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Biomedical subjects

M C Gebhardt

Publications and source records attributed to M C Gebhardt.

At least 73 records · Page 4Linked to original sources
PubMed1994

Secondary breast cancer in patients presenting with osteosarcoma: possible involvement of germline p53 mutations.

Second malignancies following treatment for osteosarcoma are unusual. Breast cancer occurring in patients with osteosarcoma has been reported following therapeutic chest irradiation. We now report three cases of breast cancer occurring in young women who were successfully treated for osteosarcoma. These women had not received therapeutic chest irradiation and in two of the three women there was no family history of breast cancer. Peripheral blood was available for study from one case. Of import, this case demonstrated a germline mutation in exon 7 of the tumor suppressor gene, p53. The mutation was detected by constant denaturing gradient gel electrophoresis and confirmed by DNA sequencing. In this particular patient, inactivation of the p53 gene may be involved in the development of both the first and second malignancy.

Adult↗
PubMed1994

Cytogenetic aberrations in osteosarcomas. Nonrandom deletions, rings, and double-minute chromosomes.

Relatively few karyotypes have been reported from short-term cultures and/or direct harvests of osteosarcomas. We describe clonal aberrations in 17 high-grade osteosarcoma specimens and in one low-grade osteosarcoma. The high-grade osteosarcomas were karyotyped after direct harvest (four cases) or after short-term culture periods of < 1 week (13 cases). Three of these specimens, a primary osteosarcoma and two lung metastases, were from the same patient and shared a number of clonal aberrations. No consistent chromosome translocations were identified in the overall group of high-grade osteosarcomas, but potential nonrandom deletions involved 6q21-->qter, 9p21-->pter, chromosome 10, chromosome 13, 17p12-pter, and chromosome 20. Ring chromosomes were detected in three cases, and double-minute (dmin) chromosomes were detected in six. All high-grade osteosarcomas had numerous nonclonal chromosome aberrations superimposed on complex clonal events. The single low-grade osteosarcoma was characterized by a balanced, nonconstitutional, t(5;10) (p13;p14-15), together with an addition to the short arm of chromosome X. This is the first translocation reported in low-grade osteosarcoma, and the simplicity of the karyotype contrasts strikingly with those in the high-grade osteosarcomas.

Adolescent↗
PubMed1994

Suramin inhibits growth and transforming growth factor-beta 1 (TGF-beta 1) binding in osteosarcoma cell lines.

Autocrine production of growth factors has been shown to be involved in the multistep process of tumorigenesis. The ability of suramin, a polyanionic anti-parasitic drug, to block growth factor-induced cell proliferation makes it a potential antineoplastic drug. We studied the effects of suramin on seven osteosarcoma cell lines. Using clinically achievable concentrations of suramin (50-400 micrograms/ml), we found a time- and dose-dependent inhibition of [3H]thymidine incorporation. We also showed that suramin is able, dose-dependently, to prevent binding of transforming growth factor (TGF)-beta 1 to its receptors. DNA synthesis inhibition by suramin was attenuated by TGF-beta 1 in some cell lines. Two cell lines that were inhibited by TGF-beta 1 were affected similarly by suramin as cell lines that were stimulated by TGF-beta 1. In conclusion, in five out of seven osteosarcoma cell lines, we showed a correlation between inhibition of growth factor-stimulated mitogenesis and binding of TGF-beta 1 to its receptor. Similar effects in TGF-beta 1-inhibited osteosarcoma cell lines suggest involvement of other mechanisms and/or growth factors. However, suramin proves to be a potent inhibitor of osteosarcoma cell proliferation in vitro.

Bone Neoplasms↗
PubMed1994

Recurrence of giant-cell tumors of the long bones after curettage and packing with cement.

The nine-year experience with sixty patients who had had a giant-cell tumor of a long bone was reviewed to determine the rate of recurrence after treatment with curettage and packing with polymethylmethacrylate cement. The demographic characteristics, including the age and sex of the patient and the site of the tumor, were similar to those that have been reported for other large series. An average of four years (range, two to ten years) after the operation, the over-all rate of initial local recurrence was 25 per cent (fifteen of sixty patients). Patients who had had a tumor of the distal aspect of the radius had a higher rate of recurrence (five of ten) than those who had had a tumor of the proximal aspect of the tibia (seven [28 per cent] of twenty-five) or of the distal part of the femur (three [13 per cent] of twenty-three). Higher rates of recurrence were also noted for patients who had had a pathological fracture (three of six), those who had had a Stage-III tumor according to the classification of Campanacci et al. (six of sixteen), and those who had not had adjuvant treatment with either a high-speed burr or phenol (eight of nineteen). Patients who had had an initial recurrence after packing with cement had a low rate of secondary recurrence when the initial recurrence had been treated with a wide resection or a second intralesional procedure (zero of ten and one of five patients, respectively), after an average of three years (range, ten months to eight years). No patient had a multicentric tumor or metastasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Quality of life in osteosarcoma survivors.

Charts of 89 osteosarcoma survivors from Massachusetts General Hospital and The Children's Hospital/Dana Farber Cancer Center, who had received primary treatment more than 1 year previously and had no evidence of disease, were reviewed. Sixty-two patients, mean 12 years from diagnosis, agreed to structured interviews. Rates of psychopathology did not differ significantly from the general population. High distress was noted in 13%. Twenty-three normal progeny had been born postchemotherapy to eight women and the wives of five male patients. One pregnancy was complicated by doxorubicin-induced cardiac toxicity. Only two with previous childhood tumors believed themselves infertile. All felt the effort to save the limb was worthwhile. In most, ongoing pain was mild; phantom pain and neuralgia common. Most survivors were in good mental and physical health with the capacity to bear children.

Adolescent↗
PubMed1993

Screening for TP53 mutations in osteosarcomas using constant denaturant gel electrophoresis (CDGE).

We have previously developed conditions to screen for TP53 point mutations inside the conserved domains II-V of the gene by using constant denaturant gel electrophoresis (CDGE). The present study reports conditions for screening more of the codons in the frequently mutated region exon 5-8 and for detecting mutations in sequences encoding functional domains in the N- and C-terminal part of the protein. The ability of the CDGE technique to detect mutations was studied using controls with known sequence deviations. The resolution power of the technique to separate different types of mutations was tested by using seven different single base pair mutants all residing in a stretch of four base pairs. All mutants were separated from the wild type. The established CDGE screening strategy was then used to look for mutations in DNA from 28 osteosarcomas. Six (21.5%) of the samples were shown to have a TP53 mutation, and the exact characterization was performed by direct sequencing. All of these were within the frequently reported mutated region exon 5-8.

Adolescent↗
PubMed1993

Pediatric bone tumors.

A variety of benign and malignant bone tumors can affect the metabolically active pediatric skeleton. A thorough investigation with pertinent imaging studies can establish an appropriate differential diagnosis and frequently allows distinction between benign and malignant tumors. By using a multidisciplinary approach to the treatment of malignant tumors, a number of advances have been made. Further research is needed to gain more understanding and improve on the remarkable advances of the past 20 years.

Bone Neoplasms↗
PubMed1993

A system for the functional evaluation of reconstructive procedures after surgical treatment of tumors of the musculoskeletal system.

The need for a standardized system of end result reporting of various surgical alternatives after limb salvaging and ablative procedures for musculoskeletal tumors was clearly recognized during the first International Symposium on Limb Salvage (ISOLS) in 1981. During the ensuing four biannual symposia, there has been an ongoing developmental experience with a system extensively field tested in 1989 by the Musculoskeletal Tumor Society (MSTS). This system of functional evaluation has been adopted by the MSTS and ISOLS for their joint studies and program presentation. In brief, the system assigns numerical values (0-5) for each of six categories: pain, and function and emotional acceptance in upper and lower extremities; supports, and walking and gait in the lower extremity; and hand positioning, and dexterity and lifting ability in the upper extremity. Demographic information and a patient satisfaction component is included. A numerical score and percent rating is calculated to allow for comparison of results. The system has been field tested in 220 patients with low (+/-) interobserver variability. It was well accepted by the participants, and its usage is recommended by the MSTS to facilitate valid comparative end result studies of musculoskeletal tumor reconstructions.

Activities of Daily Living↗
PubMed1992

Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms.

BACKGROUND: Acquired mutations in the p53 tumor-suppressor gene have been detected in several human cancers, including colon, breast, and lung cancer. Inherited mutations (transmitted through the germline) of this gene can underlie the Li-Fraumeni syndrome, a rare familial association of breast cancer in young women, childhood sarcomas, and other malignant neoplasms. We investigated the possibility that p53 mutations in the germline are associated with second primary cancers that arise in children and young adults who would not be considered as belonging to Li-Fraumeni families. METHODS: Genomic DNA was extracted from the blood leukocytes of 59 children and young adults with a second primary cancer. The polymerase chain reaction, in combination with denaturant-gel electrophoresis and sequencing, was used to identify p53 gene mutations. RESULTS: Mutations of p53 that changed the predicted amino acid sequence were identified in leukocyte DNA from 4 of the 59 patients (6.8 percent). In three cases, the mutations were identical to ones previously found in the p53 gene. The fourth mutation was the first germline mutation to be identified in exon 9, at codon 325. Analysis of leukocyte DNA from close relatives of three of the patients indicated that the mutations were inherited, but cancer had developed in only one parent at the start of the study. CONCLUSIONS: These findings identify an important subgroup of young patients with cancer who carry germline mutations in the p53 tumor-suppressor gene but whose family histories are not indicative of the Li-Fraumeni syndrome. The early detection of such mutations would be useful not only in treating these patients, but also in identifying family members who may be at high risk for the development of tumors.

Adolescent↗
PubMed1992

No alterations in exon 21 of the RB1 gene in sarcomas and carcinomas of the breast, colon, and lung.

Studies of mutant genotypes of the retinoblastoma susceptibility gene (RB1) in different solid tumors have mainly been concentrated on the demonstration of loss of heterozygosity (LOH) at both internal and external polymorphic sites. One reason for this is the complex organization of the gene. The p105RB protein has been shown to interact with both DNA and regulatory cellular proteins and oncoproteins. The amino acids encoded by exon 21 are implicated in several of these interactions. Both point mutations and intragenic deletions involving exon 21 have previously been reported in human tumors. We have examined RB1 exon 21 from a number of human tumor types where significant LOH in or around the RB1 gene has been reported. DNA from 78 primary tumors was amplified using the polymerase chain reaction (PCR) with primers covering exon 21, followed by constant denaturant gel electrophoresis (CDGE). The 78 tumors included 11 breast carcinomas, 30 nonsmall cell lung carcinomas, 6 colon carcinomas, and 31 sarcomas. The small cell lung cancer cell line NCI-H209, previously shown to harbour a point mutation in codon 706: TGT- greater than TTT (Cys- greater than Phe), was detected using CDGE. Apart from this control mutant cell line, we did not detect any mutations in the examined region in any of the tumors.

Base Sequence↗
PubMed1992

Current status of allografting for bone tumors.

Over the past 20 years the Orthopaedic Oncology Unit of the Massachusetts General Hospital has performed over 660 massive cadaveric allograft transplantations, mostly for patients with bone tumors. The overall success rate for such procedures is around 80%, with most of the failures occurring in the first 3 years as a result of fracture (19%), nonunion (14%), and infection (10%). With longer follow up, late occurring osteoarthritis has been noted in approximately 17% of those patients at risk, suggesting that the articular surface begins to "wear" at 5 years. Some problems remain with the procedure, and more study of such aspects as the immune mechanism, cryopreservation of cartilage, maintaining the status and safety of the bone banking system, and improving the techniques of surgery ultimately may lead to a more uniform and predictable success rate.

Adolescent↗
PubMed1991

Osteosarcoma in young children.

The clinicopathologic features of osteosarcoma in 12 children younger than 16 years of age treated at The Children's Hospital and Dana-Farber Cancer Institute, Boston, during a 70-year time period are presented. Only one of six children treated before 1972 is a long-term survivor. Four of six children (67%) treated after 1972 are disease-free with an average follow-up of 8.8 years. The year 1972 marked the onset of use of effective chemotherapy in osteosarcoma, namely, high-dose methotrexate and leucovorin rescue. It would appear that the pathologic features and behavior of osteosarcoma in young children is similar to that of osteosarcoma in older children and adolescents. A combination of complete (wide) surgical resection or amputation and aggressive chemotherapy offers the best chance of long-term survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Massive bone allografts for traumatic skeletal defects.

Large bone allograft transplants have been successfully used to reconstruct skeletal defects created by tumor resections and failed arthroplasties, but little has been reported on their use in traumatic defects. Of approximately 500 allograft procedures done at the Massachusetts General Hospital from 1979 to 1988, 11 were done for restoration of traumatic bone loss. The average age of the patients was 30 (range 11 to 71 years), and the location of the defect was the tibia or femur in 10 of the 11 patients studied. Eight osteoarticular grafts (six hemicondylar and two total condylar) and three intercalary grafts were used for six open and five closed fractures. The time from injury to reconstruction averaged 17 months (3 to 96 months). Primary reconstruction was done in three cases and a salvage procedure in eight. Patients were assessed by the operating surgeon and a physical therapist using an evaluation system that considers function, life-style, and emotional acceptance. According to the system, nine patients had excellent or good results (six hemicondylar grafts, three intercalary grafts), one patient had a fair result (total elbow graft), and one patient had failure of a total condylar graft and subsequently required an amputation. This study suggests that large bone allografts are of value in reconstructing traumatic skeletal defects, especially those involving an articular surface in a young patient.

Adolescent↗
PubMed1991

In vitro assay of nuclear uptake of doxorubicin hydrochloride in osteosarcoma cells of dogs.

A rapid, simple chemosensitivity assay, assessing tumor cell nuclear uptake of doxorubicin hydrochloride, was evaluated in 16 dogs with appendicular osteosarcoma. Doxorubicin was administered to dogs in 5 biweekly treatments, and surgical resection was performed after the second or third treatment. The chemosensitivity assay was performed on biopsy specimens from all dogs before chemotherapy. It was repeated on tissue from resected tumors, and tumors were evaluated histologically to determine the degree of necrosis resulting from chemotherapy. Disease-free and total survival time correlated significantly (P less than 0.05 in both cases) with the degree of postchemotherapy necrosis of the primary tumors. Significant correlation was not apparent between the percentage of tumor cells with nuclear uptake of doxorubicin (in either biopsy or resection samples) and disease-free or total survival time. The percentage of cells with nuclear uptake of doxorubicin in surgically resected tumors correlated significantly (P less than 0.05) with percentage of necrosis.

Animals↗
PubMed1991

Flow cytometric studies of human osteosarcoma.

A number of recent studies have emphasized the potential value of flow cytometry as a "marker" to assess the malignity and therefore to help predict the biologic behavior of neoplasms, including bone tumors. Using propidium iodide and a home-built flow cytometer, the authors have studied the DNA distribution in 95 patients with osteosarcoma and determined the percentage of cells in diploidy, S-phase, tetraploidy, and aneuploidy. Using these values and a derived one, mean DNA concentration, it was possible to demonstrate the extent of the abnormalities observed in this group of neoplasms and show their severity as compared with the normal pattern. When the data are compared against disease-free survival and total survival, correlations were noted that, although weak, suggested that some patterns were predictive of increased risk of metastasis and death. The effect of treatment could also be assessed by evaluating the pattern before and after chemotherapy and correlating these with survival. It seems likely that with some improvement in technology, flow cytometry will be of value in the future in assessing the prognosis for osteosarcoma and predicting whether treatment has been effective.

Adolescent↗
PubMed1991

The use of bone allografts for limb salvage in high-grade extremity osteosarcoma.

Limb preservation is increasingly being employed in the local treatment of high-grade extremity osteosarcoma. Bone allografts used to reconstruct the bony defects following tumor resection offer many advantages, including joint reconstruction and incorporation of the graft to the host bone in these relatively young patients. The results of 53 patients 30 years of age or younger were assessed to determine functional outcome. Fresh-frozen allografts were employed as osteoarticular grafts, allograft-arthrodeses, allograft-prosthesis composites, or intercalary grafts. Follow-up intervals averaged 25 months (range, two to 63 months). Life-table analysis showed that the probability of a satisfactory functional result was 73% if local tumor recurrences were excluded. Complications included 16 infections, six fractures, 12 nonunions, and six unstable joints. There were five local recurrences. Eighteen grafts ultimately failed, and in six patients, this resulted in an above-knee amputation. An additional five received a second graft. The functional "end results" of the 38 patients with two or more years of follow-up examinations were 70% satisfactory in those without a local recurrence. There was no statistically significant difference in functional outcome or local or distant relapse in those patients receiving preoperative chemotherapy. The authors conclude that allografts can be used for limb reconstruction in patients with high-grade osteosarcoma who receive aggressive adjuvant chemotherapy. The functional results are comparable to other methods of reconstruction, and once incorporated by the host, offer the advantage of longevity, compared with metallic implants.

Adolescent↗