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Biomedical subjects

C Fisher

Publications and source records attributed to C Fisher.

At least 127 records · Page 7Linked to original sources
PubMed1999

Characterization of monoclonal antibodies raised against the latent nuclear antigen of human herpesvirus 8.

Human herpesvirus 8 (HHV-8; also designated Kaposi's sarcoma-associated herpesvirus) is the likely etiological agent of Kaposi's sarcoma (KS). HHV-8 encodes a latent nuclear antigen (LNA) which is the product of the viral gene orf 73. LNA is recognized by most infected patient sera and is the basis of current immunofluorescence assays used in epidemiological studies of HHV-8 infection. Here we describe the characterization of four monoclonal antibodies raised to the C-terminal third of LNA-glutathione S-transferase fusion proteins. These monoclonal antibodies recognized discrete linear epitopes within the C terminus and repetitive region of LNA, detected antigen in primary effusion lymphoma (PEL) cells, and precipitated a 220- to 230-kDa protein doublet corresponding to LNA from HHV-8-infected PEL cell lines. In situ immunocytochemistry of KS lesions with these antibodies show that LNA is extensively expressed in KS spindle cells.

Antibodies, Monoclonal↗
PubMed1999

Natural history of stage IV epithelial ovarian cancer.

PURPOSE: In this report we present the natural history, prognostic factors, and therapeutic implications of stage IV epithelial ovarian cancer (EOC). PATIENTS AND METHODS: We reviewed 192 patients with stage IV EOC as defined in 1985 by the International Federation of Gynecology and Obstetrics. RESULTS: The site of stage IV-defining disease was cytologically positive pleural effusion in 63 patients, liver in 50 patients, lymph nodes in 26 patients, lung in six patients, other sites in 15 patients, and disease at multiple stage IV-defining metastatic sites in 32 patients. Surgery was performed before chemotherapy in 169 patients; 25 patients (14.8%) were left with only microscopic residual disease or less than 2 cm of macroscopic residual disease. The overall response rate to chemotherapy was 56%; the complete response rate was 18%. The median progression-free survival was 7.1 months, and the median overall survival was 13.4 months. The median overall survival of patients with positive pleural effusions only was 13.4 months as compared with 10.5 months for patients with visceral disease only, but this difference was not statistically significant. The 5-year survival rate was 7.6%, with only six patients surviving more than 5 years. Univariate and multivariate analysis showed that two parameters were associated with a shorter survival time: visceral involvement (lung or liver) and diagnosis before 1984. CONCLUSION: Patients with stage IV EOC initially respond to chemotherapy as often as those with less advanced disease, but the long-term prognosis is very poor. The size of residual disease is not a prognostic factor in this group of patients, and, therefore, the role of debulking surgery in these patients needs to be reconsidered.

Adult↗
PubMed1999

Development of a finite element model of a transtibial socket liner--an initial study.

A number of computer models of limb loading by lower limb prostheses have been developed to date, however their accuracy and clinical usefulness is somewhat debatable. This paper is the first in a series describing investigations into the behaviour of a transtibial socket under compressive loading. The work focuses upon the socket liner and its role in reducing and redistributing stresses within the socket. This initial study used non-linear finite element analysis to replicate the effect of pressure loading on a polyurethane socket liner in the region of a bony prominence. It is a first step in understanding the load transfer between the residual limb, socket liner and socket of a transtibial prosthesis. The Mooney Rivlin material model [1] was used to simulate the polyurethane socket liner and compression tests in accordance with BS903 [2] were performed to gain the necessary data to calculate the Mooney Rivlin constants. Experimental validation showed that a very accurate, large-strain representation of the material was achieved. Future work will model more complex, three-dimensional geometries.

Artificial Limbs↗
PubMed1998

Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: a Phase II study.

PURPOSE: To evaluate the efficacy and toxicity of tirapazamine, a hypoxic cytotoxin, combined with conventional radiotherapy (RT) for advanced head and neck carcinomas. MATERIALS AND METHODS: From Oct. 1994 to Nov. 1996, 40 patients with stage III or IV carcinomas of the head and neck were enrolled in a Phase II trial to receive conventional RT (70 Gy in 7 weeks) with concurrent tirapazamine (159 mg/m2 intravenously, 3 times per week for 12 doses). One patient subsequently withdrew from the protocol treatment, and was excluded from analyses. Among the 39 cases, the primary sites were located in the oropharynx (n = 28), supraglottic larynx (n = 6), or hypopharynx (n = 5). Twenty-seven patients had T3 or T4, and 27 had N2 or N3 disease. RESULTS: Thirty-two (82%) patients received full 12 drug doses. Thirty-two patients (82%) received full 70 Gy of RT. The most frequent drug toxicities were muscle cramps (77%) and nausea/vomiting (62%), usually grade 1 or 2. Overall, 13 patients (33%) experienced grade 3 or 4 drug-related toxicities. No excessive RT-associated acute normal tissue reactions were observed. With a median follow-up of 13 months, the 1-year and 2-year local control rate was 64% and 59% respectively. CONCLUSION: The tirapazamine regimen was well tolerated with a compliance rate of 82%. The toxicity of RT with concurrent tirapazamine was acceptable in treating advanced head and neck carcinomas. The disease control trend was encouraging. Further clinical studies are warranted.

Adult↗
PubMed1998

Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease.

Mutations in the presenilin-1 (PS-1) gene account for the majority of early onset autosomal-dominant familial Alzheimer's disease (FAD) cases. We identified three missense mutations in the coding sequence of the PS-1 gene in three early onset (EO), FAD pedigrees. Alzheimer's disease was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates of affected individuals showed two novel mutations resulting in Ser169Leu and Pro436Gln and one known mutation resulting in Glu318Gly. The two new mutations are located within predicted transmembrane domains three (TM-3) and seven (TM-7), and are associated with a very early age of onset which is consistent with a marked loss of function of the protein. The age of onset in the pedigree with Glu318Gly mutation was similar to that reported previously in a separate pedigree with this mutation.

Adult↗
PubMed1998

Postchemotherapy residual masses in germ cell tumor patients: content, clinical features, and prognosis. Medical Research Council Testicular Tumour Working Party.

BACKGROUND: In a retrospective study that included a detailed histopathologic review, the clinicopathologic features of patients with germ cell tumors (GCT) and resectable residual masses after chemotherapy were assessed. METHODS: Histologic material from 153 patients was available for review. Recorded details included primary histologic diagnosis, location, size and number of metastases, marker levels before and after chemotherapy, and completeness of surgical excision. A median of seven histologic sections per resection were reviewed by two pathologists independently (and together when disagreement occurred). In each case, details were recorded regarding fibrosis, necrosis, hemorrhage, embryonal carcinoma (undifferentiated teratoma), yolk sac tumor, choriocarcinoma (trophoblastic tumor), differentiated teratoma (mature and immature), dysplasia in somatic tissues, and non- germ cell tumor (GCT) malignancies. The percentage of the sample that each of these components comprised was also estimated. RESULTS: The median postchemotherapy follow-up time was 7 years, and 38 of 153 patients (25%) experienced disease progression. In a multivariate analysis, incomplete resection of all residual masses (in 38 patients) and the presence of malignant elements (in 23 patients) were independent risk factors for progression. In the subset of patients in whom all masses were completely resected, the presence of embryonal carcinoma (undifferentiated teratoma) was the single most significant risk factor for progression. Seven percent of patients had this factor, which was associated with a 2-year progression free survival rate of 12.5%, compared with 88.0% where this component was absent. CONCLUSIONS: Progression free survival can be predicted well by the completeness of excision of residual masses and the presence of malignant germ cell elements. The latter confers a relatively poor prognosis even if all of these elements are completely resected.

Disease-Free Survival↗
PubMed1998

Antisense phosphorothioate oligonucleotides specifically down-regulate cdc25B causing S-phase delay and persistent antiproliferative effects.

Cell cycle progression in mammalian cells is regulated by a family of cyclin-dependent kinases (cdks) that are activated by a family of 3 cdc25 phosphatases: cdc25A, cdc25B and cdc25C. We examined the expression of mRNA and protein of all 3 cdc25s during the HeLa cell cycle, and found that cdc25B protein has a unique and limited pattern of expression relative to other cdc25 homologs. Antisense oligonucleotides reduced cdc25B mRNA levels and dysregulated protein expression, while inhibiting S-phase progression in synchronized HeLa cells. Scrambled control oligonucleotides had no effect. Antisense oligonucleotides transfected in early G2-phase had no effect on cell cycle progression. A direct correlation between down-regulation of cdc25B and inhibition of thymidine incorporation was found using several oligonucleotides. Our results suggest a role for cdc25B in S-phase and demonstrate that inhibition of cdc25B has persistent antiproliferative effects.

Alternative Splicing↗
PubMed1998

No association of presenilin-1 intronic polymorphism and Alzheimer's disease in Australia.

We screened 703 Australian subjects for an intronic polymorphism in the presenilin-1 (PS-1) gene. PS-1 intronic allele 1 homozygosity was not associated with individuals with early- or late-onset sporadic Alzheimer's disease (EOAD or LOAD). Carriers for the PS-1 intronic allele 1 were also not associated with significantly increased risk for AD regardless of gender. Our results for the Australian population are consistent with those of recent reports for other populations and do not support the conclusion that the PS-1 intronic polymorphism is associated with AD.

Adult↗
PubMed1998

Free radical activity of synthetic vitreous fibers: iron chelation inhibits hydroxyl radical generation by refractory ceramic fiber.

Synthetic vitreous fibers are in widespread use but the parameters that dictate their carcinogenicity are still a matter of scientific debate. The free radical activities of a panel comprising an asbestos sample and five different respirable synthetic vitreous fiber samples were determined, to address the hypothesis that carcinogenic fibers have greater free radical activity than noncarcinogenic fibers. On the basis of recent inhalation studies, the six samples were divided into three carcinogenic fibers-amphibole asbestos, silicon carbide, and refractory ceramic fiber 1 (designated with the abbreviation RCF 1)-and three noncarcinogenic fibers--man-made vitreous fiber 10 (a glass fiber sample designated with the abbreviation MMVF 10), Code 100/475 glass fiber, and RCF4. All experiments were carried out with equal fiber numbers. Of the two assays of free radical activity used, the plasmid assay of DNA scission showed only amosite asbestos to have free radical activity, while the salicylate assay of hydroxyl activity showed that both amosite asbestos and RCF1 release hydroxyl radicals; silicon carbide fibers had no free radical activity in either of the assays. None of the noncarcinogenic fibers demonstrated free radical activity in either of the assays. The differences in the two assays in demonstrating free radical activity with RCF1 may be due to increased release of Fe from RCF1 under the more acid conditions of the salicylate assay, which was confirmed by the fact that soluble iron caused hydroxylation of salicylate. Presence of an iron chelator inhibited the ability of the RCF1 fibers to cause hydroxylation of salicylate, demonstrating that RCF1 generates hydroxyl radical by Fenton chemical reaction in the same way as amphibole asbestos.

Animals↗
PubMed1998

Chromosome translocations in sarcomas and the analysis of paraffin-embedded material.

The identification of specific chromosome translocations in various sarcomas and the elucidation of their molecular consequences has raised the possibility of detecting their presence for diagnostic and prognostic purposes in a manner analogous to the haematological malignancies. However, it is important to correlate particular translocations, and also other genetic aberrations, with current histological diagnoses and the behaviour of tumours, in order to assess the potential benefits, if any, of identifying rearrangements. Recent developments which enable specific translocations to be identified in archival material are likely to play an increasing role in the assessment and, eventually, the management of patients with sarcomas.

Humans↗
PubMed1998

Quantitative prognostic features in FIGO I ovarian cancer patients without postoperative treatment.

To identify FIGO I ovarian cancer patients at high risk, prognostic values of quantitative pathological features (volume percentage of epithelium, mitotic activity index, mean (MNA) and standard deviation of nuclear profile area, and volume-weighted mean nuclear volume (MNV) have been investigated in comparison with clinical features, histological grade, and type in 102 adequately staged patients with FIGO Ia, Ib, and Ic ovarian cancer of the common epithelial types. None of these patients received any postoperative treatment. Overall survival of patients alive and well was 78%, and 90% were alive. Of the clinical features, FIGO substage was the strongest prognosticator (Mantel-Cox = 7.2, p = 0.03, hazard ratio (HR) = 4.6). Histologic grade had significant prognostic value as well (Mantel-Cox = 9.7, p = 0.008, HR = 5.9), but histologic type did not. MNA and MNV were the strongest single prognostic factors for overall survival (Mantel-Cox = 12.3 for both; p = 0.0004 and 0. 0005). If MNA </= 55.6 micron2, none of the patients (n = 52) died; if MNA >55.6 micron2, 6-year overall survival was 69%. For MNV </=460 micron2, none of the patients (n = 53) died; if MNV >460 micron2, 6-year overall survival was 70%. A multivariate combination of MNA and FIGO (early cancer of the ovary prognostic score, ECOPS) had the strongest prognostic value (p < 0.0001 and Mantel-Cox value = 22.8, HR = 29.2). If ECOPS </= 5.4 (n = 66), 6-year overall survival was 97%; if ECOPS >5.4 (n = 36), 6-year overall survival was 54%. The results from this and earlier studies emphasize the strong prognostic value of easy to assess and highly reproducible morphometric nuclear features in ovarian tumors and offer a useful instrument for the definition of patient groups for future clinical trials.

Adolescent↗
PubMed1998

Granulosa cell tumours of the ovary: demographics, survival and the management of advanced disease.

Ovarian granulosa cell tumours (OGCT) are rare, accounting for only 3%-5% of primary ovarian tumours. As a result of oestrogen production OGCTs tend to present with early stage disease, which has a good prognosis. For patients with advanced disease, surgery and radiotherapy have been the major modalities of treatment. More recently, platinum-based chemotherapy has been shown to have important activity in advanced disease. In this retrospective study, we have reviewed the results of 62 patients who were treated for adult OGCT at the Royal Marsden Hospital between 1969 and 1995, with particular emphasis on the management of advanced disease. The median age at primary diagnosis was 53 years (range 13-77). Sixty-one per cent of these patients had Stage I disease, 21% Stage II disease, 16% Stage III and 2% Stage IV. Stage I patients had a good prognosis with 5- and 10-year overall survival rates of 95% and 90%. Eleven Stage I patients received adjuvant pelvic radiotherapy, with no apparent benefit to recurrent rate or overall survival. Disease progression occurred in 40% of Stage I patients at a median interval of 76 months (range 12-240), and in 62% of the Stage II patients, at a median interval of 31 months (range 2-57). The median interval from progression of Stage I/II disease to death was 22 months (range 3-144). For patients with inoperable disease, radiotherapy produced a number of long-term remissions with an overall response rate of 50%. Platinum-based chemotherapy also appears active, with responses documented in four out of five patients treated with the PVB regimen (cisplatin, vinblastine, bleomycin) as first line therapy. There were no responses documented to non-platinum chemotherapy or to hormonal manipulation. The results from this study confirm the activity of platinum-containing chemotherapy regimens in OGCT and support the need for further trials to optimize the management of this rare tumour.

Adolescent↗
PubMed1998

Aortic reconstructive surgery for limb ischaemia: immediate and long-term follow-up to provide a standard for endovascular procedures.

PURPOSE: Aortobifemoral and aortobiliac bypass has been a preferred treatment of severe aortoiliac occlusive disease. Recently, endovascular procedures and unilateral bypass grafting have been introduced. We report the results of aortic reconstructive surgery over a 19-year period (1975-1994). METHODS: A total of 285 patients underwent surgery. Follow-up data from clinical notes, general practitioner questionnaire or phone interview was available in 93.3% (266/285). RESULTS: Of the total 68% were male (180/226) and the median age was 63 years (range 22-85 years). Indications for surgery were tissue loss/gangrene (n = 32), rest pain (n = 84), severe claudication (n = 40), moderate claudication (n = 110). Total of 177 bifurcated grafts, 51 iliofemoral, eight left/right aortofemoral, and 30 other procedures were performed. The median duration of follow-up was 49.8 months. Cumulative secondary graft patency for 2, 5 and 10 years was 97.7%, 95.9%, and 94.4%. The amputation rate was 4.5% (12/266). Early mortality occurred in eight of 266 patients (3%) and late mortality in 60 patients. The most common cause of late death was ischaemic heart disease (24/60 followed by cancer (14/60). Data was further analysed by type of graft, risk factors, complications and previous and subsequent surgery. In our experience, aortic reconstructive surgery is a successful option for the management of severe aortoiliac occlusive disease. The outcome of other methods of maintaining arterial patency should be measured against this standard.

Adult↗
PubMed1998

Synovial sarcoma.

Synovial sarcoma is a rare soft tissue tumor of children and adults that is unrelated to synovium and can occur in almost any part of the body. The familiar biphasic synovial sarcoma has discernible glandular or solid epithelial structures, and monophasic forms have characteristic ovoid or spindle cells with only immunohistochemical or ultrastructural evidence of epithelial differentiation. There are several morphologic patterns, including myxoid and hemangiopericytic, and behaviorally distinct calcifying, ossifying, and poorly differentiated subtypes can be recognized. Most synovial sarcomas are immunoreactive for cytokeratin, epithelial membrane antigen, and bc12 protein, and negative for CD34, and many express S100 protein and CD99 (MIC2). Nearly all synovial sarcomas have a specific t(x;18) (p11.2;q11.2) chromosomal abnormality, resulting in fusion of either of two variants of the SSX gene with the SYT gene; the genetic features may relate to morphology and outcome. The differential diagnosis can include a wide range of spindled, polygonal, or round cell sarcomas. Clinically, there have been marked recent improvements in local control of disease and lesser ones in management of metastases. The pathology, differential diagnosis, and behavior of this unique tumor are reviewed.

Adult↗
PubMed1998

Dendritic fibromyxolipoma: clinicopathologic study of a distinctive benign soft tissue lesion that may be mistaken for a sarcoma.

Twelve cases are described of a distinctive benign soft tissue lesion that may be mistaken for a sarcoma. The tumors occurred in 11 men and a woman aged 33 to 81 years (mean, 64 years), and measured from 2 to 11 cm in greatest diameter (mean, 6 cm). They were grossly described as soft, well-circumscribed, yellow-gray, with a mucoid cut surface. All cases were superficially located in the subcutis or muscular fascia of the head and neck region or the chest and back. Histologically, the tumors were characterized by a proliferation of spindle or stellate fibroblastic cells variably admixed with mature adipose tissue embedded in an abundant myxoid and collagenized stroma. The spindle and stellate fibroblastic cells were characterized by slender dendritic prolongations of their cytoplasm, which appeared to extend for short distances along connective tissue planes. Electron microscopy in two cases confirmed the dendritic nature of the fibroblastic cells, which showed elongated cytoplasmic processes lacking external lamina and displaying foci of pinocytotic activity. Immunohistochemical studies in 11 cases showed strong positivity of the spindle cells with vimentin, CD34 and bcl-2, and negative staining for smooth muscle actin, muscle-specific actin (HHF35), desmin, S-100 protein, keratin, and EMA. Because of their prominent myxoid stroma and relatively large size, some of these tumors were initially misinterpreted as low-grade sarcomas. Clinical follow-up in five cases, however, showed that the patients were alive and well without evidence of recurrence between 5 and 13 years (mean follow-up, 8 years) after simple local excision. The present cases appear to represent a distinctive form of benign soft tissue neoplasm that should be distinguished from myxoid liposarcoma and other benign and malignant myxoid tumors of superficial soft tissues.

Adult↗