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Biomedical subjects

Hilary Thomas

Publications and source records attributed to Hilary Thomas.

At least 37 records · Page 2Linked to original sources
PubMed2005

Tibolone and endometrial cancer: a cohort and nested case-control study in the UK.

OBJECTIVE: Case series and spontaneous reports of endometrial cancer have raised the question as to whether the use of tibolone (introduced into the UK in 1991) is associated with an increased risk of endometrial cancer. This study set out to evaluate whether tibolone use is associated with an increased risk of endometrial cancer. METHODS: Age-adjusted incidence rate ratios (IRRs) of endometrial cancer were calculated for tibolone use compared with the use of other hormone replacement therapy (HRT). Separate sets of controls, matched for age and general practice, were compared with cases, all nested within a cohort of HRT users identified from the UK General Practice Research Database (GPRD). Conditional logistic regression analysis, adjusted for potential confounders, was used to study the association between tibolone use and the risk of endometrial cancer. RESULTS: 4995 women used tibolone as their first HRT product; 10 783 (4.3%) of the users of combined HRT had changed to tibolone at some time during the study period. Amongst women whose HRT began with tibolone, the age-adjusted IRR relative to those who started with combined sequential HRT was 1.83 (95% CI 1.19, 2.82). The nested case-control study comprised 162 cases, each matched to two sets of 972 controls. There were 43 tibolone-exposed subjects, 28 of whom had used other HRT before or after tibolone. The adjusted odds ratio of the risk of endometrial cancer in women who had ever used tibolone, compared with users of combined sequential HRT, was 1.54 (95% CI 1.03, 2.32) in the age-matched set and 1.58 (95% CI 1.01, 2.47) in the practice-matched set. Sensitivity analyses did not decrease the risk estimates found. DISCUSSION: Tibolone may be associated with an increased risk of endometrial cancer compared with conventional forms of HRT, but our data are fragile. Residual bias and uncontrolled confounding cannot be excluded, and follow-up time is insufficient to draw any firm conclusions with respect to the endometrial safety of tibolone.

Aged↗
PubMed2005

Coexpression, prognostic significance and predictive value of EGFR, EGFRvIII and phosphorylated EGFR in colorectal cancer.

In colorectal cancer, epidermal growth factor receptor (EGFR) expression is reported in 8-100% of the cases examined and there has been no clear association between EGFR expression and prognosis, or response to EGFR inhibitors. In this retrospective study, 87 archival specimens from node positive (Dukes' C) colorectal cancer patients were analysed immunohistochemically, for the expression of EGFR, mutant EGFR (EGFRvIII) and phosphorylated EGFR (pEGFR, tyr1068). Each section was scored on the basis of location and intensity of staining, and the immunostaining was considered positive if greater than 10% of the tumour cells were stained by the antibody. The association between these scores and overall survival was estimated using univariate and multivariate (Cox) analysis. Overall, we found that 76% and 100% of cases were EGFR positive using antibodies to the external or internal domain of EGFR respectively, and 34% of the cases were EGFRvIII positive. However, only 8% of the cases expressed pEGFR and pEGFR immunostaining was never present in more than 10% of tumour cells. The expression of EGFR, EGFRvIII, pEGFR, or coexpression of EGFR and EGFRvIII was not associated with overall survival. Cytoplasmic expression of EGFR (p = 0.0141) or EGFRvIII (p = 0.005) was, however, associated with improved survival in patients receiving radiotherapy. Our results suggest that coexpression of cytoplasmic EGFR and EGFRvIII occurs in a significant proportion (34%) of Dukes' C colorectal cancer and the cytoplasmic expression of EGFR or EGFRvIII is a good indicator of response to radiotherapy.

Aged↗
PubMed2004

Cancer care. Service redesign. A dangerous game to play.

Duplicating improvements in breast cancer services to less common tumour types brings a raft of new challenges. Establishing multidisciplinary teams means health professionals moving and changing professional base, which could destabalise existing services. Individual trusts' cancer plans need to take account of their effect on other services to ease the pressure on PCT capacity planning.

Breast Neoplasms↗
PubMed2004

Information-clinical analysis. The data today. Real-time monitoring can alert trusts to clinical performance problems--before the star-ratings do it for them.

Collecting, analysing and distributing data on clinicians' performance has long been considered a touchy, even taboo, subject. However, a growing number of trust chief executives and medical directors are realising the value of creating an accurate picture of what they are doing and how well they are doing it--and in as close to real time as possible. As one put it: 'We can't afford to wait until the star-ratings are published to know if we are not doing well enough.' The spur for many has been the publication of standardised mortality ratio data for individual hospitals by health information providers Dr Foster. The poor performers wanted to pinpoint where their weaknesses were and the good performers wanted to know what they needed to do to maintain it. Over the past two years, the company has been working with acute trusts to introduce real-time monitoring and analysis of clinical information, which includes measurement of clinical outcomes, admission trends, mortality, length of stay, readmissions, base costs and infection rates. Some plan to show individual clinicians how their performance compares to colleagues and other departments, while others are being more cautious. Independently, HSJ spoke to a selection to find out how they were implementing the systems and what they hoped to achieve.

Hospital Mortality↗
PubMed2004

A multicenter Phase I gene therapy clinical trial involving intraperitoneal administration of E1A-lipid complex in patients with recurrent epithelial ovarian cancer overexpressing HER-2/neu oncogene.

PURPOSE: HER-2/neu oncogene is overexpressed in 10-30% of epithelial ovarian cancers and is associated with a poor prognosis. The E1A gene product of adenovirus type 5 down-regulates HER-2/neu and causes tumor regression in animal models. In the current study, we sought to determine the toxicity and biological activity of E1A-lipid complex in ovarian cancer patients. EXPERIMENTAL DESIGN: A Phase I trial involving intraperitoneal (i.p.) administration of E1A-lipid complex was initiated in ovarian cancer patients to assess biological activity (E1A gene transfer/transcription/translation and HER-2/neu expression) and to determine the maximum tolerated dose. Successive cohorts received E1A-lipid complex at doses of 1.8, 3.6, and 7.2 mg DNA/m(2), given as weekly i.p. infusions for 3 of 4 weeks (each cycle) up to a maximum of six cycles. Peritoneal fluid was sampled at baseline and twice monthly for cellularity, cytology, CA-125, and biological activity RESULTS: Fifteen patients, with a median age of 57 years (range, 43-81) were recruited. Three (1.8 mg DNA/m(2)), 4 (3.6 mg DNA/m(2)), and 8 patients (7.2 mg DNA/m(2)) received i.p. E1A. A total of 91 infusions (range, 1-18) was administered. Abdominal pain was the dose-limiting toxicity, and the maximum-tolerated dose was 3.6 mg DNA/m(2). E1A gene transfer and expression was observed in all of the patients and at all of the dose levels. HER-2/neu down-regulation could be demonstrated in the tumor cells of 2 patients (18%). There was no correlation between dose and biological activity. CONCLUSIONS: I.P. EIA-lipid complex gene therapy is feasible and safe. Future studies, either alone or in combination with chemotherapy, particularly in patients with minimal residual disease, should be evaluated.

Abdominal Pain↗
PubMed2004

Women's postnatal experience following a medically complicated pregnancy.

Within the social science literature on reproduction, relatively little attention has been paid to the areas of major illness during pregnancy and postnatal physical health. In this paper I present the results of a qualitative study of the postnatal health experiences of 15 women who had suffered a serious illness during pregnancy, the onset of which either predated or developed during pregnancy. Recently delivered women with continuing health problems face additional difficulties at a time when they are recovering from the physical and psychological processes of birth and are adjusting to the care of the new baby or grieving a loss. A few women in this study had experienced health problems that were resolved at or soon after the birth. Those with continuing or chronic illness described attempts to regain normality that involved both restoring bodily health and reestablishing their control over symptoms of the illness. Professional help with this process was often reported to be limited.

Adaptation, Psychological↗
PubMed2004

The expression and prognostic significance of HER-2 in colorectal cancer and its relationship with clinicopathological parameters.

The prognostic role of HER-2 has been established in breast cancer but remains controversial in colorectal cancer. In this study, 170 archival specimens of Dukes' B and C colorectal cancer were analysed immunohisto-chemically, using an anti-HER-2 monoclonal antibody HM64.13. Immunostaining was classified as cytoplasmic or membranous, and the intensity of the immunostaining was graded negative, weak or strong. The association between these scores and survival was estimated using Cox survival analyses. Overall, 87% of cases showed cytoplasmic HER-2 staining, with 54% exhibiting strong intensity cytoplasmic immunostaining. Membranous HER-2 was seen in 41% of cases, with most of these being of strong intensity. No correlation with clinical outcome was seen with membranous HER-2. Positive cytoplasmic immunostaining was found to be associated with a significantly better overall survival (HR 0.46, CI95 0.24-0.87) in the Dukes C cancers, but no survival benefit was seen in the Dukes' B cancers. Tumour grade, depth of tumour invasion and positive apical node were also found to be independent prognostic factors in Dukes' C cancers. We conclude that HER-2 over-expression occurs in a significant number of colorectal cancers. Since cytoplasmic HER-2 is incapable of transmitting the strong mitogenic signal via heterodimerization with other members of the Epidermal Growth Factor Receptor (EGFR) family, this may partly explain the correlation between cytoplasmic HER-2 over-expression and a better prognosis in the Dukes' C colorectal cancers. In addition, high levels of membraneous HER-2 in colorectal cancer could make HER-2 a good target for monoclonal antibody-based immunotherapy.

Antibodies, Monoclonal↗
PubMed2003

Targeting of cells expressing wild-type EGFR and type-III mutant EGFR (EGFRvIII) by anti-EGFR MAb ICR62: a two-pronged attack for tumour therapy.

With a view to their use in cancer therapy, we have produced rat monoclonal antibodies (MAbs) directed against 5 distinct epitopes (A-E) on the external domain of the wild-type human EGF receptor (EGFR). Here, we have investigated the relative binding and anti-tumour activity of our anti-EGFR MAbs against HC2 20d2/c cells, which have been engineered to overexpress the type-III mutated form of the human EGFR (EGFRvIII). We found that anti-EGFR MAbs that are the most effective antagonists of EGFR ligands (e.g., ICR16, ICR62 and ICR80) also bind to cells that overexpress the EGFRvIII. Although these antibodies are potent inhibitors of the growth of cells which express wild-type EGFR, they did not directly inhibit the growth in vitro of EGFRvIII expressing HC2 20d2/c cells, or the constitutive tyrosine kinase activity of this receptor. However, in the presence of human peripheral blood mononuclear cells (PBMC), the rat IgG2b MAb ICR62 induced strong antibody-dependent cell-mediated cytotoxicity (ADCC) against HC2 20d2/c cells in culture. Interestingly, MAb ICR62 also inhibited very effectively experimental lung metastases of HC2 20d2/c cells in athymic nude mice. Our results suggest that anti-EGFR MAb ICR62, which binds to the EGFRvIII, may have potential in the treatment of tumors which overexpress the EGFRvIII via immunological mechanisms such as ADCC. Since tumours that are EGFRvIII positive may also overexpress the wild-type EGFR, the use of anti-EGFR MAbs that target both wild-type and mutant receptors may have advantages over those that target only1form.

Animals↗
PubMed2003

Assessment of multidrug resistance reversal using dielectrophoresis and flow cytometry.

In cancer, multidrug resistance (MDR) is the simultaneous resistance of tumor cells to different natural product anticancer drugs that have no common structure. This is an impediment to the successful treatment of many human cancers. A common correlate of MDR is the overexpression of a membrane protein, P-glycoprotein. Many studies have shown that MDR can be reversed after the use of substrate analogs, called MDR modulators. However, our understanding of MDR modulation is incomplete. In this article, we examine the electrical properties of the human leukemic cells (K562) and its MDR counterpart (K562AR) using dielectrophoresis and flow cytometry (with a membrane potential sensitive dye, DIOC5), both before and after treatment with XR9576 (a P-glycoprotein-specific MDR-reversal agent). The results show significant differences in the cytoplasmic conductivity between the cell lines themselves, but indicate no significant changes after modulation therapy. We conclude that the process of MDR modulation is not associated with changes in the electrical properties of cancer cells. Moreover, the results demonstrate that using the flow cytometry method alone, with MDR cells, may produce artifactual results--whereas in combination with dielectrophoresis, the results show the role of MDR modulators in preventing drug efflux in MDR cells.

Blotting, Western↗