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Biomedical subjects

J H Healey

Publications and source records attributed to J H Healey.

At least 91 records · Page 5Linked to original sources
PubMed1994

Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers.

The human fibroblast activation protein alpha (FAP alpha) is a M(r) 95,000 cell surface antigen selectively expressed in reactive stromal fibroblasts of epithelial cancers, granulation tissue of healing wounds, and malignant cells of bone and soft tissue sarcomas. Normal adult tissues are generally FAP alpha-, but some fetal mesenchymal tissues transiently express the molecule. Because of its restricted normal tissue distribution and abundant expression in the stroma of over 90% of breast, colorectal, and lung carcinomas, FAP alpha is under clinical evaluation as a target for immunodetection and immunotherapy of epithelial cancers. In the present study, we have isolated a full-length cDNA for FAP alpha through expression cloning in COS-1 cells. The FAP alpha cDNA codes for a type II integral membrane protein with a large extracellular domain, transmembrane segment, and short cytoplasmic tail. FAP alpha shows 48% amino acid sequence identity to the T-cell activation antigen CD26, a membrane-bound protein with dipeptidyl peptidase IV (DPPIV) activity; however, unlike FAP alpha, CD26 is widely expressed in normal tissues. Three catalytic domains shared by DPPIV homologues in different species and by other serine proteases are conserved in FAP alpha. Immunochemical analysis of COS-1 cells coexpressing FAP alpha and CD26 revealed that the two molecules form heteromeric cell surface complexes, suggesting that a previously identified FAP alpha-associated M(r) 105,000 protein of cultured fibroblasts and growth factor-stimulated melanocytes, FAP beta, is identical to CD26. In vivo coexpression of FAP alpha and CD26 is found in reactive fibroblasts of healing wounds but not in tumor stromal fibroblasts or sarcomas (FAP alpha +/CD26-). The putative serine protease activity of FAP alpha and its in vivo induction pattern may indicate a role for this molecule in the control of fibroblast growth or epithelial-mesenchymal interactions during development, tissue repair, and epithelial carcinogenesis.

Amino Acid Sequence↗
PubMed1994

The value of thallium and three-phase bone scans in the evaluation of bone and soft tissue sarcomas.

Thirty-seven patients with newly diagnosed or treated sarcomas had 47 sets of sequential thallium scans (TS) followed by three-phase bone scan (TPBS) on the same day. The diagnosis in all patients was verified by biopsy (n = 40) or long-term follow-up studies (n = 7). The sensitivity, specificity, and accuracy of TS and TPBS in detecting sarcomatous lesions was calculated: TS sensitivity was 88%, specificity 69%, and accuracy 83%; blood flow (BF) and blood pool (BP) sensitivity was 91%, specificity 54%, and accuracy 81%; delayed bone scan (DB) sensitivity was 88%, specificity 38%, and accuracy 74%. In 17 studies the flow and blood pool parts of the TPBS and TS demonstrated the soft tissue component of sarcomas, which would have been missed if only the delayed bone scan had been performed. The TS lesion to normal tissue ratio alone was not very helpful in differentiating sarcomas from benign conditions because some benign lesions are highly cellular and vascular while some malignant lesions, such as chondrosarcoma, have poor vascularity and a less cellular chondroid matrix. However, when the thallium ratio was correlated with similar ratios calculated from the BP image, it was found that if the TS lesion to normal tissue ratio exceeded the BP lesion to normal tissue ratio (12 patients), the specificity for detecting sarcomatous lesions was 100%. Nevertheless, the reverse was not true. The positive predictive value of this observation was 100% and the negative predictive value was 37%.

Adolescent↗
PubMed1994

Allograft reconstruction after proximal tibial resection for bone tumors. An analysis of function and outcome comparing allograft and prosthetic reconstructions.

Seventeen patients (age, 12-63 years; median, 22 years) treated with proximal tibial allografts were identified. Nine cases were intercalary and eight were osteoarticular allografts. Complications, number of operations, and oncologic and functional results were reviewed. The functional results of the allografts were compared with a prior cohort of patients who had endoprosthesis at the same institution by the same surgeons. There were 14 malignant tumors, two benign aggressive tumors, and one sclerosing osteomyelitis mimicking osteosarcoma. Twelve of 17 patients had complications, the most common being fracture, deformity, and infection. Six patients required more than one procedure, and three had amputations after allograft reconstruction. The ultimate function was excellent in three patients, good in seven, fair in six, and poor in one. There were 14 patients with endoprosthetic reconstruction. Wound problems followed by prosthetic loosening were the most common complications. Of the eight patients requiring a second procedure, three had an amputation. Three had excellent, seven good, and four fair functional results at the final evaluation. No patient in either group had a local recurrence. Allograft provides an alternative to endoprosthetic reconstruction; however, the high incidence of complications makes the outcome unpredictable. Allograft or prosthetic reconstruction provides better functional results than amputation without sacrificing oncologic results.

Adolescent↗
PubMed1993

Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin.

The human fibroblast activation protein (FAP), defined by monoclonal antibody F19, is expressed in vivo in reactive stromal fibroblasts of epithelial cancers, subsets of bone and soft tissue sarcomas, and granulation tissue of healing wounds. FAP is generally absent from the stroma of benign epithelial tumors and normal adult tissues. In vitro FAP induction is observed in proliferating cultured fibroblasts and in melanocytes grown with fibroblast growth factor and phorbol ester. In the present study, we show that fibroblast and melanocyte FAP is a cell surface protein comprising noncovalently linked M(r) 95,000 (p95) and M(r) 105,000 (p105) subunits. In contrast, cultured sarcoma and melanoma cell lines express only p95 or are FAP negative. Immunoblot experiments show that p95, but not p105, carries the epitope defined by monoclonal antibody F19. Furthermore, peptide maps of purified p95 and p105 differ, suggesting that they may be distinct gene products. Loss of FAP or a change from p95/p105 to p95 expression accompanies the acquisition of growth factor independence and tumorigenicity in several in vitro test systems, including simian virus 40 transformation of normal fibroblasts, Ha-ras transformation of normal melanocytes, supertransformation of osteosarcoma cells, and enhanced N-MYC expression in variant neuroblastoma cells, whereas serum-starved normal fibroblasts continue to express p95/p105. Thus, fAP expression appears to be linked to the growth factor-dependent proliferative capacity of normal cells and is not merely a secondary event in proliferating cells; furthermore, FAP expression is inversely correlated with growth factor independence and tumorigenicity in transformed cell lines. This distribution pattern is consistent with a role for p95/p105 in mediating extrinsic, growth regulatory signals in normal cells, possibly as a heteromeric cell surface receptor. Such a physiological function may be obviated when oncogenes with cytoplasmic or nuclear sites of action are activated, reducing extrinsic growth factor dependence and permitting down-regulation of FAP in certain transformed cells.

Antigens, Neoplasm↗
PubMed1993

MDM2 gene amplification in metastatic osteosarcoma.

The human homologue of the murine double minute 2 gene (MDM2), a p53-binding protein which may act as a regulator of p53 protein function, has recently been cloned. Initial studies of this gene in a variety of human tumors have shown frequent gene amplification in most types of sarcomas, including osteosarcomas. Amplification of the MDM2 gene may produce a functional inactivation of the p53 protein. To examine possible clinical or pathological correlates of MDM2 gene amplification in osteosarcoma, we studied 28 specimens on 26 patients with high grade osteosarcoma (16 primary, 11 metastatic, and 1 local recurrence) for MDM2 gene amplification by Southern blot analysis, using two MDM2 complementary DNA probes isolated by polymerase chain reaction. Four specimens (14%) showed amplification, including 3 metastases and 1 local recurrence. None of the primary osteosarcoma specimens had detectable MDM2 gene amplification. None of the specimens tested showed MDM2 gene rearrangement. In the present series, MDM2 gene amplification was detected significantly more frequently in metastatic or recurrent osteosarcomas than it was in primary osteosarcomas (P = 0.02). Our data suggest that MDM2 gene amplification may be associated with tumor progression and metastasis in osteosarcoma. Further investigation is warranted on the potential clinicopathological correlates of MDM2 gene amplification in osteosarcoma.

Adolescent↗
PubMed1993

Osteogenic sarcoma with clinically detectable metastasis at initial presentation.

PURPOSE: Chemotherapy and surgery have improved the length of survival for patients with osteogenic sarcoma (OS) who present without metastatic disease. We reviewed our experience with patients with OS who presented with clinically detectable metastasis to determine the prognostic factors and the effects of surgery on the primary tumor and on metastatic disease. PATIENTS AND METHODS: From 1975 to 1984 we treated 62 patients who had previously untreated OS with metastasis detected at presentation. All of these patients received intensive chemotherapy that included high-dose methotrexate; doxorubicin; and bleomycin, cyclophosphamide, and dactinomycin (BCD). Selected patients also received cisplatin. The intent of surgery was resection of the primary tumor and metastatic disease. RESULTS: Survival was extremely poor; only 11% of patients survived, with a median survival of 20 months. Survival was not affected by use of preoperative chemotherapy versus immediate surgery, and did not correlate with serum lactate dehydrogenase (LDH) level, alkaline phosphatase level, or the site of the primary tumor. Survival did correlate with age, location of metastatic disease, histologic response to preoperative chemotherapy, and completeness of surgical resection of all sites of tumor. Resection of all sites of tumor identified at initial presentation was necessary for survival. CONCLUSION: OS that presents with metastatic disease has a very poor prognosis with therapy, although therapy has achieved good results for patients without metastasis detected at diagnosis. Aggressive surgical resection of tumor is necessary for survival. The use of novel therapies at initial presentation is justified with this group of patients.

Adolescent↗
PubMed1993

EWS rearrangement in Ewing's sarcoma and peripheral neuroectodermal tumor. Molecular detection and correlation with cytogenetic analysis and MIC2 expression.

The translocation t(11;22)(q24;q12) can be identified in its classical or variant form in approximately 90% of cases of Ewing's sarcoma (ES) and peripheral neuroectodermal tumor (PNET). In this tumor group in which the histopathologic diagnosis is often one of exclusion, the cytogenetic demonstration of this translocation has become an invaluable positive diagnostic marker. With the recent cloning of the breakpoint regions of the t(11;22), molecular genetic approaches to the detection of this translocation have become possible. By Southern blotting, the position of the breakpoints on chromosome 22 has been found to be tightly clustered within a 7-kilobase (kb) fragment of the genomic DNA, within a gene designated EWS. In the present study, we examined the efficacy of an EWS complementary DNA (cDNA) probe in detecting the t(11;22) in Southern blots of EcoRI- or HindIII-digested DNA extracted from cases of ES and PNET. We also compared the results of the molecular and cytogenetic analysis with the expression of the ES cell surface antigen MIC2, as demonstrated by immunoperoxidase staining with the monoclonal antibodies O13 and HBA71. Twenty-three specimens were studied, including 18 ES and five PNET. Of 16 cases with clonally abnormal karyotypes, 14 (88%) showed a typical or variant t(11;22). Rearrangements were demonstrated within the EWS gene with the EWS cDNA probe in 20 of 23 specimens (87%), including all of the 14 cases, as well as in one case that displayed clonal numerical chromosome abnormalities only. The MIC2 antigen was expressed in 19 of 20 cases (95%), including all three cases lacking EWS rearrangement.(ABSTRACT TRUNCATED AT 250 WORDS)

12E7 Antigen↗
PubMed1993

Sporadic amplification of the MYC gene in human osteosarcomas.

The MYC proto-oncogene has been shown to be overexpressed in several types of sarcomas, including some osteosarcomas. In most cases, the overexpression is due to gene amplification. The total number of osteosarcoma patients studied, however, remains too small to derive any conclusions regarding the true prevalence and the possible clinical significance of MYC gene amplification. To address the issue more thoroughly, we studied 27 specimens from 25 patients with high-grade osteosarcoma (16 primary, 11 metastatic; 11 adult, 14 pediatric) for MYC gene alterations by Southern blot analysis. Two of 27 specimens (7%) showed MYC gene amplification: a primary fibrohistiocytic osteosarcoma of the femur in a 37-year-old man showed threefold amplification, and a primary Paget's osteosarcoma of the tibia in a 60-year-old man showed fourfold amplification. None of the specimens tested showed MYC gene rearrangement (zero of 27) or activating point mutations at the PvuII site in MYC exon-1 (zero of 26). Hence, the MYC gene is amplified in a subset of osteosarcomas. The possible clinical or biological significance of MYC gene amplification in osteosarcoma may warrant further investigation.

Adult↗
PubMed1993

Prosthetic and extremity survivorship after limb salvage for sarcoma. How long do the reconstructions last?

Ninety-three consecutive prosthetic reconstructions performed for limb salvage after the resection of sarcomas of the lower extremity were reviewed to determine how long the reconstructions lasted, how successful they were in avoiding amputation in the long term, how significant a problem was aseptic loosening, and what was the associated patient survival. Reconstruction was of the proximal femur in 16, distal femur in 61 and proximal tibia in 16 patients. Minimum follow-up time was 24 months, with a median of 66 months and mean of 80 months. If any event leading to the removal of the prosthesis is considered a reason for failure, the event-free prosthetic survival at five years for the proximal femur was 88%, distal femur 59%, and proximal tibia 54%. Limb survival at five years was significantly better, with the proximal femur at 88%, distal femur at 88%, and proximal tibia at 78% intact. Aseptic loosening survival was better than the event free prosthetic survival, which demonstrates the influence of factors such as sepsis (hematogenous) or wound necrosis that lead to prosthetic removal. Aseptic loosening survivorship of the proximal femur at five years was 100%; distal femur, 78%; and the proximal tibia, 73%. At five years, patient survival was low for the proximal femur (62%) and distal femur (75%) but notably better for the proximal tibia (93%). Prosthetic, extremity, and patient survival differed depending on the site. Wound necrosis was a significant cause of prosthetic removal and loss of limb early in this series, but the more aggressive use of soft tissue procedures has improved this.(ABSTRACT TRUNCATED AT 250 WORDS)

Actuarial Analysis↗
PubMed1992

Identification of endosialin, a cell surface glycoprotein of vascular endothelial cells in human cancer.

Cell surface antigens of transformed cells are the traditional targets for antibody-guided detection and therapy of solid neoplasms. Alternative targets may be found in the tumor stroma, which contains newly formed blood vessels, reactive fibroblasts, and extracellular matrix proteins. The F19 cell surface glycoprotein of reactive fibroblasts is a prototypic stromal antigen since it is found in the stroma of > 90% of common epithelial cancers but is absent or expressed at low levels in normal tissues and benign epithelial tumors. In the present study, we define an additional tumor stromal antigen, FB5, that is selectively expressed in vascular endothelial cells of malignant tumors. Immunohistochemical analysis of 128 tumors identified FB5 in endothelial cells in 67% of the samples (including 41 of 61 sarcomas, 26 of 37 carcinomas, and 18 of 25 neuroectodermal tumors) whereas normal blood vessels and other adult tissues tested lacked FB5 expression. In vitro studies showed that FB5 is a M(r) 165,000 cell surface glycoprotein, comprised of a M(r) 95,000 core polypeptide and highly sialyated O-linked oligosaccharides but few if any N-linked sugars, and that the FB5 gene is located on chromosome 11q13-qter. The restricted tissue distribution of the FB5 protein, which we refer to as endosialin, suggests strategies for tumor imaging and therapy that are aimed primarily at the tumor vasculature.

Adult↗
PubMed1992

Soft-tissue management with prosthetic replacement for sarcomas around the knee.

The soft-tissue management was reviewed in 46 consecutive primary and nine revision segmental knee resections with prosthetic reconstruction performed for sarcomas around the knee. From January 1983 until August 1986, before the extensive use of free-tissue transfer in these patients, 20 primary segmental knee reconstructions were performed with five patients receiving gastrocnemius rotation flaps, and one patient receiving a late free flap (Group I). In this group, three patients were converted to an above-knee amputation because of wound problems. From August 1986 to August 1988, free-tissue transfer was available and extensively used in addition to rotation flaps to manage 26 primary (Group II) and nine revision (Group III) segmental knee reconstructions. In contrast to Group I, none of the patients in Groups II or III required amputation or conversion to a nonlimb-sparing procedure for soft-tissue management. None of the patients in this study received radiation therapy to their extremities. Chemotherapy protocols were similar in Groups I and II with 22 of 26 patients in Group I and 19 of 20 in Group II receiving treatment. The availability and expertise to perform free and rotational flaps at the time of initial excision provides greater selection and improved outcome for those patients whose wounds are closed primarily. The capability to perform free and rotation flaps at initial resection and for postoperative wound management is a major determinant of ultimate success in patients having reconstruction after excision of sarcomas about the knee.

Bone Neoplasms↗
PubMed1991

Multiple giant cell tumors and Paget disease of bone: radiographic and clinical correlations.

The clinical and radiographic findings of four patients with multicentric giant cell tumor (GCT) of bone and Paget disease were retrospectively reviewed. Three patients underwent magnetic resonance (MR) imaging evaluation; all patients underwent computed tomography (CT). The MR characteristics of the bone component in pagetic GCT appeared to reflect the pagetic phase; a sclerotic pattern was largely represented by hypointense marrow signal intensity on images obtained with both long and short repetition times (TRs) and echo times (TEs). Conversely, a tumor appearing in a mixed pagetic phase demonstrated more heterogeneous signal intensity with all pulse sequences. Extensive soft-tissue components, noted in all cases, showed largely intermediate signal intensity on short TR/TE images and foci of increased signal intensity on longer TR/TE images. In most cases, dramatic reduction in tumor bulk was noted with the use of steroids alone. An awareness of this entity is important because the appearance of lytic lesions with soft-tissue extension in patients with Paget disease does not necessarily imply a grave prognosis. Serial CT or MR imaging is helpful in monitoring the remissions and exacerbations that reflect response to therapy in Paget disease and GCT.

Aged↗
PubMed1991

Radiation and pagetic osteogenic sarcomas.

Radiation and pagetic osteogenic sarcomas should be distinguished from classical osteogenic sarcoma. Both occur in older patients with significantly greater comorbidity. Roentgenographically, radiation osteogenic sarcoma is typically sclerotic, whereas pagetic osteogenic sarcoma is lytic and associated with pathologic fracture. Radical resections give the best result, local control, and survival. Chemotherapy has not proven effective to date. Improvements in tumor imaging and more intensive chemotherapy regimens may permit limb-sparing surgery. Overall results remain poor, with approximately 15% five-year survival in each condition.

Adolescent↗
PubMed1991

The effect of chemotherapy on growth in the skeletally immature individual.

One hundred twenty-two children with nonmetastatic osteogenic or Ewing's sarcoma were studied to assess the effect of multiagent adjuvant chemotherapy on skeletal growth and final stature. No deviations from the height distributions of a normal population were noted at diagnosis. There was a marked retardation of linear growth during the year of intensive chemotherapy. Only 15% of the patients grew at the expected rate during that year. The distribution of nutritional status scores was significantly different at the end of the first year than at baseline. The distribution of ultimate height scores was significantly different than the baseline distribution. The overall final distribution was also significantly different from the normal population expectation. Any absolute difference in height, however, is likely to be small. The subgroups that were observed to full adult stature showed mean heights of 162 cm for girls and 176 cm for boys.

Adolescent↗
PubMed1991

Cardiac arrest during hip arthroplasty with a cemented long-stem component. A report of seven cases.

Seven patients had a cardiac arrest during hip arthroplasty with a cemented long-stem femoral component. Four patients died in the operating room, and three patients were successfully resuscitated. When the three survivors were eventually discharged from the hospital, they had no known permanent cardiac, pulmonary, or neurological sequelae. Factors that were common to all of the patients were advanced age, osteoporotic bone, a previously undisturbed intramedullary canal, and use of a long-stem femoral component and several batches of methylmethacrylate. Hip arthroplasty with a long-stem femoral component is associated with substantial risk in these patients. Excessive pressurization of cement should be avoided, and invasive hemodynamic monitoring should be used when the described conditions are present.

Aged↗