analysed. In 40/126 osteosarcomas, and 14/34 other bone-related tumors, Tag sequences could be amplified. Sequence analysis of the DNA amplified from seven different tumors confirmed that the amplified sequences corresponded to SV40 Tag, with some demonstrating deletions in the intron region but not in the Rb-pocket binding domain. The extent of SV40 genome sequences present in the DNA samples was further analysed in two osteosarcomas. PCR amplification, Southern blot hybridization, and sequence analysis revealed that these samples also contained sequences for the carboxy-terminal domain of Tag, the viral regulatory region, and the VP1 capsid protein. These results indicate that SV40-like sequences are present in human bone tumors.

Base Sequence↗

PubMed1989

Genetic analysis of childhood sarcoma.

A survey of cancer in 159 3-year survivors of childhood soft tissue sarcoma and their relatives revealed a cancer excess in first-degree relatives primarily due to cancers occurring before the age of 35 years and a highly significant excess in relatives of patients with second malignant neoplasms. Tumors of soft tissue and bone, breast, and brain were in excess in relatives and as second malignant neoplasms in patients. To determine the most likely explanation for the observed cancer distribution, we applied segregation analysis under a unified version of the mixed model. The observed data were most compatible with a rare autosomal dominant gene with high penetrance (gene carriers had a 50% probability of cancer by age 30, increasing to 90% by age 60) as compared with a chance occurrence or a multifactorial explanation. We contrasted the relative odds of observing each pedigree under a sporadic, multifactorial, or major gene model, and identified 11 pedigrees in which familial clustering of cancer was significant, with the distribution of cancer strongly favoring a major gene in 9 pedigrees. The tumors in these kindreds have been associated with alterations in specific genetic loci by tumor-specific genetic analysis. In particular, we observed soft tissue sarcoma, osteosarcoma and premenopausal ductal breast carcinoma tumors, perhaps attributable to loss of the Rb-1 suppressor gene on chromosome 13q, in the same patients and families. Study of the cancer predisposition segregating in 10 families by genetic linkage with markers of chromosome 13q and the Rb-1 gene have to date given negative LOD scores at 0 = 0 of Z = -1.2 to -13.0.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Neoplasms↗

PubMed1998

Abnormalities of the FHIT transcripts in osteosarcoma and Ewing sarcoma.

In a study of FHIT gene abnormalities by reverse transcription-polymerase chain reaction (RT-PCR) and sequence analysis of the PCR products, we found normal and abnormal PCR products in 11 osteosarcomas, one osteosarcoma cell line and 3 Ewing sarcomas, and a normal PCR product only in 5 osteosarcomas and 8 Ewing sarcomas. Sequence analysis of the abnormal PCR products revealed 7 osteosarcomas lacking exons 4 to 6, 7, 8 or 9, two lacking exons 5 to 7 or 10, and two lacking exons 6 to 8 or 10. In the aberrant transcripts of the 11 osteosarcomas, fusion had occurred in the exon/intron junctions in 2 tumors, between a segment within an exon and a complete exon in 3, and between segments within exons in 6. The 3 Ewing sarcomas had lost exon 4 or 5 to exon 6 or 10, and fusion had occurred in the exon/intron junction in one, and between segments within exons in 2. These findings suggest that both abnormal or variant splicing and other mechanisms such as genomic instabilities in the FHIT locus may have resulted in the expression of aberrant transcripts. One osteosarcoma and one cell line established from this osteosarcoma showed different abnormal FHIT transcripts, indicating that the tumor cells with the initial aberrant transcripts may not have had a selective advantage for proliferation. The FHIT abnormalities did not seem to be correlated with lung metastasis or a poor clinical outcome in our patients with osteosarcoma or Ewing sarcoma.

Acid Anhydride Hydrolases↗

PubMed2004

[Hematogenous osteomyelitis in adults].

Hematogenous osteomyelitis (HOM) in adults is a very rare event in industrialised countries. However, in tropical regions the morbidity of HOM is more important, primarily due to the impact of sickle cell disease, thalassemia, HIV-infection and tuberculosis. HOM is most commonly caused by pyogenic bacteria and mycobacteria, but infections by fungi, viruses and parasites must also be considered. In spite of modern diagnostic procedures such as nuclear and magnetic resonance imaging, the histopathologic and microbiologic examination of bone remains the gold standard for diagnosing OM. Other diagnoses should also be considered. Nonbacterial osteomyelitic lesions (plasmacellular OM, sclerosing OM, SAPHO syndrome) as well as acute leukemia, malignant bone tumors (i.e., Ewing's sarcoma, osteosarcoma) are conditions with similar presentations. Acute HOM is best managed by appropriate antibiotic therapy. In case of failure and in chronic HOM, surgical debridement is mandatory.

AIDS-Related Opportunistic Infections↗

PubMed1995

Antitumour activity and retinotoxicity of ethyldeshydroxy-sparsomycin in mice.

The colony formation in agar of human tumour xenografts was used as a test system to study the cytostatic activity of ethyldeshydroxy-sparsomycin (EdSm) at the cellular level. EdSm was additionally studied in vivo in human tumour xenografts and murine tumour models. EdSm showed a clear dose-response effect in vitro. At continuous exposure with 0.01 micrograms/ml, 2 out of 11 of the tumours responded (a gastric and a small cell lung carcinoma). At 0.1 mu/ml EdSm, the tumour response was 5/11 tumours and at 1 microgram/ml the compound was active in all tumours. The maximal tolerable doses of EdSm in vivo have been determined in non-tumour bearing CDF1 mice. In the intraperitoneally (i.p.) given multiple dose schedules the respective LD10 doses indicated that the tolerable cumulative dose increases when lower doses are given more frequently. This also enhances the antitumour activity in L1210 leukaemia to 172% T/C. On the other hand, continuous infusion strongly diminished the tolerable dose as well as the antitumour activity. EdSm was also active against i.p. inoculated P388 leukaemia (150% T/C), B16 melanoma (156% T/C), and RC carcinoma (197% T/C), and the subcutaneously (s.c.) inoculated L1210 (139% T/C) and RC (138% T/C). Absence of tumour responses was found in the following s.c. implanted murine tumours: M5076 sarcoma, osteosarcomas C22LR and CP369, and the LL carcinoma, as well as in the human tumour xenografts: LXFG 529, a non-small cell lung carcinoma; GXF 251, a gastric carcinoma; and FMa, an ovary carcinoma. Possible long-range retinotoxic effects of EdSm were investigated in tumour-bearing mice, cured after surviving treatment with LD50 doses of EdSm, by assaying the protein biosynthetic capacity of the retinal by assaying the ocular rhodopsin and opsin levels as parameters. In none of these cases could a significant reduction in either opsin or rhodopsin levels be measured and no changes were seen histologically.

Animals↗

PubMed1983

The usefulness of percutaneous fine-needle aspiration biopsy in infants and children.

During the past 2 years percutaneous fine-needle aspiration biopsy has been employed to help establish or confirm diagnosis in 32 infants and children. A 22-gauge needle is used to aspirate the site of suspected disease. For lesions inside the chest or abdomen, the needle is guided with the help of fluoroscopy, ultrasound, or computed tomography (CT) scan. Nineteen of the 32 patients had malignant disease, including lymphoma, neuroblastoma, rhabdomyosarcoma, Ewing's sarcoma, osteosarcoma, and leukemia. In all patients with solid tumors, tissue obtained at operation confirmed the accuracy of the diagnosis. In seven children with suspiciously enlarged lymph nodes, an open biopsy was avoided when the needle aspirate was clearly benign. In four children, the early appearance of metastatic or recurrent malignancy was confirmed without the need for open biopsy. In this small series, there were no false-negative or false-positive needle aspirates, and no complications directly related to the procedure. The skill and experience of the cytopathologist is essential to the success of this technique. Percutaneous fine-needle aspiration biopsy is a safe and reliable alternative method of establishing a diagnosis in infants and children with suspected malignant disease.

Adolescent↗