Localization of PDGF-B protein in macrophages in all phases of atherogenesis.

Lesions of atherosclerosis occur in the innermost layer of the artery wall and consist primarily of proliferated smooth muscle cells surrounded by large amounts of connective tissue, numerous lipid-laden macrophages, and varying numbers of lymphocytes. Growth-regulatory molecules may be involved in intimal accumulation and proliferation of smooth muscle cells responsible for the occlusive lesions of atherosclerosis. Platelet-derived growth factor (PDGF) B-chain protein was found within macrophages in all stages of lesion development in both human and nonhuman primate atherosclerosis. Thus macrophages may play a critical role in the disease by providing PDGF, a potent chemotactic and growth-stimulatory molecule, to the intimal smooth muscle cells.

Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme.

Primary brain tumors of glial origin often overexpress epidermal growth factor receptors (EGF-Rs). This may be associated with amplification of the EGF-R gene. We have examined tissue from 23 glioblastoma multiforme tumors and found amplification and rearrangement of the EGF-R gene in four of these. The cytoplasmic domain of the EGF-R gene was invariably amplified in these four tumors, while the epidermal growth factor binding domain was not uniformly amplified in three of these tumors. Western blot analysis of the EGF-R protein revealed high levels of a truncated EGF-R protein in two of the four tumors with EGF-R gene amplification.

Malignant effusions.

Recurrent malignant effusions present a difficult management problem and are a major cause of morbidity. This article reviews the pathophysiology of serosal effusions, with particular reference to those occurring in malignant diseases. A detailed review of the investigations available and the characteristic findings in malignant effusions is presented. The influence of serosal cavity fluid dynamics on the pharmacology of intracavitary chemotherapy is discussed, and a rational approach to intracavitary treatment is presented. The treatment options for patients with malignant effusions are described and the present status of medical treatment is discussed.

Expression of transforming growth factor alpha messenger RNA in the normal and neoplastic gastro-intestinal tract.

The presence of TGF alpha mRNA has been reported previously to occur in primary colon cancers. We report the expression of the normal 4.5 kb TGF alpha transcript in the mucosa of the normal human gastro-intestinal tract from oesophagus through to colon. The highest levels of human TGF alpha mRNA occurred in the duodenum but significant levels were present in all of the mucosa. Similarly, in the rat gastro-intestinal tract, TGF alpha transcripts were detected in the lower gastro-intestinal tract mucosa. The relative abundance of the TGF alpha mRNA appeared to decrease in distal regions of the gastro-intestinal tract. The level of the TGF alpha mRNA was similar in both the normal and the neoplastic colon tissue. Similarly, in 2 patients with carcinomas, the TGF alpha mRNA was expressed at similar levels in the tumour and in adjacent mucosa. Although TGF alpha mRNA is associated with transformed cells from the gastro-intestinal tract, the presence of this mRNA at equivalent concentrations in normal mucosa suggests that over-production of TGF alpha is not an essential feature of carcinomas in the gastro-intestinal tract.

Combined cyclophosphamide, adriamycin and cis-platinum in advanced ovarian cancer resistant to chlorambucil and cis-platinum.

Seventeen patients with advanced ovarian adenocarcinoma recurring or progressing after prior treatment with chlorambucil and cis-platinum were treated with cyclophosphamide, adriamycin, and cis-platinum (CAP) every 3 weeks. In seven patients there was objective tumor response (41%) with a median response duration of 7.6 months and a survival advantage over nonresponders. Patients whose tumors had previously responded to chlorambucil or cis-platinum were less likely to respond to CAP than those who had not responded. Myelosuppression was the main toxicity, febrile neutropenia occurring after 8% of treatments.

The influence of oxidatively modified low density lipoproteins on expression of platelet-derived growth factor by human monocyte-derived macrophages.

Platelet-derived growth factor (PDGF) is secreted by several cells that participate in the process of atherogenesis, including arterial wall monocyte-derived macrophages. Macrophages in human and non-human primate lesions have recently been demonstrated to contain PDGF-B chain protein in situ. In developing lesions of atherosclerosis, macrophages take up and metabolize modified lipoproteins, leading to lipid accumulation and foam cell formation. Oxidatively modified low density lipoproteins (LDL) have been implicated in atherogenesis and have been demonstrated in atherosclerotic lesions. The effects of the uptake of various forms of modified LDL on PDGF gene expression, synthesis, and secretion in adherent cultures of human blood monocyte-derived macrophages were examined. LDL oxidized in a cell-free system in the presence of air and copper inhibited the constitutive expression of PDGF-B mRNA and secretion of PDGF in a dose-dependent fashion. Oxidatively modified LDL also attenuated lipopolysaccharide-induced PDGF-B mRNA expression. These changes were unrelated to the mechanism of lipid uptake and the degree of lipid loading and were detectable within 2 h of exposure to oxidized LDL. The degree of inhibition of both basal and lipopolysaccharide-induced PDGF-B-chain expression increased with the extent of LDL oxidation. Monocyte-derived macrophages exposed to acetylated LDL or LDL aggregates accumulated more cholesterol than cells treated with oxidized LDL, but PDGF expression was not consistently altered. Thus, uptake of a product or products of LDL oxidation modulates the expression and secretion of one of the principal macrophage-derived growth factors, PDGF. This modulation may influence chemotaxis and mitogenesis of smooth muscle cells locally in the artery wall during atherogenesis.

Dying of cancer. Factors influencing the place of death of patients.

An analysis of factors influencing the place of death of patients seen by two medical oncology units is reported. There were 1295 recorded deaths of patients from the Royal Prince Alfred Hospital, Sydney, and 688 from The Royal North Shore Hospital of Sydney during 1979-1981; the places of death were known in 1724 instances (87%). Of these, 73% of patients died in hospital, 9% died in terminal nursing care (TNC) institutions, and the remainder at home. Factors influencing the place of death were the place of residence, age, home circumstances-social support, diagnosis, and interval from first contact with the medical oncology unit. Our data indicate that a complex interrelation of these factors determines the place of death. Improvements in community services may allow more patients with cancer to die at home or in TNC institutions, but a substantial proportion of these will still die in major hospitals. Therefore, there is a need for the improvement of palliative care services in these institutions.

Erythrocyte ammonia in liver disease.

This study reports the relevance of plasma and erythrocyte ammonia concentrations in patients with liver disease. Three groups of subjects were studied: group 1, 47 normal subjects; group 2, 73 patients with liver disease; and group 3, 14 patients with portal-systemic encephalopathy (PSE). The difference in plasma ammonia concentrations between groups 1 and 2 was not significant, but for erythrocyte ammonia this was significant (p less than 0.05). Group 3 subjects had significantly elevated plasma (p less than 0.001) and erythrocyte ammonia (p less than 0.001) compared with the other two groups (Mann-Whitney U-test). In group 3, two patients had plasma ammonia values within the reference range, whereas six patients had values within the range of group 2 subjects. However, none of group 3 subjects had erythrocyte ammonia concentrations within the range of either group 1 or 2. A cut-off level of 65 mumol/l was assigned to differentiate group 3 from group 2 subjects. We conclude that erythrocyte ammonia measurement is a better biochemical index of PSE than plasma ammonia.

Mitolactol chemotherapy for malignant melanoma: a phase II study.

Fifty-one patients (43 evaluable) with malignant melanoma were treated with mitolactol in an intermittent oral schedule. There were four objective tumor responses, all occurring in patients previously treated with dacarbazine.