Subcutaneous inflammation mimicking metastatic malignancy induced by injection of mistletoe extract.
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Breast Neoplasms↗
Biomedical subjects
W D Thompson
Publications and source records attributed to W D Thompson.
Microvessel density for melanoma prognosis.
AIMS: Two-hundred and four accessible cases of malignant melanoma from the Grampian region of Scotland, collected over a period of 4 years, were studied for standard prognostic indicators for comparison with microvessel density. METHODS AND RESULTS: The range of tumour thickness varied from in-situ melanoma to 14.8 mm. Microvessel density was assessed using the Chalkley technique on sections immunostained with CD31 antibody to identify endothelium. Vessel counts were performed in the peritumoral host tissue of all specimens. Strong correlation was observed between microvessel density at the tumour edge and tumour thickness (P < 0.001). Multifactorial regression analysis confirms Chalkley estimation as a reliable predictor of the risk of recurrence of melanoma (P < 0.005). The predictive value was found to be superior to the Breslow score, for tumours more than 2 mm thick. CONCLUSIONS: Microvessel assessment of primary melanoma using the Chalkley score technique provides reliable prognostic information on the risk of recurrence of the tumour, particularly for melanomas deeper than 2 mm. It remains to be seen whether this methodology can predict response to novel anti-angiogenic therapies currently entering trials.
Adult↗
ATM variants 7271T>G and IVS10-6T>G among women with unilateral and bilateral breast cancer.
Recent reports suggest that two ATM gene mutations, 7271T>G and IVS10-6T>G, are associated with a high risk of breast cancer among multiple-case families. To assess the importance of these two mutations in another 'high-risk' group, young women (under age 51) with multiple primaries, we screened a large population-based series of young women with bilateral breast cancer and compared the frequency of these mutations among similar women diagnosed with unilateral breast cancer. The 1149 women included were enrolled in an ongoing population-based case-control study of the genetic factors that contribute to bilateral breast cancer; they were not selected on the basis of family history of cancer. Screening for 7271T>G and IVS10-6T>G ATM gene mutations was conducted using DHPLC followed by direct sequencing. The 7271T>G mutation was detected in one out of 638 (0.2%) women with unilateral breast cancer and in none of the bilateral cases, and the IVS10-6T>G mutation in one out of 511 (0.2%) bilateral and in eight out of 638 (1.3%) unilateral breast cancer cases. Carriers of either mutation were not limited to women with a family history. Given the likelihood that young women with bilateral breast cancer have a genetic predisposition, the observed mutation distribution is contrary to that expected if these two mutations were to play an important role in breast carcinogenesis among individuals at high risk.
Adult↗
Does screen-detected breast cancer have better survival than symptomatic breast cancer?
OBJECTIVES: Evidence obtained from several randomized control trials suggest that mortality from breast cancer could be reduced by mammographic screening. However, a recent meta-analysis questioned the general acceptance that screening for breast cancer is beneficial. The purpose of the study was to analyze prospectively collected data from our unit and produce overall and comparative 5-year survival rates for screen-detected and symptomatic breast cancer. METHODS: Prospectively collected data on all patients diagnosed with invasive breast cancer between January 1993 and December 1994 (24 months), and monitored until the end of 1999, were collated and analyzed. Five-year survival was estimated and broken down by age at diagnosis, tumour size, grade and nodal status. The overall 5-year survival for women with screen-detected cancers was compared with that for women with symptomatically presenting cancers. RESULTS: Between January 1993 and December 1994, 308 patients with invasive breast cancer were referred to the unit (162 via the breast screening programme and 146 presenting symptomatically). The overall 5-year survival was 85.5% (confidence interval [CI], 80.8-89.1). Small tumour size, low grade and negative nodal status were associated with higher survival rates. Five-year survival of the screen-detected cancer patients (91.7%; CI, 85.8-95.2) was higher than that of patients presenting symptomatically (78.6%; CI, 70.6-84.6; p < 0.001). CONCLUSIONS: These findings suggest that patients with screen-detected breast cancer may have better survival compared to those with symptomatically detected breast cancer. The results support the argument in favour of a beneficial impact of breast screening programmes on patients' survival.
Adult↗
Infection of chick chorioallantoic membrane (CAM) as a model for invasive hyphal growth and pathogenesis of Candida albicans.
We report the development of a simple model for assessing the ability of the fungal pathogen Candida albicans to invade the chorioallantoic membrane (CAM) of fertilized hens' eggs. Wild-type and mutant strains of C. albicans were inoculated onto CAM surfaces either as a liquid suspension or on a sterile filter disc. Invasion of the membrane led to death of the embryo due to damage of the CAM, which could be examined histologically to show cell distribution and morphology, and by RT-PCR for assessment of patterns of fungal gene expression in vivo. Prophylactic or co-administration of fluconazole with the inoculum protected the embryo from infection. Secretory aspartyl protease (Sap) mutant strains with reported attenuation of virulence were virulent in the CAM model. However, a C. albicans strain with mutations in two transcription factors Efg1 and Cph1 was unable to form hyphae on the CAM or to penetrate it. The chick CAM, therefore, represents an experimentally tractable and inexpensive alternative to rodent or tissue culture-based invasion models, and can be used to investigate fungal pathogenesis and the genetic regulation of infection and membrane penetration of C. albicans.
Allantois↗
Immunohistochemical detection of CD30 remains negative in nodular lymphocyte-predominant Hodgkin's disease using enhanced antigen retrieval.
AIMS: The aims of this study were to confirm that CD30 is reproducibly negative in cases of nodular lymphocyte-predominant Hodgkin's disease (nLPHD), and its relationship to further antibody targets for the distinction of L&H cells from classical Hodgkin's and Reed-Sternberg cells. METHODS AND RESULTS: We examined 16 cases of nLPHD from two centres in the UK to characterize immunohistochemically L&H cells for CD30, EMA, J-chain and Oct2, using different methods of antigen retrieval, antigen amplification and antigen detection systems. Two cases could not be stained with J-chain and Oct2. All cases were negative for CD30 following manual and automated staining. Only one case became positive for EMA after manual staining using tyramide amplification. J-chain and Oct2 were negative in all cases following manual staining. J-chain showed a positive result of variable degree in all but one case using automated Dako ChemMate amplification system staining. Oct2 demonstrated a positive, albeit variable, staining pattern in all cases following automated staining. CONCLUSIONS: CD30 remains negative in L&H cells of nLPHD using enhanced antigen retrieval and can therefore reliably be used to distinguish nLPHD from classical Hodgkin's disease. The value of EMA in the diagnosis of nLPHD remains uncertain, as it does not reproducibly mark L&H cells, even after the use of enhanced antigen retrieval. J-chain and Oct2 appear to be useful markers in the diagnosis of nLPHD using enhanced immunostaining and should therefore be included in lymphoma panels. Automated enhanced staining, using standardized protocols, precoated slides and the full system of prepared reagents, further diminishes the occurrence of errors associated with manual staining, and thereby improves confidence and reliability in diagnosing nLPHD.
Adult↗
Haemangiopericytoma of the sigmoid mesocolon. An unexpected finding during laparoscopic tubal evaluation.
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Adult↗
Tumour versus patient: vascular and tumour survival versus prognosis.
The concept that malignant solid tumour growth depends on angiogenesis is widely recognized. For some tumour types, there is a measurable range of vascularity and the link between prognosis and increased vascular density, best observed at the hotspots at the edge, is now established. What is less discussed are the corollaries: that tumour invasion requires tissue destruction; that the neovasculature must be not only protected but also sustained, especially at the tumour edge; that for tumour survival the edge is the future and the centre is history; and that angiogenesis is essential not only for tumour growth but also for tumour invasion. Different patterns of vascular density in tumour edge and centre have been observed, and these are linked to lymphatic spread and prognosis. The variation is attributable to differing interactions between endothelium and the tumour cell that dictate vascular and tumour survival; this may become relevant to anti-angiogenesis therapies.
Cell Survival↗
Fibrin fragment E stimulates the proliferation, migration and differentiation of human microvascular endothelial cells in vitro.
Various factors involved in haemostasis also regulate the development of new blood vessels by a process called angiogenesis. Enzymatic cleavage of fibrin yields a variety of fibrin degradation products, particularly in areas of intense angiogenesis such as in healing wounds and active atherosclerotic plaques. One of these, fibrin fragment E (FnE), is a potent angiogenic factor in the chick chorioallantoic membrane assay of angiogenesis. Here, we extend these studies to show that FnE stimulates the proliferation, migration and differentiation of human dermal microvascular endothelial cells (HuDMECs) in vitro, both in the absence and presence of such additional endothelial growth factors as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF). We also show that these stimulatory effects occur at concentrations of the protein known to be present in angiogenic tissues in vivo. FnE enhanced the angiogenic effects of VEGF or bFGF, indicating a possible synergy between the signalling pathways used by these three angiogenic factors.
Adult↗
Smooth muscle cell outgrowth stimulated by fibrin degradation products. The potential role of fibrin fragment E in restenosis and atherogenesis.
This study is based on the observation that deposition of thrombus within the arterial wall and on its surface is a consistent response to the vascular injury of angioplasty and of angioplasty lesions at risk of rapid restenosis. Mitogenic activity is stimulated by fibrin degradation products in extracts of human atherosclerotic plaques and plasmin digests of fibrin, and this has been attributed to products that include fibrin fragment E. The effect of human fibrin degradation products on smooth muscle outgrowth from rabbit aortic medial explants now has been explored in culture. Every batch of fibrin degradation products was first tested on the in vivo chick chorioallantoic membrane model for the ability to stimulate cell proliferation, including angiogenesis as shown previously. Increasing concentrations of fibrin degradation products were stimulated significantly earlier and with greater outgrowth of smooth muscle cells than controls, up to an optimum at 92 microg/mL fibrin degradation products. The effect of fibrin degradation products was blocked by the prior admixture of a specific antifragment E antiserum, but not by an antifragment D antiserum. Purified commercial fibrinogen E is inactive, but when treated with thrombin to resemble fibrin E it stimulated smooth muscle cell outgrowth, and this was not seen with comparable dosages of fragment D. We propose that fibrin degradation products, in particular fibrin fragment E, provide an abundant in situ early initiator of smooth muscle cell migration and proliferation in restenosis and atherogenesis.
Angioplasty↗
The clinical manipulation of angiogenesis: pathology, side-effects, surprises, and opportunities with novel human therapies.
The first phase of angiogenesis research has provided knowledge of the basic pathobiology of angiogenesis and its manipulation in models, mouse, and man. The first line of therapeutic substances has been devised and is now in clinical trials. New lessons are being learned from clinical observations. Unexpected side-effects are being noted, particularly affecting the nervous system. Other side-effects may be anticipated from a sound knowledge of clinical pathology and recognition of the commonality of angiogenesis to multiple disease mechanisms, but these may be tolerable or avoidable. Angiogenesis researchers await further feedback and ideas from the clinic to stimulate the next phase of basic and applied research.
Angiogenesis Inducing Agents↗
Quantitative assays for the chick chorioallantoic membrane.
Focal application of angiogenic substances to the chick chorioallantoic membrane is quick and easy as a rapid screening test, but is susceptible to artefactual stimulation induced by carriers, hyperosmolarity, proteolytic activity, and indeed any cause of damage to the CAM. This can be deceptive and unanticipated. Focal application methods can be used for subsequent measurement by morphometry of the increased vascularity forming the typical spokewheel pattern of supply vessels. If test and control substances are applied in liquid form to the whole dropped CAM surface, then a much wider variety of quantitative morphometric, histological and biochemical techniques can be applied. Assessment of arterial vascularity, terminal arterial branching, supply vessels in cross-sections, and CAM haemoglobin content are direct measures of angiogenic effects, but are time-consuming. Biochemical assays of collagen, protein and DNA synthesis parallel the other assays, and these parameters can be estimated more quickly within the working week. There is inherent variability in the outbred strains of hen eggs currently commercially available. This means that all assays require substantial group numbers to achieve statistical validity, generally not less than 10 eggs per group. The biochemical assays yield interesting time-course patterns that distinguish between different types of angiogenic stimulants.
Animals↗
Locating the active site for angiogenesis and cell proliferation due to fibrin fragment E with a phage epitope display library.
The plasmin-mediated lysis of fibrin present in a wound, or in chronic inflammatory disease, results in the release of fibrin degradation products. One of the two major products is fibrin fragment E, which has been shown to stimulate cell proliferation in many cell types including endothelium, fibroblasts, and smooth muscle cells, and to be angiogenic in the chick chorioallantoic membrane (CAM) system. The activity of fibrin fragment E is dependent on N-terminus thrombin action. Antibodies against fibrin E, which block the cell proliferative activity, were used to locate the active site. Phage epitope display libraries were used to identify the sequence of a peptide, which resembles a region of the N terminus structure. The equivalent synthetic peptide (WTM110) has optimal stimulatory properties at equimolar concentrations to the parent molecule. Such peptide information has therapeutic potential for both stimulating and suppressing angiogenesis and cell proliferation.
Amino Acid Sequence↗
Fenbendazole treatment without environmental decontamination eradicates Syphacia muris from all rats in a large, complex research institution.
Syphacia muris parasitism was eliminated from rats and voles by feeding fenbendazole-medicated chow (150 ppm) for five 7-day periods; treatment periods were separated by 7-day periods of feeding non-medicated chow, yielding atotal treatment course of 9 weeks. No other manipulations to facilitate eradication, including the use of filter tops, autoclaved cages, environmental decontamination, colony depopulation, breeding cessation, and research restriction, were done. The examination of 3143 cellophane-tape impressions of the anus and 160 cecal examinations from euthanized rats and voles during the treatment period and for 7 months afterwards confirmed the efficacy of treatment. Treatment was rapidly effective in voles. In rats, pinworm eggs persisted at high levels for 2 weeks after the start of treatment, but no eggs were found after 22 days.
Anal Canal↗
The clinical manipulation of angiogenesis: pathology, side-effects, surprises, and opportunities with novel human therapies.
The first phase of angiogenesis research has provided knowledge of the basic pathobiology of angiogenesis and its manipulation in models, mouse, and man. The first line of therapeutic substances has been devised and is now in clinical trials. New lessons are being learned from clinical observations. Unexpected side-effects are being noted, particularly affecting the nervous system. Other side-effects may be anticipated from a sound knowledge of clinical pathology and recognition of the commonality of angiogenesis to multiple disease mechanisms, but these may be tolerable or avoidable. Angiogenesis researchers await further feedback and ideas from the clinic to stimulate the next phase of basic and applied research.
Angiogenesis Inhibitors↗
The relationship between diet and breast cancer in men (United States).
OBJECTIVES: The purpose of this paper was to investigate the relationship between food and beverage consumption and the development of breast cancer in men. METHODS: Possible relationships of dietary factors to risk of breast cancer in men were assessed in a case-control study conducted between 1983 and 1986. Cases (N = 220) were ascertained from ten population-based cancer registries. Controls (N = 291) were selected by random-digit dialing (< age 65) and from Health Care Financing Administration Medicare beneficiary lists (> or = age 65). RESULTS: No trends in risk were observed with increasing intakes of specific foods, except for an increase in risk with citrus fruits. No increase in risk with increasing amounts of specific fats, vitamins, or minerals or with amounts of protein, fiber, carbohydrate, starches, nitrites, or alcohol consumed was observed, except for an increase in risk with dietary vitamin C consumption. A decreasing trend in risk with dietary niacin and with coffee and an increasing trend in risk with tea consumption were observed. No associations were found with use of any dietary supplements, including vitamin C. CONCLUSIONS: The observed associations are not consistent with findings from studies of breast cancer in women and probably do not represent causal relationships. Dietary factors are unlikely to be strong determinants of breast cancer in men.
Adult↗
Cigarette smoking and other risk factors in relation to p53 expression in breast cancer among young women.
p53 mutations may be a fingerprint for cigarette smoking and other environmental carcinogens, including breast carcinogens. This study was undertaken to explore whether p53 mutations are associated with environmental or other suspected or established risk factors for breast cancer. p53 protein detection by immunohistochemistry (which is more easily quantified in large epidemiological studies than are mutations, and are highly correlated with them) was determined for 378 patients from a case-control study of breast cancer. In this population-based sample of women under the age of 45 years, 44.4% (168/378) of the cases had p53 protein detected by immunohistochemistry (p53+). Polytomous logistic regression was used to calculate the odds ratios (ORs) for p53+ and p53- breast cancer, as compared with the controls, in relation to cigarette smoking and other factors. The ratio of the ORs was used as an indicator of heterogeneity in risk for p53+ versus p53- cancer. The ratio of the ORs in a multivariate model was substantially elevated among women with a greater than high school education [2.39; 95% confidence interval (CI), 1.43-4.00], current cigarette smokers (1.96; 95% CI, 1.10-3.52), and users of electric blankets, water beds, or mattresses (1.78; 95% CI, 1.11-2.86). Nonsignificant heterogeneity was noted for family history of breast cancer and ethnicity but not for other known or suspected risk factors. Coupled with the strong biological plausibility of the association, our data support the hypothesis that in breast cancer, as with other tumors, p53 protein immunohistochemical detection may be associated with exposure to environmental carcinogens such as cigarette smoking.
Adult↗
Oral contraceptive use and other risk factors in relation to HER-2/neu overexpression in breast cancer among young women.
This study was undertaken to explore whether the incidence of breast tumors that overexpress HER-2/neu protein product (HER-2/neu+) is more strongly associated with oral contraceptives (OCs) and other factors than is the incidence of tumors that do not (HER-2/neu-). In a population-based sample of women <45 years, 42.9% (159 of 371) of in situ and invasive breast cancer cases were HER-2/neu+ as assessed by immunohistochemistry in archived tissue. Polytomous logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for HER-2/neu+ and HER-2/neu-breast cancer, as compared with 462 population-based controls, in relation to OCs and other factors. The ratio of the ORs (HER-2/neu+ versus HER-2/neu-tumors) was used as an indicator of heterogeneity in risk. There was little heterogeneity in risk for OC use of 6 months or more by HER-2/neu status (age-adjusted ratio of ORs, 1.29; 95% CI, 0.83-2.00). Among early pill users (< or =18 years of age) heterogeneity was apparent (2.39; 95% CI, 1.08-5.30), which was attenuated in a multivariate model (1.99; 95% CI, 0.87-4.54); among cases with estrogen receptor-negative tumors, heterogeneity increased to 5-fold. For other risk factors, there was no marked heterogeneity between + and - tumors for HER-2/neu. In summary, the incidence of breast cancer among younger women in relation to OC use at an early age varied with HER-2/neu status, with the odds ratio for +tumors twice that for -tumors.
Adult↗