The glucagonoma syndrome.
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Biomedical subjects
Publications and source records attributed to N Kirkham.
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In a combined retrospective and prospective study, clinical and autopsy data were collected to assess the changes in autopsy rate in recent years, the attitudes of clinicians and pathologists to the autopsy, and the accuracy of ante-mortem diagnosis when compared with autopsy findings. Between 1962 and 1986, the total autopsy rate for hospital patients remained relatively constant, with an increase in Coroner's and a decrease in the hospital autopsy rate. Analysis of 5064 deaths over a 6-year period showed a significantly greater number of males than females coming to autopsy and a decrease in autopsy rate with age for both sexes. Attitudes to the autopsy were assessed using a questionnaire. The majority of clinicians considered the autopsy to be an important investigation despite new diagnostic techniques and confirmed its value in teaching and research. Seventy-seven per cent agreed that autopsy findings occasionally led to modification of the treatment of subsequent patients with the same condition. Pathologists disagreed that the autopsy is outdated in its present form and considered that not enough hospital autopsies are being requested. They also upheld its use and value in education. The cause of death as given by clinicians for a group of 60 patients was inaccurate in 12 cases.
Morphological tumour differentiation has been shown in numerous studies to give a good prognosis in breast cancer, but as histological grading is based upon a subjective assessment of microscopical appearances, difficulties in consistency and reproducibility are inevitable. A review of the many conventional methods served to highlight a common limitation in their approach; lack of structure. We introduce a new approach which seeks to overcome the problem, by formalizing the methods and identifying aspects which are well suited to computer aided analysis, these being incorporated into a microcomputer system facilitating the collection and appraisal of morphometric data. Within the Information Technology Institute (ITRI) at Brighton Polytechnic a research team is carrying out multidisciplinary work into the elucidation of biological systems. This programme, entitled 'Intelligent Medical Systems', used methods of mathematical signal processing and artificial intelligence, applied to a number of areas, one of which is described in this paper. The aim has been to utilize the inherent skill exercised by the histopathologist in interpreting microscopical images, whilst making quantitization more accurate and reproducible. the system has been developed within a highly structured framework and will have applications in teaching and routine histological analysis. The value of artificial intelligence techniques in the wider issues of this area is discussed.
Two cases of neurofibroma of the paranasal sinuses are presented. The tumours presented as space-occupying lesions and were treated by local excision. Histologically one was a typical neurofibroma, whilst the other showed some features of a schwannoma. The patients show no evidence of tumour recurrence at 18 and 6 months respectively.
The sites of tumour development for 6 rat tumours injected into syngeneic rats via different vascular routes was determined. Xenografts of human tumours were also injected intra-arterially (i.a.) into immunosuppressed rats. Following intravenous (i.v.) and intraportal (i.ptl.) injection of cells tumour colonies localized in lung and liver respectively due to tumour cell arrest. Arterially injected radiolabelled cells disseminated and arrested in a similar distribution to cardiac output and did not 'home' to any organs. Following arterial injection of unlabelled tumour cells colonies grew in many organs. While the pattern of growth for a particular tumour varied with the cell dose, the 'arterial patterns' for all of the tumours studied followed a similar pattern. Some organs (eg adrenals, ovaries and periodontal ligament) were consistently preferred, others (eg skin and skeletal muscle) only supported tumour growth following the delivery of large numbers of cells, while in some tissues (eg spleen and intestines) tumour never grew. Viable tumour cells could be demonstrated by bioassay in many organs for up to 24h after i.a. injection. However tumour growth only occurred in certain organs and the pattern of this growth was not related to the number of tumour cells arrested or their rate of autolysis. This site preference could be expressed quantitatively as the probability of an arrested cell developing into a tumour and was considered a 'soil effect'. Site preference was not directly related to organ vascularity. Organ colonisation was promoted by steroid treatment but the mechanism was unclear and was not secondary to T-cell immunosuppression or prostaglandin synthesis suppression. The adrenal glands were preferred sites of tumour growth but pharmacological manipulation of adrenal function did not alter tumour growth to this organ. Sites of injury and healing were preferred sites of tumour colonisation and this could not be accounted for by increased delivery of tumour cells to these regions. The possibility that the macrophage component of the inflammatory response promoted tumour growth was suggested from studies in which the interval between trauma and inoculation of tumour cells was varied as well as by promotion of intraperitoneal (i.p.) tumour growth by a macrophage infiltrate.
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The pattern of bloodborne tumour spread has been studied experimentally in syngeneic rats. A variety of tumour types has been injected intravenously, intraportally and also intra-arterially via the left ventricle. Tumour cell arrest as a factor in the localization of metastases in the lung following intravenous injection of cells, and in the liver following intraportal injection, is emphasized. Once tumour cells have entered the arterial circulation they disseminate to almost all organs in similar proportions to the distribution of cardiac output. The dissemination and arrest of cells is not found to correlate with the later distribution of metastases. For example, certain organs (especially the adrenals) which receive only low fractions of injected cells, are always preferred sites for bloodborne metastasis. A strikingly similar pattern of 'arterial metastasis' is also seen for all the tumours used despite their very different histological and biological natures.
Microbiological and electron microscopy studies were carried out on rectal biopsy specimens and faecal samples from eight practising male homosexuals and five heterosexual controls. Rectal spirochaetosis was present in five of the eight homosexual men. The organism was cultured and morphologically identified as a large anaerobic host associated treponeme. The degrees of infestation and depletion of microvilli were also measured. The results are discussed in relation to the possible clinical importance of rectal spirochaetosis.
Malignant lymphoma complicating coeliac disease has been characterised on morphological and immunocytochemical grounds as malignant histiocytosis of the intestine (MHI). Fresh tissue from four cases of MHI was studied by means of a panel of monoclonal antibodies; in three cases tumour DNA was studied for immunoglobulin and T-cell receptor (TCR) gene rearrangement. Immunocytochemistry showed a T-cell phenotype in all four cases, confirmed by the demonstration of a rearranged TCR beta-chain gene in the three cases studied. Lymphoma complicating coeliac disease thus appears to be of T-cell, rather than histiocyte, origin.
The authors have used the indirect immunoperoxidase technique to examine the presence and distribution of milk fat globule membrane antigens in 12 cases of mammary Paget's disease using two monoclonal antibodies, HMFG-1 and HMFG-2. These stain breast epithelial cells but do not stain normal epidermis. The Paget's cells showed a similar pattern of cytoplasmic staining to that seen in the underlying intraduct or invasive carcinoma, therefore confirming them to be malignant ductal cells. To support this one of the cases was stained with the antibody LE 61 which is specific for nonepidermal epithelial cytokeratins. The result was strongly positive in Paget's cells in the epidermis but not in squamous cells.
The monoclonal antibodies HMFG1 and HMFG2 identify antigens of the milk fat globule membrane which are also found on breast epithelial cells. Immunohistochemical staining was performed using both antibodies on formalin fixed, paraffin embedded sections of 93 breast carcinoma, 36 histologically benign lesions and 29 histologically normal breast tissue blocks. In both normal and benign breast disease the staining was largely extracellular whilst in malignant tissue the staining was variable and often intracellular. Nine carcinomas did not stain with either antibody. The staining patterns of malignant tissues were graded and no correlation was found between the grades and survival or indices of prognosis, (the oestrogen receptor status, Bloom's grade and the presence or absence of metastases to the axillary nodes.) This study indicates that with the present methods available for grading staining patterns, although of diagnostic value, these monoclonal antibodies are unlikely to assist in determining either the degree of tumour differentiation or prognosis in breast carcinoma.
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Cells with the capacity for clonogenic growth in vitro can be isolated from primary human colorectal carcinomas. In this study colonies were grown, composed of cells which expressed epithelial membrane antigen and CEA, confirming their neoplastic character. Adequate growth for assessing the cytotoxicity of drugs for use in clinical chemotherapy regimes was obtained from 64% of the specimens. Colony forming efficiency of the tumour cells was not related to clinical stage or pathological grade of the parent tumour. The S-Phase fraction of the tumour was established in vitro using pulse thymidine labelling. The thymidine labelling index for Dukes' stage A and B tumours was significantly higher (median 15.7%, range 10.1-23.6%) than for Dukes' stages C and D (median 11.7%, range 0.1-13.6%). Colony forming efficiency in vitro was independent of the thymidine labelling index of the tumour. These findings are discussed with reference to the known heterogeneity of colorectal adenocarcinomas.
The effect of low dose warfarin and high dose warfarin on epithelial cell kinetics (as determined by stathmokinetic techniques), and preneoplastic morphological changes was studied during azoxymethane induced carcinogenesis in the rat. Warfarin, at either low or high dose, had no effect on crypt cell production rate (CCPR) at any time interval whereas tumour incidence in both low dose warfarin and high dose warfarin groups was significantly reduced. Morphological changes were observed using scanning electron microscopy, which by conventional histology were shown to be adenoma precursors. In the control group the number of microadenomas increased with time after starting azoxymethane. In warfarin treated animals, the number of microadenomas also increased with time, but the actual incidence was reduced when compared with controls. These results suggest that the effects of warfarin on tumour development is unrelated to its anticoagulant effect, because increased dose did not result in greater tumour reduction. Furthermore, there was no overall change in CCPR when warfarin was administered. Warfarin may exert a specific effect, by preventing neoplastic change in cells which have undergone morphologically undetectable changes associated with early carcinogenesis.
We have analysed the data of biopsy, tumour size, size, side and axillary lymph node status in a group of 866 patients presenting with breast cancer in Southampton from September 1975 to August 1981 and a group of 1424 women presenting with benign disease in the same period. The whole group showed a seasonal variation, with a peak presentation in June. The pre-menopausal age group account for almost all of this seasonality. The cause of the variation is not established and requires further investigation. The control group of benign breast disease cases did not show a seasonal variation.