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Biomedical subjects

M C Gebhardt

Publications and source records attributed to M C Gebhardt.

At least 55 records · Page 3Linked to original sources
PubMed1997

Scintigraphy of lower extremity cadaveric bone allografts in osteosarcoma patients.

PURPOSE: To describe scintigraphic characteristics of bone allografts used in limb salvage reconstruction after resection of lower extremity osteosarcoma. MATERIALS AND METHODS: The authors reviewed 85 skeletal scintigrams of 20 pediatric patients followed up for 0.5-5.7 years after resection of lower extremity osteosarcoma and allograft reconstruction. Uptake in the allograft and adjacent host tissues was assessed visually. RESULTS: Lack of tracer uptake in the allografts was seen in 99% of the studies and a faint rim of tracer localization outlining the allograft's periphery was seen in 95% of the studies. Increased uptake was noted at the allograft-host bone junction in 78% of the studies. Uptake was increased in the joint surfaces of native bones articulating with allografts (97% of studies), including the patella (93% of studies) when the knee was involved. These findings were stabilized as time passed. CONCLUSION: Cadaveric bone allografts have a characteristic scintigraphic appearance in this selected patient group that reflects the physiology of their incorporation process.

Adolescent↗
PubMed1997

The results of transplantation of intercalary allografts after resection of tumors. A long-term follow-up study.

We reviewed the results of 104 intercalary allograft procedures that had been performed, between April 1974 and August 1992, in 100 patients, usually after resection of a segment of bone because of an osseous neoplasm. The median duration of follow-up was 5.6 years. Retention of the graft and return to essentially normal function were the measures of success and, on that basis, eighty-seven (84 per cent) of the 104 reconstructions were successful. Of the fifteen limbs in which the reconstruction failed, four were salvaged with insertion of a second allograft and three, with use of some other technique. Of the 104 allograft procedures, eight (including two in patients who had a recurrent tumor) were followed by an amputation; thus, the ultimate rate of salvage was 92 per cent for the entire series. Thirty-one grafts failed to unite at one junction with the host or both, within one year after the operation, and this necessitated eighty-one additional operative procedures to achieve a good result. Life-table regression analysis showed that age, gender, anatomical site, and length of the graft were not associated with significant differences in the over-all outcome. Infection (p = 0.0001); fracture (p = 0.002); stage of the lesion (p = 0.007); and use of adjuvant chemotherapy or radiation, or both (p = 0.008), all had an adverse effect on the survival of the allograft. Despite the relatively high rate of non-union that necessitated additional operations, these data indicate that transplantation of allografts for the treatment of intercalary defects has a high rate of success and usually results in a functional limb.

Adolescent↗
PubMed1997

Prognostic factors for local control of sarcomas of the soft tissues managed by radiation and surgery.

During the past decade, local control of primary sarcomas of the extremities by radiation and conservative surgery has supplanted more radical compartmental resections or amputations. Reviews of others and our published data show that the probability of achieving local control is highly dependent on achieving negative surgical margins. Other factors, such as pathological grade and size, histopathology, and concomitant chemotherapy may also affect local control, to a much lesser extent, although these are strongly correlated with the likelihood of distant metastatic disease. Appreciation of the importance of these different prognostic factors has been fundamental to the development of the current rationale for sarcoma management.

Antineoplastic Agents↗
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↗
PubMed1996

P-glycoprotein is expressed in the mineralizing regions of the skeleton.

Using oligonucleotide primers specific for the human MDR 1 gene, we were able to identify a specific amplicon using RT-PCR from total bovine growth plate chondrocyte RNA. The identification of MDR mRNA in growth plate chondrocytes led us to examine the precise distribution of MDR P-glycoprotein in bone and cartilage. We applied two monoclonal antibodies (C219 and C494) to human fetal, neonatal, and childhood growth plates and bone. In growth plates, P-glycoprotein was detected at high levels in a perilacunar distribution in the calcifying zone and at lower levels in hypertrophic, but not proliferative or reserve zone, chondrocytes. P-glycoprotein was also observed in perichondrial chondrocytes, in perivascular chondrocytes and matrix in the fetal cartilage anlage, and in osteoblasts and the surface osteoid matrix of newly formed bone trabeculae in the primary spongiosa. The recently described chloride channel of P-glycoprotein suggests a potential role of P-glycoprotein in growth plate chondrocyte hypertrophy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Long-term results of allograft replacement in the management of bone tumors.

Over the past 24 years, the authors have implanted >870 massive frozen cadaveric allografts mostly for the treatment of defects created by the resection of a bone tumor. Most of the grafts were obtained from the authors' institutional bone bank. The results show that only stage and type of graft affected outcome predictably. Specifically, grafts for a Stage 2 or Stage 3 tumor had a poorer outcome than those for Stages 0 and 1. The results for allograft arthrodeses were considerably poorer than osteoarticular, intercalary, and allograft plus prosthesis. The other major factors in results were complications--recurrence, infection, fracture, and nonunion--with the former 2 having a profound negative effect on outcome. After the first year of susceptibility to infection (10%) and the third year of increased risk of fracture (19%), the grafts become stable, and approximately 75% are retained by patients and are considered to be successful for >20 years after implantation. Osteoarthritis becomes a problem at approximately 6 years for osteoarticular grafts, and so far, 16% of the patients with distal femoral, proximal tibial, or proximal femoral grafts have required total joint replacements. Although the current results are adequate, they are imperfect, and research should be directed at improving the results.

Adolescent↗
PubMed1996

Experimental models for the study of drug resistance in osteosarcoma: P-glycoprotein-positive, murine osteosarcoma cell lines.

P-glycoprotein is an adenosine triphosphate-dependent drug-efflux pump that extrudes drugs from cells and causes drug-resistance. P-glycoprotein is believed to mediate drug-resistance in a wide variety of tumors. In this study, we developed two P-glycoprotein-positive, murine osteosarcoma cell lines that were resistant to Adriamycin (doxorubicin) (MOS/ADR1 and MOS/ADR2). We created the cell lines by short-term pulse exposures of the parent cell line to Adriamycin followed by single-cell cloning. The MOS/ADR1 and MOS/ADR2 cells were sevenfold and eighteenfold more resistant to Adriamycin than the cells from the parent line. Expression of P-glycoprotein, as examined with an immunofluorescence method, was detected in most of the MOS/ADR1 and MOS/ADR2 cells but not in the parent cells. After the cells had been incubated with Adriamycin for one hour, there was less accumulation of the drug in the resistant cell lines than in the parent cell line. The reduced accumulation was due to the increased efflux of Adriamycin. The Adriamycin-resistant cell lines demonstrated greater alkaline phosphatase activity than the parent cell line and produced more differentiated osteoblastic sarcomas in mice. Dose survival studies with use of a tetrazolium colorimetric assay showed that the MOS/ADR1 cells were cross-resistant to vincristine, vinblastine, etoposide, bleomycin, mitomycin C, and actinomycin D but not to dacarbazine, cisplatin, carboplatin, cytosine arabinoside, carmustine, cyclophosphamide, ifosfamide, methotrexate, and 5-fluorouracil. Although the MOS/ADR2 cells exhibited a similar spectrum of cross-resistance, they were more resistant than the MOS/ADR1 cells. We also tested the effect of three different resistance-modifying agents on the reversal of resistance to Adriamycin. We found that verapamil and trifluoperazine substantially reversed resistance to Adriamycin in the P-glycoprotein positive cell lines, whereas cyclosporin A was relatively ineffective. Because these cell lines retain the histological and biochemical features of bone-producing sarcomas and display the multidrug-resistant phenotype, they may be useful models for additional investigations of drug resistance in osteosarcoma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Molecular biology of sarcomas.

There has been a virtual explosion of information relating to the biology of sarcomas with which we as orthopaedists deal. Much more is yet to be learned. These findings will teach us more about the etiology of these tumors. More important, the findings will alter the way in which these tumors are treated. It is unlikely that we will continue to treat osteosarcoma or Ewing's sarcoma patients with currently available drug regimens and surgery or make treatment decisions based on the histologic classification of tumors we know today. If we are to remain active in the management of these patients we must be aware of the findings as they occur. That will ensure both that we remain the primary caretakers of these patients, and that we will continue to be stimulated intellectually by these intriguing scientific investigations.

Chromosome Aberrations↗
PubMed1996

Pediatric musculoskeletal neoplasms. Evaluation with MR imaging.

MR imaging is an essential tool for the evaluation of musculoskeletal neoplasms in children. It provides useful information for diagnosis, determination of extent of disease, assessment of response to treatment, and detection of complications and effects of therapy. This article reviews the current role of MR imaging in each of these situations. A protocol for the evaluation of these lesions is suggested. Also addressed are issues related to differentiating pathologic conditions, normal marrow, and cartilaginous structures of the pediatric skeleton.

Bone Neoplasms↗
PubMed1995

Transforming growth factor-beta: possible roles in Dupuytren's contracture.

Transforming growth factor-beta (TGF-beta) is a multifunctional polypeptide that stimulates extracellular matrix deposition and fibroblast proliferation. Because both these features characterize Dupuytren's contracture, we investigated a possible role for TGF-beta in the etiology of this disorder. We studied receptor expression for TGF-beta, effects of TGF-beta 1 on DNA-synthesis, and in vitro production of TGF-beta 1 and TGF-beta 2 in both normal and Dupuytren-derived fibroblasts. We also studied the effects of epidermal growth factor (EGF) on growth of the different cell types. TGF-beta receptor profiles were different between the two cell types, as were TGF-beta 1 and EGF-induced stimulation of cell growth. Both cell types secreted both active and latent TGF-beta. Our results suggest that growth factors such as TGF-beta and EGF may play a role in Dupuytren's contracture.

Adult↗
PubMed1995

p53 overexpression in Ewing's sarcoma/primitive neuroectodermal tumour is an uncommon event.

Aim-To determine the presence of p53 overexpression in Ewing's sarcoma/primitive neuroectodermal tumours (ETs) and to assess whether p53 accumulation has any prognostic value.Methods-From a prospectively compiled database of 76 patients with ETs, suitable tumour tissue was available for 38. The monoclonal antibody pAb1801 was used to detect p53 nuclear protein overexpression. Results-Nuclear staining was detected in the tumours of three (8%) of the 38 patients. Where tumours stained positively, over 10% of the tumour nuclei were postively stained. All three patients whose tumours overexpressed p53 died and in a relatively short time compared with the patients who did not overexpress p53 (mean 3.7 months compared with a mean of 38.7 months in the p53 negative group).Conclusion-Overexpression of p53 in ETs is an uncommon event. Overexpression of p53 has repeatedly been shown to correlate closely with p53 point missense mutations and therefore this oncogenic event appears not to be of primary pathogenic importance in ETs. There is a tentative indication that those uncommon ETs in which p53 overexpression can be detected may be-have more aggressively.

Journal Article↗
PubMed1995

Osteoid osteoma: percutaneous radio-frequency ablation.

PURPOSE: To evaluate a percutaneous technique for in situ destruction of osteoid osteoma. MATERIALS AND METHODS: Radio-frequency ablation was performed in 18 patients with osteoid osteoma (17 male, one female; age range, 8-42 years). Diagnosis was established by means of clinical and radiographic features and confirmed by means of needle biopsy findings. No attempt was made to remove the lesion. A small radio-frequency electrode introduced into the lesion through the biopsy track was used to produce thermal necrosis of a 1-cm sphere of tissue. RESULTS: Symptoms were completely relieved in 16 (89%) of 18 patients. In one patient, a second procedure was required for pain relief. All but two patients underwent treatment as outpatients: These two were hospitalized for 1 night only. All patients resumed normal daily activities immediately. No casts or external supports were required; there were no complications. Twelve patients were followed up for more than 1 year. There were no recurrences CONCLUSION: Radio-frequency ablation of osteoid osteoma is a promising alternative to surgery in selected patients.

Activities of Daily Living↗
PubMed1995

Role of surgical resection in pelvic Ewing's sarcoma.

PURPOSE: The improved survival in patients with Ewing's sarcoma over the past two decades has placed increased importance on achievement of local disease control. Ewing's sarcoma that arises in the pelvis has been recognized to have a worse prognosis than that in the appendicular skeleton, and the role of surgical resection in these cases remains controversial. The current study attempts to identify a benefit to surgical resection in these patients. METHODS: We retrospectively examined 39 patients who presented with Ewing's sarcoma in a pelvic location, all of whom were treated systemically with chemotherapy. Twenty patients received radiation only as a means of local control, and 19 underwent resection with or without radiation therapy. The patients were evaluated with end points of disease-free survival and overall survival for a minimum of 24 months and a mean of 58 months. RESULTS: There was an even distribution among patients who underwent surgical resection for local control as compared with those who received only radiation therapy with respect to age, site, date of treatment, and stage of disease. Despite uncontrolled biases including tumor size and response to chemotherapy that would be expected to favor patients who undergo resection, surgery in addition to or in substitution for radiation therapy did not result in a statistically significant increase in disease-free survival or overall survival. Local disease control was comparable between those who underwent resection and those who did not: three patients in each group developed a local recurrence. CONCLUSION: Currently, morbidity of surgical resection should be weighed against the efficacy and secondary complications of radiation therapy in the decision-making process for local disease control. The issue of whether overall survival and local disease control is improved in patients who undergo surgical resection remains controversial and may require a prospective randomized trial to be answered definitively.

Adolescent↗
PubMed1994

Expression of transforming growth factor-beta (TGF-beta) receptors, TGF-beta 1 and TGF-beta 2 production and autocrine growth control in osteosarcoma cells.

Transforming growth factor-beta (TGF-beta) is a polypeptide with multiple physiological functions. Isoforms of this growth factor have important roles in control of the cell cycle, in regulation of cell-cell interactions and in growth and development. Malignant transformation has been shown to be associated with increased expression of TGF-beta. Since bone is the largest storage site and producer of TGF-beta, we speculated on the existence of an autocrine mechanism in osteosarcoma, a malignant bone tumor. Expression of TGF-beta cell surface receptors, effects on growth of TGF-beta and TGF-beta antibodies and production of 2 TGF-beta isoforms were studied in a panel of 7 osteosarcoma cell lines. In contrast to most previous reports on the effects of TGF-beta on osteosarcoma cell growth, we found a mitogenic effect of TGF-beta 1 in 4 of 7 osteosarcoma cell lines. Receptor profiles for TGF-beta were aberrant in 5 of the 7 cell lines tested, and production of TGF-beta 1 and TGF-beta 2 varied among cell lines. Addition of anti-TGF-beta antagonized the effects of endogenous TGF-beta. Our results suggest a potential role of TGF-beta in autocrine growth control of osteosarcoma cells.

Antibodies↗
PubMed1994

An assay to measure adriamycin binding in osteosarcoma cells.

Adjuvant chemotherapy is currently employed in the treatment of patients with osteosarcoma, but the drug regimens, although effective in improving disease-free survival, are unsuccessful in 20-40% of patients and very toxic. It would be useful to know whether tumor cells are sensitive to a given drug prior to its use. To this end, we developed a method of assessing Adriamycin (doxorubicin) binding to tumor nuclei as a possible means of detecting sensitivity to the drug. Adriamycin-sensitive murine osteosarcoma cells were used to develop the assay. The in vitro conditions (drug concentration, duration of incubation, and temperature) were optimized with use of the murine osteosarcoma cells in culture. After the cells had been incubated with Adriamycin, cell viability was determined and Adriamycin fluorescence intensity was measured with a cytofluorometer. The optimal parameters for Adriamycin binding were found to be a 30-minute incubation in a 10 micrograms/ml concentration of Adriamycin at 37 degrees C; the frequency of cells that emitted Adriamycin fluorescence from the nucleus compared with the total number of living cells reached 100% under these conditions. In a murine leukemia cell line with known sensitivity to Adriamycin, the cells emitted red fluorescence from the nucleus and cytoplasm, whereas in a resistant line the cells emitted Adriamycin fluorescence from only the cytoplasm. We demonstrated that it is possible to differentiate nuclear from cytoplasmic concentration of Adriamycin in a tumor cell with use of a fluorescent microscope and that resistant cell lines can be distinguished from sensitive cell lines by this method.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗