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J H Healey

Publications and source records attributed to J H Healey.

At least 73 records · Page 4Linked to original sources
PubMed1997

Molecular analysis of the fusion of EWS to an orphan nuclear receptor gene in extraskeletal myxoid chondrosarcoma.

The pathogenesis of myxoid chondrosarcoma (CS) is poorly understood. A recurrent translocation, t(9;22) (q22;q12), has been recognized in CS, specifically in extraskeletal myxoid CS. Recently, this translocation has been shown to represent a rearrangement of the EWS gene at 22q12 with a novel gene at 9q22 designated CHN (or TEC). Sequence analysis suggests that CHN encodes a novel orphan nuclear receptor with a zinc finger DNA-binding domain. The structure of this gene fusion has been characterized in only a limited number of extraskeletal myxoid CSs and its presence in other types of CS has not been extensively examined. We studied 46 cases of CS (8 extraskeletal myxoid, 4 skeletal myxoid, 4 mesenchymal, and 30 other) for the EWS/CHN gene fusion by reverse transcriptase polymerase chain reaction, Southern blotting, and long-range DNA polymerase chain reaction. The EWS/CHN gene fusion was present in 6 of 8 extraskeletal myxoid CSs and was not detected in any of the remaining cases, including the 4 skeletal myxoid CSs. The negative findings in the latter cases suggest that skeletal myxoid CS is pathogenetically distinct from its extraskeletal counterpart. Notably, 2 cases of extraskeletal myxoid CS showed neither an EWS/CHN fusion transcript nor EWS/CHN genomic fusion nor EWS or CHN genomic rearrangement, suggesting genetic heterogeneity within extraskeletal myxoid CS. Finally, we also provide evidence for alternative splicing of the 3' end of the fusion transcript. Extraskeletal myxoid CS thus represents yet another sarcoma type containing a gene fusion involving EWS.

Adult↗
PubMed1996

Treatment of femoral Ewing's sarcoma.

BACKGROUND: The treatment of Ewing's sarcoma consists of chemotherapy for systemic and local disease. However, the role of radiation therapy, and/or surgical resection for definitive local treatment has yet to be determined. METHODS: A retrospective review of 32 patients (24 males and 8 females) treated for femoral Ewing's sarcoma between 1970 and 1985 was performed. Patients were divided into 3 treatment groups: chemotherapy and radiotherapy (CR) (10); chemotherapy and surgery (CS) (9); and chemotherapy, surgery, and radiotherapy (CSR) (13). Patients in the CR group received a mean of 5320 centigray (cGy) of radiation and patients in the CSR group received a mean of 3590 cGy. Multiagent cyclophosphamide/doxorubicin based chemotherapy was used in all cases. Surgery consisted of wide resection or amputation. RESULTS: Patients in the CR group had a higher risk of local recurrence than patients in the CS and CSR groups (P=0.02, log rank). The combination of local recurrences and treatment complications necessitated surgery for 7 of 10 CR patients, whereas 1 of 9 and 4 of 13 in the CS and CSR groups required additional surgery. The median survival for the entire group was 39 months. Minimum follow-up for surviving patients was 45 months. Five-year survival consisted of 1 of 10 patients in the CR group, 2 of 9 in the CS group, and 7 of 13 in the CSR group. There were no statistically significant differences among the three survival curves. Tumor location within the femur was a significant prognostic variable. Distal femoral location had a survival advantage compared with proximal and mid-femur locations (P = 0.049, log rank). CONCLUSIONS: Femoral Ewing's sarcoma remains a disease with a poor prognosis. Radiation alone for local treatment results in a high rate of local recurrence and complications. Our current local treatment strategy for femoral Ewing's sarcoma includes surgery in all and adjuvant radiotherapy in many of the patients.

Adolescent↗
PubMed1996

A randomized controlled trial of salmon calcitonin to prevent bone loss in corticosteroid-treated temporal arteritis and polymyalgia rheumatica.

Patients treated with high-dose or long-term corticosteroids are at risk of accelerated osteoporosis and spontaneous vertebral and traumatic fractures. To assess the efficacy of salmon calcitonin in preventing corticosteroid- induced osteoporosis, 48 patients with newly diagnosed polymyalgia rheumatica, temporal arteritis, and other vasculitides were enrolled in a 2-year, double-blind, randomized, controlled trial. Patients were randomized to receive subcutaneous injections t.i.w. of either 100 IU of salmon calcitonin (25 patients) or placebo (23 patients). After 2 years, 19 and 21 patients, respectively, were evaluable. All patients also received supplemental calcium carbonate (1500 mg daily in divided doses) and vitamin D3 (400 IU daily). Baseline and serial radiologic assessments included dual-energy X-ray absorptiometry (DXA) of the lumbar spine and hip, and spine radiographs to detect vertebral fractures. There were no significant baseline differences between the two study groups. The mean within-subject percentage change in DXA lumbar spine density in the two groups over the 2-year period of the study was only -0.1% (calcitonin plus calcium) versus -0.2% (placebo plus calcium) a nonsignificant difference despite the high mean cumulative corticosteroid doses of 5371 mg and 4680 mg, respectively (NS). The incidence of vertebral fracture was 12.5% (calcitonin plus calcium: 11%, versus placebo plus calcium: 14%, NS), with four fractures in the first year and one fracture in the second year. Higher cumulative cortico-steroid dose was associated with a greater loss in bone density. In rheumatic disease patients starting high-dose, long-term corticosteroids, salmon calcitonin with calcium and vitamin D3 provided no greater bone preservation than that observed with calcium and vitamin D3 alone.

Absorptiometry, Photon↗
PubMed1995

Clinical reproducibility of dual energy x-ray absorptiometry.

Dual energy x-ray absorptiometry is a technique advocated for the measurement of bone mass throughout the skeleton, and recently it has been used to measure changes in periprosthetic bone mass after joint replacement. The accuracy and precision of the method in clinical patient populations have not been firmly established. This study sought to establish the short-term reproducibility of measurements made with dual energy x-ray absorptiometry of multiple sites in a large sample of elderly patients with rheumatic disease. Reproducibility was assessed in the lumbar spine and in three femoral sites in 69 patients participating in a longitudinal clinical trial. In each patient, absorptiometry was performed twice in the same day at as many as five time points over a 2-year period. The mean (+/- SD) baseline bone density was 0.783 +/- 0.128 g/cm2 for the femoral neck and 1.015 +/- 0.218 g/cm2 for the lumbar spine. The correlations between the duplicate baseline measurements of the spine were excellent (r = 0.9936, p < 0.001) and were stable over the 2-year period; the mean difference between the duplicate baseline measurements was 1.82 +/- 1.54% and the mean coefficient of variation was 1.29%. Measurements in the femur were much less precise; these values were 3.61 +/- 3.14% and 2.55% in the femoral neck, 3.66 +/- 4.35% and 2.59% in the greater trochanter, and 5.28 +/- 5.61% and 3.73% in Ward's triangle. This study evaluated the short-term reproducibility of dual energy x-ray absorptiometry in a clinical population.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorptiometry, Photon↗
PubMed1995

MDM2 and CDK4 gene amplification in Ewing's sarcoma.

Amplification of the MDM2 gene, which maps to chromosome band 12q13 and encodes a p53-binding protein, may result in functional inactivation of p53 and has been observed in various bone and soft tissue sarcomas. Published studies have included few cases of Ewing's sarcoma (ES) or peripheral neuroectodermal tumour (PNET), a tumour group in which alterations of the p53 pathway have so far not been extensively studied. We examined two ES cell lines, RD-ES and SK-ES-1, and 30 specimens from 27 patients (24 ES, 6 PNET; 19 primary, 4 local recurrence, 7 metastasis) for MDM2 gene amplification by Southern blot analysis. All 30 clinical specimens had been confirmed to contain sufficient ES/PNET DNA by the demonstration of a rearrangement of the t(11;22)-associated EWS gene using an EWS cDNA probe on the same blots. MDM2 gene amplification was detected in 3 of 30 specimens (10 per cent), including two ES and one PNET, but in neither of the cell lines. The three cases with amplification were morphologically typical primary tumours. Two of the three cases also showed co-amplification of the CDK4 gene, which encodes a cyclin-dependent kinase and also maps to band 12q13. Clinically, all three cases had metastatic disease at diagnosis, compared with only 1 of 15 MDM2-negative cases where the primary tumour was studied. The difference was statistically significant (P = 0.005), suggesting an association of MDM2 amplification with advanced stage.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Giant cell tumor of the distal radius.

We compared the outcome of patients with giant cell tumor of the distal radius treated by curettage/cryosurgery and en bloc resection, evaluating oncologic success, functional results, and complications. Thirty consecutive cases of giant cell tumor of the distal radius were treated at our institution between 1958 and 1988. Twenty-six patients were available for follow-up examination, with a minimum follow-up period of 3 years and median follow-up period of 9 years. Primary curettage/cryosurgery had a local recurrence in 3 of 12, and repeat curettage/cryosurgery achieved local control in in 16 of 18 primary and recurrent cases. The major complications in this group included skin necrosis, transient nerve palsies, and fragmentation with carpal collapse. An average of 60% of contralateral range of wrist motion was preserved. Ten patients underwent en bloc excision and arthrodesis for either primary or recurrent tumor; none developed local recurrence. The main complication in this group was failure of internal fixation and non-union at the graft-radius junction. Resultant strength and function were similar in both groups. Intralesional excision with adjunctive cryosurgery is an effective alternative to en bloc excision with the advantage of preserving the distal radius and wrist joint function, but with a notable complication rate. En bloc excision with arthrodesis is more suitable for extensive local disease with poor residual bone stock and as salvage for failed intralesional excision.

Adolescent↗
PubMed1995

Very-high-dose short-term chemotherapy for poor-risk peripheral primitive neuroectodermal tumors, including Ewing's sarcoma, in children and young adults.

PURPOSE: To improve the prognosis of patients with poor-risk peripheral primitive neuroectodermal tumors (pPNETs; including peripheral neuroepithelioma and Ewing's sarcoma), while testing the feasibility of intensive use in adolescents and young adults of high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV). PATIENTS AND METHODS: This report concerns previously untreated patients with newly diagnosed pPNET deemed poor-risk because of a tumor volume more than 100 cm3 or metastases to bone or bone marrow. The P6 protocol consists of seven courses of chemotherapy. Courses 1, 2, 3, and 6 include 6-hour infusions of cyclophosphamide on days 1 and 2 for a total of 4,200 mg/m2 per course (140 mg/kg per course for patients < 10 years old), plus 72-hour infusions of doxorubicin 75 mg/m2 and vincristine 2.0 mg/m2 beginning on day 1 (HD-CAV). Courses 4, 5, and 7 consist of 1-hour infusions of ifosfamide 1.8 g/m2/d and etoposide (VP-16) 100 mg/m2/d, for 5 days. Granulocyte colony-stimulating factor (G-CSF) and mesna are used. Courses start after neutrophil counts reach 500/microL and platelet counts reach 100,000/uL. Surgical resection follows course 3 and radiotherapy follows completion of all chemotherapy. RESULTS: Among the first 36 consecutive assessable patients (median age, 17 years), HD-CAV achieved excellent histopathologic or clinical responses in 34 patients and partial responses (PRs) in two patients. For 24 patients with locoregional disease, the 2-year event-free survival rate was 77%; adverse events were two locoregional relapses, one distant relapse, and one secondary leukemia. All six patients with metastatic disease limited to lungs achieved a complete response (CR) and did not relapse; one is in remission 36+ months from diagnosis, but the other patients are not assessable in terms of long-term efficacy of the P6 protocol because of short follow-up time (n = 3), additional systemic therapy (bone marrow transplantation), or septic death (autopsy showed no residual pPNET). All six patients with widespread metastases had major responses, including eradication of extensive bone marrow involvement, but distant relapses ensued. Myelosuppression was severe, but most patients received the first three courses of HD-CAV within 6 to 7 weeks. Major nonhematologic toxicities were mucositis and peripheral neuropathy. CONCLUSION: Excellent antitumor efficacy and manageable toxicity support the dose-intensive use of HD-CAV for pPNET in children, as well as in young adults. Consolidation of remissions of pPNET metastatic to bone and bone marrow remains a therapeutic challenge.

Adolescent↗
PubMed1995

Treatment of soft-tissue sarcomas of the hand.

We studied the clinical features, radiographic and pathological findings, treatment, and results for twenty-three patients who had been managed for a soft-tissue sarcoma of the hand between 1982 and 1990. The ages of the patients ranged from sixteen to seventy-six years (median age, thirty-one years). The most common clinical finding was a small, painless soft-tissue mass. Twenty of the tumors were high-grade, and eighteen were less than five centimeters in diameter. The most common diagnosis was synovial sarcoma, which was identified in eight patients. Leiomyosarcoma, rhabdomyosarcoma, and malignant fibrous histiocytoma developed in three patients each; epithelioid sarcoma, in two patients; and angiosarcoma, liposarcoma, neuroectodermal tumor, and clear-cell sarcoma, in one patient each. Curative wide excision or amputation was attempted in twenty-two patients; the margins were positive for tumor cells in eight, and local recurrence was seen in nine. Of the twenty-three patients, fourteen had survived, without evidence of disease, after a median duration of follow-up of forty-nine months, and nine had died of disease. The median rate of survival did not differ significantly on the basis of the size or grade of the tumor or the use of adjuvant treatment. However, the rate of survival of the patients who had a soft-tissue sarcoma of the hand that was less than five centimeters in diameter was significantly lower (p = 0.0008) than that of 152 patients who had a similar tumor at another site in an extremity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

A custom distal femoral prosthesis for reconstruction of large defects following wide excision for sarcoma: results and prognostic factors.

Between 1979 and 1986, 37 patients with sarcoma of the distal femur underwent limb salvage using a custom prosthetic knee replacement. Thirteen (35%) had early complications. Fourteen (38%) had late complications, which consisted of 6 aseptic femoral loosenings, 1 aseptic tibial loosening, 2 tibial fractures, 2 contractures, 1 femoral fracture, 1 prosthetic fracture, and 1 septic loosening. By 1988, nine patients died. Thirteen prostheses failed in 12 patients, resulting in 9 revisions, 2 above-knee amputations, and 2 Van Nes rotationplasties. The 2- and 5-year prosthetic survival rates were 82% and 57%, respectively. Twenty-two of the 26 survivors (85%) had successful limb salvage. Preventable factors were implicated in the loosening of six femoral components and in one femoral fracture. The mean Hospital for Special Surgery Knee Score was 69 (range: 62 to 86).

Adolescent↗
PubMed1995

The treatment of aneurysmal bone cyst.

Forty-four patients with aneurysmal bone cysts were treated with curettage with or without bone grafting, and in 26 (59%) recurrence developed. Of 11 patients treated with radiation, in only 1 (9%) the disease was not controlled. In 1 patient, radiation-induced sarcoma developed. Since the introduction of cryosurgery 27 years ago, 51 patients have been treated with cryosurgery. The patients had an average age of 13 years (range, 2-32 years). Thirty-four primary aneurysmal bone cysts and 17 secondary aneurysmal bone cysts occurred in association with 7 giant-cell tumors, 5 chondroblastomas, 2 fibromyxomas, 2 nonossifying fibromas, and 1 unicameral bone cyst. The tumors were classified as inactive in 9 patients, active in 31, and aggressive in 11. Treatment consisted of local intralesional excision followed by application of liquid nitrogen. The defect was either allowed to heal spontaneously (n = 26) or was reconstructed using an intramedullary rod (n = 2), bone grafts (n = 5), fibular strut grafts (n = 14), or polymethylmethacrylate with Steinmann pins (n = 4). At median followup of 85 months (range, 24-311 months), the overall cure rate was 82%. This was increased to 96% after a second, or repeat, cryosurgery. The disease in all patients eventually was controlled by cryosurgery. The mean functional rating was 90% (range, 63%-100%). Intralesional excision with adjunctive cryosurgery is an effective method for the treatment of aneurysmal bone cyst.

Adolescent↗
PubMed1994

Conservative surgery for giant cell tumors of the sacrum. The role of cryosurgery as a supplement to curettage and partial excision.

BACKGROUND: Giant cell tumors (GCTs) of the sacrum are a difficult clinical problem. Wide excision (total sacrectomy) is associated with high morbidity and pelvic/spinal instability. Curettage with or without supplemental radiotherapy is associated with a high recurrence rate. In view of the proven effectiveness of cryosurgery as an adjunct to curettage for extremity GCT, cryosurgery was used for treatment of GCTs of the sacrum. METHODS: Seven patients with GCTs of the sacrum were treated at our institution by conservative surgery from 1973 to 1992. Four patients presented with recurrent tumors after failing previous radiation treatment (dose, 5040 cGy). Four patients were treated with curettage with cryosurgery and three with limited excision with cryosurgery. In the latter procedure after limited excision of the caudal (below S2) part of the tumor, the upper sacral segments were treated with curettage and cryosurgery. This spared the important upper sacral roots and maintained the skeletal integrity. RESULTS: At a median follow-up of 12.25 years (range, 2-14.2 years), all patients were disease free. Local recurrence developed in two patients. Both of these underwent repeat curettage and cryosurgery and have since remained disease free. Two patients had positive second look biopsy with microscopic tumor. Both of these were treated with repeat cryosurgery and have remained disease free. Two patient who developed solitary pulmonary metastases, underwent wedge resection and are alive without disease. No patient suffered neurologic deterioration. CONCLUSION: Conservative surgery (curettage or partial excision) with adjunct of cryosurgery is our preferred technique for the treatment of GCT of the sacrum. Satisfactory local control could be obtained by close observation, second look biopsy and repeat cryosurgery. The chief advantages of this method include preservation of pelvic and spinal continuity, speed and ease of surgical procedure and less potential blood loss. We recommend it over more radical sacrectomy due to low morbidity and less resultant neurologic deficits.

Adolescent↗
PubMed1994

Immunohistochemical detection of bone morphogenetic proteins in bone and soft-tissue sarcomas.

BACKGROUND: Bone morphogenetic proteins (BMPs) are potent inducers of bone formation. Functional and immunohistochemical studies have identified BMPs in a subset of osteosarcomas. In the present study, the authors extend the analysis of BMP expression to other bone and soft tissue sarcomas. METHODS: Monoclonal antibody AbH3b2/17 against human BMP-2 and BMP-4 was used in avidin-biotin-immunoperoxidase assays with frozen sections of bone tumors (71 specimens), soft tissue sarcomas (69 specimens), and normal tissues. RESULTS: Among bone tumors, BMP was detected in osteosarcomas (17 of 29 samples), malignant fibrous histiocytomas (MFHs) (6 of 6), and the spindle cell sarcomatous components of spindle cell (dedifferentiated) chondrosarcomas (4 of 4), but not in conventional chondrosarcomas (0 of 10) or Ewing's sarcomas (0 of 14). Histologic subtypes of osteosarcoma differed for BMP expression, with 8 of 9 fibrohistiocytic, 9 of 13 osteoblastic, and 0 of 5 chondroblastic lesions showing immunostaining. In all BMP-positive bone tumors, immunostaining was localized in the cytoplasm of primitive mesenchymal cells, with little or no staining in tumor matrix and more mature osteoblastic/chondrocytic cells. Among soft tissue sarcomas, MFHs (11 of 12), liposarcomas (5 of 11), leiomyosarcomas (3 of 9), and malignant schwannomas (3 of 8) showed cytoplasmic BMP immunostaining. Synovial sarcomas (0 of 9), rhabdomyosarcomas (0 of 8), and fibrosarcomas (0 of 7) were BMP-negative. All normal human tissues tested, including the tissues of a 16-week-old fetus, lacked BMP immunoreactivity. CONCLUSIONS: Bone morphogenetic protein is expressed in a subset of osteosarcomas, a high proportion of MFHs of bone and soft tissue, and in spindle cell chondrosarcomas. In these tumors, BMP is localized predominantly to the cytoplasm of malignant cells with primitive mesenchymal features; no or little BMP is detected in the more differentiated elements of bone and soft tissue sarcomas. Different histologic types of bone and soft tissue sarcomas may mimic discrete stages of mesenchymal differentiation as defined by BMP expression and histologic criteria.

Antibodies, Monoclonal↗
PubMed1994

Fibroblast activation protein: purification, epitope mapping and induction by growth factors.

The human fibroblast activation protein (FAP) defined by monoclonal antibody (MAb) F19 is a cell surface antigen expressed in reactive stromal fibroblasts of breast, colorectal, lung and other epithelial cancers. In contrast to its stroma-specific localization in epithelial neoplasms, FAP is expressed in the malignant mesenchymal cells of bone and soft tissue sarcomas. FAP is transiently expressed in some fetal mesenchymal tissues but is absent or expressed at low levels in most adult tissues. FAP is induced in cultured fibroblasts and, in these cells, consists of a M(r) 95,000 subunit (FAP alpha) carrying the F19 epitope and a non-covalently bound M(r) 105,000 subunit (FAP beta) lacking the F19 epitope. Using MAb F19 and 5 newly derived MAbs, we identify 3 distinct epitopes on FAP alpha and tentatively assign one epitope to FAP beta. Analysis of detergent extracts of a FAP alpha high beta- sarcoma cell line by size exclusion-high performance liquid chromatography (HPLC) revealed that FAP alpha does not elute as a M(r) 95,000 species but as part of a high-molecular weight complex (M(r) > 400,000) that dissociates into M(r) 95,000 subunits in SDS gels. Immunoaffinity purification of FAP alpha followed by tryptic digestion, reversed-phase HPLC and microsequencing identified 3 unique FAP alpha peptides, with 2 showing sequence similarity (23/38 identical amino acids) to segments of CD26, a T-cell activation antigen. CD26 is a membrane-bound enzyme (dipeptidyl aminopeptidase IV), but immunopurified FAP alpha has little if any dipeptidase activity with typical CD26 substrates. Finally, studies with FAPlow leptomeningeal fibroblasts revealed that transforming growth factor-beta, 12-O-tetradecanoyl phorbol-13-acetate and retinoids can upregulate FAP expression, whereas serum and several other factors had no or little effect on FAP levels. FAP and CD26 may belong to a family of structurally related but functionally distinct activation proteins that are expressed on different cell types and show unique modes of regulation in normal and malignant cells.

Amino Acid Sequence↗