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Biomedical subjects

P Savage

Publications and source records attributed to P Savage.

At least 19 recordsLinked to original sources
PubMed2006

The place of VEGF inhibition in the current management of renal cell carcinoma.

Vascular endothelial growth factor (VEGF) is overexpressed in around 80% of patients with clear cell carcinoma of the kidney owing to the inactivation of von Hippel Lindau gene activity. VEGF stimulates angiogenesis and acts as an autocrine growth factor. A number of different agents are now available which target VEGF and its signalling pathways. A significant body of evidence has accumulated demonstrating that antagonism of VEGF and its downstream pathways is clinically useful in a significant proportion of patients with metastatic clear cell carcinoma of the kidney. Enough data is now available to recommend that patients with metastatic clear cell carcinoma of the kidney should at some point during the course of their disease be offered entry into a clinical trial enabling exposure to a targeted inhibitor of VEGF or its signalling pathways. Assuming early clinical trial data is substantiated by ongoing registration studies, efforts should be made to minimise the time taken between licensing and general availability of these active agents.

Antibodies, Monoclonal↗
PubMed2006

Residual lung lesions after completion of chemotherapy for gestational trophoblastic neoplasia: should we operate?

The significance of residual lung metastasis from malignant gestational trophoblastic neoplasm (GTN) after the completion of chemotherapy is unknown. We currently do not advocate resection of these masses. Here, we investigate the outcome of these patients. Patients with residual lung abnormalities after the completion of treatment for GTN were compared to those who had a complete radiological resolution of the disease. None of the residual masses post-treatment were surgically removed. In all, 76 patients were identified. Overall 53 (70%) patients had no radiological abnormality on CXR or CT after completion of treatment. Eight (11%) patients had residual disease on CXR alone 15 patients had residual disease on CT (19%). During follow-up, two patients (2.6%) relapsed. One of these had had a complete radiological response post-treatment whereas the other had residual disease on CT. Patients with residual lung lesions after completing treatment for GTN do not appear to have an increased chance of relapse compared to those with no residual abnormality. We continue to recommend that these patients do not require pulmonary surgery for these lesions.

Adolescent↗
PubMed2006

Redirection of CMV-specific CTL towards B-CLL via CD20-targeted HLA/CMV complexes.

B-cell chronic lymphocytic leukaemia (B-CLL) is a slowly progressing malignancy of CD5(+) B cells, for which at present no curative treatment is available. In our current study, we apply a novel bridging reagent to redirect cytomegalovirus (CMV)-specific cytotoxic T lymphocytes (CTL) to target B-CLL. A streptavidin-fused anti-CD20 single-chain variable fragment (scFv) is used in combination with biotinylated MHC class I molecules containing CMV pp65 peptide (HLA/CMV). We demonstrate that B-CLL cells coated with this CD20-HLA/CMV complex can be lysed by autologous CMV-specific CTL with similar efficiency as B-CLL cells directly loaded with CMV peptide. Killing is HLA restricted and occurs at scFv CD20 concentrations of >/=100 ng ml(-1) and HLA/CMV concentrations of >/=20 ng ml(-1). Furthermore, complex-coated B-CLL cells induce both proliferation and cytokine production (interferon gamma, tumour necrosis factor alpha and macrophage inflammatory protein-1 beta) in CMV-specific CD8(+) T cells. Hereby, a necessary step towards possible application of CD20-HLA/CMV complexes for immunotherapy of B-cell malignancies is constituted.

Antigens, CD20↗
PubMed2005

Overdiagnosis of complete and partial hydatidiform mole in tubal ectopic pregnancies.

Partial or complete hydatidiform mole (HM) affects approximately 1 in 500 to 1,000 pregnancies. Previous small series suggest that histopathologic diagnosis of HM may be difficult in tubal ectopic pregnancies. The histopathology database of a regional Trophoblastic Disease Unit was searched to identify cases with a referral diagnosis of tubal HM, and the histopathologic findings were reviewed. During the study period (1986-2004 inclusive), there were 132 cases. After central review by specialist histopathologists, the final diagnosis was ectopic partial mole in two, ectopic complete mole in five, and ectopic hydatidiform mole (not otherwise specified) in one. The final diagnosis of definite hydatidiform mole was made in eight (6%) cases, significantly less than in referred uterine curettage specimens, in which approximately 90% have a confirmatory diagnosis of HM (Z = 12.9; p < 0.0001). No cases in this series developed persistent gestational trophoblastic disease, the human chorionic gonadotropin concentration spontaneously returning to normal. Ectopic pregnancies, where managed surgically, should be submitted for histopathologic examination; however, the pathologist should be aware that the degree of extravillus trophoblastic proliferation may appear more florid compared with evacuated uterine products of conception. Molar pregnancy should only be diagnosed when strict criteria regarding morphologic abnormalities previously described in uterine evacuation material are applied.

Female↗
PubMed2004

Managing errors in radiology: a working model.

AIM: To develop a practical mechanism for reviewing reporting discrepancies as addressed in the Royal College of Radiologists publication "To err is human. The case for review of reporting discrepancies". MATERIALS AND METHODS: A regular meeting was developed, and has evolved, within the department to review discrepancies. Standard forms were devised for submission of cases as well as recording and classification of discrepancies. This has resulted in availability of figures that can be audited annually. RESULTS: Eighty-one cases involving error were reviewed over a 12-month period. Seven further cases flagged as discrepancies were not identified on peer review. Twenty-four reports were amended subsequent to the meeting. Nineteen additional cases were brought to the meeting as illustrative of teaching points or for discussion. CONCLUSION: We have evolved a successful process of reviewing reporting errors, which enjoys the confidence and support of all clinical radiologists, and is perceived as a method of improving patient care through an increasing awareness of lapses in performance.

Clinical Competence↗
PubMed2004

Coronary stent strut size dependent stress-strain response investigated using micromechanical finite element models.

Cardiovascular stents are metal scaffolds that are used in the treatment of atherosclerosis. These devices are typically composed of very thin struts (< or = 100 microm thickness, for coronary applications). At this size-scale the question arises as to the suitability of using bulk material properties in stent design. This paper investigates the use of finite element analysis to predict the mechanical failure of stent struts, typical of the strut size used in coronary stents. 316 L stainless steel in uniaxial loading was considered. To accurately represent the constitutive behavior of the material at this size-scale, a computational micromechanics approach was taken involving an explicit representation of the grain structure in the steel struts, and the use of crystal plasticity theory to represent the constitutive behavior of the individual grains. The development of the finite element models is discussed and results are presented for the predictions of tensile mechanical behavior as a function of strut thickness. The results showed that using this modelling approach, a size effect, already seen experimentally, is produced. This has significant implications for stent design, especially in the context of the desire to produce smaller stents for small bore neurovascular and peripheral artery applications.

Biocompatible Materials↗
PubMed2004

Transmission of donor melanoma to multiple organ transplant recipients.

Malignant melanoma represents the most common tumour responsible for donor-derived post transplantation malignancies. We report the varied presentation and outcome of three graft recipients (two kidney and hepatic) who developed metastatic melanoma following cadaveric organ transplantation from a single multiorgan donor. Two of the recipients presented with symptomatic metastatic lesions and the third patient, despite being carefully monitored, developed evidence of metastatic cutaneous melanoma. Two of the patients died as a direct result of their melanomas. The recipients of corneal and cardiac grafts remain disease-free. We conclude that despite careful screening, donor-derived tumours remain a not uncommon clinical entity. The identification of a lesion in one recipient should prompt immediate examination and investigation of the remaining recipients of multiorgan donations.

Adult↗
PubMed2004

Patient and operator dose during fluoroscopic examination of swallow mechanism.

Dose-area product (DAP) measurements were made for 21 patients undergoing a modified barium swallow. The procedures were performed by a radiologist and speech and language therapist, to characterize swallowing disorders in patients with head or spinal injury, stroke, other neurological conditions or simple globus symptoms, in order to inform feeding strategies. The DAP values were used to estimate effective dose to the patient, in order to provide a measure of the radiation risk associated with the procedure. Whole body doses to operators, together with equivalent doses to extremities and eyes were also measured to inform the employer's risk assessment. Median DAP for the series was 3.5 (3.1-5.2) Gycm(2) with a corresponding effective dose to the patient of 0.85 (0.76-1.3) mSv, and a low associated risk, mainly of cancer induction, of about 1 in 16 000. The organ receiving the greatest dose was the thyroid, with a calculated median equivalent dose of 13.9 (12.3-20.7) mSv. Median screening time was 3.7 (2.5-4.3) min. Mean operator doses were 0.5 mSv equivalent dose (eyes), 0.9 mSv (extremities), and less than 0.3 mSv whole body dose. Extrapolating for an annual workload of 50 patients per year, this work will lead to annual operator doses of less than 0.6 mSv whole body dose, and approximately 1 mSv equivalent dose (eyes) and 1.8 mSv (extremities), against corresponding legal dose limits of 20 mSv, 150 mSv and 500 mSv, respectively.

Barium Sulfate↗
PubMed2003

An investigation of fetal, postnatal and childhood growth with insulin-like growth factor I and binding protein 3 in adulthood.

OBJECTIVE: Weight at birth and adult height are positively associated with cancer risk. These patterns may be mediated by the insulin-like growth factor (IGF) axis. We have examined whether pre- and postnatal growth patterns have a long-term influence on adult IGF-I and IGFBP-3 levels. DESIGN: A follow-up study of a randomized controlled trial of milk supplementation in pregnancy and childhood. SUBJECTS: A total of 951 individuals took part in a study of diet and growth in South Wales between 1972 and 1974 followed up from birth until their mid-20s. MEASUREMENTS: Anthopometric measures at birth, postnatally up to 5 years of age and in adulthood, and serum measures of IGF-I and IGF-I to IGFBP-3 ratio at mean age of 25 years. RESULTS: A total of 63 subjects (70%) provided blood for analysis. We found no association between birth dimensions and adult IGF-I. Subjects who exhibited 'catch-down growth' had lower IGF-I levels (P-value for trend 0.02). Adult height was positively related to IGF-I, for every one standard deviation increase in adult height, IGF-I increased by 3.75 ng/dl (95% CI 0.46-7.08, P = 0.03). Adiposity was inversely associated with the IGF-I and IGF-I to IGFBP-3 ratio and positively associated with IGFBP-3. The strength of the associations increased with age. Downward centile crossing at any time in childhood was associated with lower IGF-I whilst the highest levels were observed in subjects who were tall throughout their early life course. Adult height remained a significant predictor of IGF-I even after adjustment for earlier growth. CONCLUSIONS: Our results indicate that IGF-I levels in early adulthood are associated with patterns of childhood growth as well as adult stature and adiposity. These associations suggest the IGFs may contribute to anthropometric associations with cancer risk.

Adult↗
PubMed2003

The stress-strain behavior of coronary stent struts is size dependent.

Coronary stents are used to re-establish the vascular lumen and flow conditions within the coronary arteries; the typical thickness of a stent strut is 100 microm, and average grain sizes of approximately 25 microm exist in stainless steel stents. The purpose of this study is to investigate the effect of strut size on the stress strain behavior of 316 L stainless steel. Other materials have shown a size dependence at the micron size scale; however, at present there are no studies that show a material property size dependence in coronary stents. Electropolished stainless steel stent struts within the size range of 60-500 microm were tensile tested. The results showed that within the size range of coronary stent struts a size dependent stress-strain relationship is required to describe the material. Finite element models of the final phase of fracture, i.e., void growth models, explained partially the reason for this size effect. This study demonstrated that a size based stress-strain relationship must be used to describe the tensile behavior material of 316 L stainless steel at the size scale of coronary stent struts.

Arteries↗
PubMed2002

Induction of viral and tumour specific CTL responses using antibody targeted HLA class I peptide complexes.

The production of cytotoxic T cells with specificity for cancer cells is a rapidly evolving branch of cancer therapeutics. A variety of approaches aim to amplify anti-tumour cytotoxic T cell responses using purified peptides, tumour cell lysates or recombinant HLA/peptide complexes in differing antigen presenting systems. Using a two-step biotin-streptavidin antibody targeting system, recombinant HLA-class I/peptide complexes were attached to the surface of B cells via the anti-CD20 B9E9-scFvSA antibody-streptavidin fusion protein. Flow cytometry with a conformation dependant monoclonal antibody to HLA class I indicated that targeted HLA-class I/peptide complexes remain on the surface of B cells in culture for periods in excess of 72 h. PBMCs were stimulated in vitro for 8-14 days using the autologous B cells as antigen presenting cells. Following a single cycle of stimulation specific cytotoxic T cell responses to targeted HLA-A2 complexes containing the M1, BMLF1 and Melan A peptides could be demonstrated by tetramer staining and Cr release assays. With the HLA-A2/BMLF1 complex up to 2.99% of CD8+ve cells were tetramer positive producing 20% lysis (E : T 10 : 1) of CIR-A2 target cells in an in vitro cytotoxicity assay compared to baseline levels of 0.09% tetramer +ve and 2% lysis in the unstimulated population. PBMCs from a healthy donor treated with two cycles of stimulations with targeted HLA-A2/Melan A complexes, demonstrated expansion of the melanA tetramer +ve population from 0.03% to 1.4% producing 15% lysis of Melan A pulsed target cells. With further consideration to the key variables of HLA/peptide complex density, the ratio of stimulator to effector cells and optimum cytokine support, this system should offer an easy and effective method for the in vitro amplification of specific cytotoxic T cell responses and warrants development for the in vivo induction of cytotoxic T cell responses in cancer therapy.

Antibodies↗
PubMed2001

Synthesis and biological activity of novel potent endothelin-converting enzyme-1 inhibitors.

Through directed screening of metalloprotease inhibitors, CGS 30084 (1) has been identified as a potent endothelin-converting enzyme-1 (ECE-1) inhibitor in vitro (IC50 = 77 nM). Herein we report the syntheses and biological activities of analogues derived from this lead, based on modifications of the biphenyl moiety. Compound 10, the thioacetate methyl ester prodrug derivative of compound 6m, was found to be an orally active and potent inhibitor of ECE-1 activity in rats.

Alanine↗
PubMed2001

Tamoxifen is not detrimental to endothelial function in postmenopausal women with breast cancer.

BACKGROUND: Tamoxifen has mixed estrogen agonist and antagonist properties in estrogen-regulated tissues. Its effect on the cardiovascular system is not well defined. We carried out a study to investigate the effect of tamoxifen on peripheral vascular endothelial function. METHODS: Three groups of postmenopausal women (median age, 56 years; range, 39 to 69 years) with breast cancer were studied. Patients in group 1 (n = 10) were newly diagnosed with breast cancer and studied before and after 4 weeks treatment with tamoxifen. Group 2 women (n = 6) had been receiving long-term tamoxifen (3 to 5 years) and were studied while taking tamoxifen and 4 weeks after stopping it. The final group of 6 subjects were in remission from primary breast cancer and were not receiving or had previously received tamoxifen. Ultrasound assessments of endothelial function were done before and 4 weeks after the initiation or discontinuation of tamoxifen with the nontreatment group acting as control. All ultrasound imaging was made by a single investigator blinded to the therapeutic status of the subject. Brachial artery diameter was measured by ultrasound at baseline and 1 minute after reactive hyperemia. Flow-mediated reactivity (FMR) was defined as percent change in artery diameter from baseline 1 minute after reactive hyperemia. RESULTS: There was no change in FMR in patients before compared with 4 weeks after starting tamoxifen (4.06% +/- 1.44% vs 3.97% +/- 1.20%, respectively, mean +/- standard error of the mean [SEM], P =.97). There was no significant change in FMR on withdrawal from tamoxifen (1.84% +/- 1.98% vs -0.42% +/- 1.44% on tamoxifen vs off tamoxifen, mean +/- SEM, P =.36). FMR in subjects taking tamoxifen was no different from the control group (3.17% +/- 1.05% vs 3.16% +/- 0.91%, respectively, mean +/- SEM, P =.995). CONCLUSIONS: Tamoxifen does not appear to affect endothelial function in the short term in postmenopausal women with breast cancer.

Adult↗
PubMed2000

Design and synthesis of potent thiol-based inhibitors of endothelin converting enzyme-1.

Through directed screening of compounds prepared as metalloprotease inhibitors a compound, CGS 30084, that had potent endothelin converting enzyme-1 (ECE-1) in vitro inhibitory activity (IC50 = 77 nM) was identified. Herein we report the synthesis and optimization of ECE-1 inhibitory activity of additional analogues from this lead. Compound 3c, the thioacetate methyl ester derivative of compound 4c, was found to be a long acting inhibitor of ECE-1 activity in rats after oral administration.

Animals↗
PubMed2000

Potent and selective non-peptidic inhibitors of endothelin-converting enzyme-1 with sustained duration of action.

Potent and selective non-peptidic inhibitors of human endothelin-converting enzyme-1 (ECE-1) have been designed as potential modulators of endothelin (ET-1) production in vivo. Because of its unique structural characteristics and long duration of action in vivo, the dual ECE-1 and neutral endopeptidase 24.11 (NEP) inhibitor, CGS 26303, was selected as an attractive lead for further optimization of potency and selectivity. Replacement of the P(1)' biphenyl substituent of CGS 26303 by a conformationally restricted 3-dibenzofuranyl group led to more potent and more selective ECE-1 inhibitors, such as the tetrazole 27. The remarkable effect of this P(1)' modification allowed for the first time phosphonomethylcarboxylic acids, such as 29, to display both potent (IC(50) = 22 nM) and selective (104-fold vs NEP) ECE-1 inhibition. Chemoenzymatic syntheses of the new alpha-amino acid (S)-3-dibenzofuran-3-ylalanine intermediate were developed, and improved procedures to generate substituted alpha-aminoalkylphosphonic acids were devised to support the production of various analogues. Although additional gains in intrinsic ECE-1 inhibitory potency could occasionally be achieved by addition of a P(1) side chain, these compounds (e.g. 43a) showed poor functional activity in vivo in the big ET-1 pressor test. Phosphonoalkyl dipeptides featuring 3-dibenzofuranyl groups in both the P(1)' and P(2)' positions were also very potent ECE-1 inhibitors, albeit lacking the desired selectivity against NEP. Functionally, 27and 29 were the two most efficacious compounds from this study, producing sustained inhibition of ECE-1 activity in rats, as measured by their ability to block the hypertensive effects induced by big ET-1. This profile was similar to that of a potent ET(A)/ET(B) dual receptor antagonist, SB 209670. Due to their favorable in vitro and in vivo profiles, 27 (CGS 34043) and 29 (CGS 35066) constitute new pharmacological tools useful in assessing the role of ECE-1 in pathological conditions.

Animals↗
PubMed2000

CGS 34043: a non-peptidic, potent and long-acting dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11.

Endothelin-1 (ET- 1) is a potent vasoconstrictor. Its biosynthesis is catalyzed by endothelin converting enzyme (ECE). In contrast, atrial natriuretic peptide (ANP) is a potent vasorelaxant and diuretic, and it is mainly degraded by neutral endopeptidase 24.11 (NEP). Therefore, compounds that can suppress the production of ET-1 by inhibiting ECE while simultaneously potentiating the levels of ANP by inhibiting NEP may be novel agents for the treatment of cardiovascular and renal dysfunction. CGS 34043 is one such compound, which inhibited the activities of ECE-1a and NEP with IC50 values of 5.8 and 110 nM, respectively. In vivo, it inhibited the pressor response induced by big ET-1, the precursor of ET-1, dose-dependently in rats, and the inhibition was sustained for at least 2 hr. In addition, CGS 34043 increased plasma ANP by 150% up to 4 hr after an intravenous dose of 10 mg/kg in conscious rats infused with ANP. However, this compound had no effect on the angiotensin I-induced pressor response. These results demonstrate that CGS 34043 is a potent and long-lasting dual inhibitor of ECE-1 and NEP. Consequently, it may be beneficial for the treatment of diseases in which an overproduction of ET-1 and/or enhanced degradation of ANP plays a pathogenic role. The activity of CGS 34753, an orally active prodrug of CGS 34043, is also described.

Animals↗