Showing papers by "St Bartholomew's Hospital published in 1989"

Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds meeting.

Abstract: The Ann Arbor classification for describing the stage of Hodgkin's disease at initial presentation has formed the basis upon which treatment is selected and has allowed comparison of results achieved by different investigators for almost two decades. A meeting was convened to review the classification and modify it in the light of experience gained in its use and new techniques for evaluating disease. It was concluded that the structure of the classification be maintained. It was particularly recommended: (1) that computed tomography (CT) be included as a technique for evaluating intrathoracic and infradiaphragmatic lymph nodes; (2) that the criteria for clinical involvement of the spleen and liver be modified to include evidence of focal defects with two imaging techniques and that abnormalities of liver function be ignored; (3) that the suffix 'X' to designate bulky disease (greater than 10 cm maximum dimension) be introduced; and (4) that a new category of response to therapy, unconfirmed/uncertain com...

A randomized trial to evaluate the effect of schedule on the activity of etoposide in small-cell lung cancer.

Abstract: Etoposide is an increasingly used and well-tolerated drug in cancer medicine. Its cytotoxic action is phase-specific and it has demonstrated schedule dependency in both in vitro and animal studies, but clinical evidence of the importance of drug scheduling is uncertain. The two administration schedules of etoposide that have been compared in this randomized study of 39 patients with previously untreated extensive small-cell lung cancer treated with single-agent etoposide were 500 mg/m2 as a continuous intravenous (IV) infusion over 24 hours or five consecutive daily 2-hour infusions each of 100 mg/m2. Both regimens were repeated every 3 weeks, for a maximum of six cycles. Patients received combination chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VAC) or radiotherapy on failure to respond or at relapse, depending on their Karnofsky performance status. The same therapy was used in both arms of the study. All patients are evaluable for response to etoposide. In the 24-hour arm, two patients achieved a partial remission, resulting in an overall response rate of 10%. In the 5-day schedule, 16 patients had a partial response and one had a complete remission, producing an overall response rate of 89%, which was significantly superior to that in the 24-hour arm (P less than .001). The median duration of remission to etoposide in the 5-day arm was 4.5 months. Bone marrow toxicity was similar in both schedules. Etoposide pharmacokinetics were measured in all patients, and total areas under the concentration versus time curves (AUCs) were equivalent in both regimens. This study has clearly demonstrated the importance of etoposide scheduling in humans, and the superiority of five daily infusions over a 24-hour continuous infusion. The response rate to single-agent etoposide using an efficacious schedule in extensive small-cell lung cancer has been determined to be in excess of 80%.

The osteoclast functional antigen, implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor.

Abstract: We have defined the structure of the Osteoclast Functional Antigen (OFA) by immunological and biochemical means. OFA is an abundant surface antigen in human and animal osteoclasts and has been characterized previously by monoclonal antibodies 13C2 and 23C6, one of which mimicks the inhibitory activity of calcitonin on osteoclastic bone resorption. By the following criteria we show that OFA is a member of the integrin family of extracellular matrix receptors and is identical, or at least highly related, to the vitronectin receptor (VNR) previously isolated from placenta and melanoma cells. Immunoprecipitation analysis demonstrates that OFA from osteoclasts and a monkey kidney cell line Vero is a heterodimeric molecule of 140 kD (alpha chain) and 85 kD (beta chain) under nonreducing conditions; on reduction at least one low molecular mass (alpha') species (of approximately 30-kD size) is released, resulting in a 120/100-kD dimer. Immunoblots of OFA isolated from osteoclasts and Vero cells and VNR purified from placenta and probed with heterosera to OFA and monoclonal antibodies to platelet gp111a (VNR beta chain) show immunological cross-reactivity between the alpha chains of OFA and VNR and the use of gp111a as a beta chain by both. OFA from Vero cells binds to an Arg-Gly-Asp containing peptide (GRGDSPPK) isolating a heterodimer recognized by anti-OFA monoclonal antibodies, 13C2 and 23C6. Immunohistochemical analysis showed a similar tissue distribution in humans for the antigen recognized by anti-OFA antibodies, a monoclonal antibody, LM142, raised to melanoma VNR, polyclonal antibodies to the placental VNR and a monoclonal antibody to the presumptive VNR beta chain, platelet glycoprotein 111a. Finally, NH2 terminal amino acid sequencing showed that the amino-terminus of the monkey alpha chain was identical in the 12 assigned residues to that of human VNR alpha chain. The beta chain sequence of OFA differed at least 1 (and up to 4) positions from platelet gp111a (VNR beta) in the first 18 amino acids sequenced. These, and other, data provide the first indication of a function for the VNR and suggest that cell-cell and cell-extracellular matrix interactions involving integrins may play an important role in bone physiology.

Human neutrophils and mononuclear cells inhibit platelet aggregation by releasing a nitric oxide-like factor.

Abstract: Incubation of neutrophils or mononuclear cells with washed platelets (all prepared from human venous blood) resulted in an inhibition of thrombin-induced platelet aggregation that was dependent on the number of nucleated cells added. The inhibition was potentiated by superoxide dismutase and reversed by oxyhemoglobin. In the case of neutrophils the inhibition was associated with an increase in cGMP, whereas with mononuclear cells both cAMP and cGMP were increased. The inhibitory activity of neutrophils or mononuclear cells was prevented by their preincubation with NG-monomethyl-L-arginine methyl ester. L-Arginine reversed the action of NG-monomethyl-L-arginine methyl ester, whereas D-arginine was ineffective. Preincubation of the cells with catalase or mannitol did not prevent their inhibitory action on platelet aggregation. The inhibition of platelet aggregation was not due to platelet damage or to uptake of thrombin by neutrophils or mononuclear cells. It was overcome by increasing the concentration of thrombin and was absent in cell-free supernatants obtained from a suspension of neutrophils or mononuclear cells or from mixtures of platelets with neutrophils or platelets with mononuclear cells. These data provide evidence for the release of a nitric oxide-like factor from human neutrophils and mononuclear cells. In addition, evidence is provided that, as in stimulated murine macrophages and endothelial cells, the precursor of this factor is L-arginine.

Endothelin-1 and endothelin-3 release EDRF from isolated perfused arterial vessels of the rat and rabbit.

Abstract: We have previously shown that porcine endothelin (ET-1) releases endothelium-derived relaxing factor (EDRF) in the rat isolated perfused mesentery. Here we show that both ET-1 (1-100 pmol) and rat endothelin (ET-3, 1-300 pmol) release EDRF in this preparation and that ET-1 releases EDRF from the luminally perfused aorta of the rabbit. Furthermore, we confirm that, as a pressor agent, ET-1 is greater than 10 times more potent than ET-3. Vasodilatations in the rat isolated perfused mesentery in response to ET-1 and ET-3 were due to the release of EDRF since they were inhibited by removal of the endothelium, methylene blue (100 microM), or hemoglobin (30 microM). ET-3 was more selective than ET-1 as a vasodilator because ET-1 induced vasodilatations were limited and in the higher doses overwhelmed by concurrent vasoconstrictions. Release of EDRF from the rabbit aorta in response to ET-1 but not to other agonists (acetylcholine, substance P, or adenosine diphosphate) was potentiated by infusion of potassium chloride (3 mM). Bay K 8644 failed to release EDRF in either system or to constrict the nondepolarized rat mesentery. Thus, both ET-1 and ET-3 release EDRF by activation of receptors or channels that differ from dihydropyridine-sensitive calcium channels.

Mitochondrial myopathies: Clinical and biochemical features of 30 patients with major deletions of muscle mitochondrial DNA

Abstract: Analysis of mitochondrial DNA (mtDNA) in muscle and blood from 72 patients with mitochondrial myopathy showed that 30 had major deletions of a variable proportion of muscle mtDNA. All of these 30 patients presented with progressive external ophthalmoplegia and limb weakness, and 8 had the additional features of the Kearns-Sayre syndrome. Of the 42 patients without detectable muscle mtDNA deletions, 10 had progressive external ophthalmoplegia and limb weakness, 2 had the Kearns-Sayre syndrome, 11 had limb weakness without extraocular involvement, and 19 had multisystem disorders predominantly affecting the central nervous system. Only 2 patients with mtDNA deletions had clinically affected relatives, compared with 10 of those without deletions. In the 4 patients with polarographic defects exclusively involving complex I (NADH coenzyme Q reductase), the deleted protein-coding genes were confined to those for complex I subunits. Thirteen other patients with apparently identical deletions had variable clinical and biochemical features. Immunoblots of complex I polypeptides from patients with deletions were either indistinguishable from controls or showed only a mild generalized decrease in all identifiable subunits.

Pathophysiology of reverse cholesterol transport. Insights from inherited disorders of lipoprotein metabolism.

Abstract: O n the basis of its kinetic behavior, the total cholesterol of body tissues can be divided into three major pools, which differ in their mean rates of exchange with plasma cholesterol. Each pool can be expanded by addition of endogenously synthesized cholesterol, cholesterol from the diet, or both. The only route of excretion of quantitative significance is via the hepato-biliary system, as cholesterol itself and as bile acids. Although endogenous synthesis is under feedback control, it cannot be completely suppressed; on the average, a minimum of about 20 mg is produced per kilogram of body weight per day. As cholesterol absorption by the jejunum is not actively regulated, the maintenance of a near-constant body content of cholesterol must be largely dependent on the efficiency of its elimination via the liver.

Expression of disulfide-linked and non-disulfide-linked forms of the T cell receptor γ/δ heterodimer in human intestinal intraepithelial lymphocytes

Abstract: Immunohistochemistry has been used to investigate disulfide- and non-disulfide-linked forms of the T cell receptor gamma/delta heterodimer (TcR gamma/delta) in blood and intestinal epithelium of normal human small intestine, intestine of patients with untreated coeliac disease (in whom T cells expressing TcR gamma/delta are disproportionately raised), intestine of patients with tropical malabsorption, and in the human fetus. In blood from adult volunteers, 90% of T cells expressing TcR gamma/delta use the disulfide-linked form. In contrast in the epithelium in normal small intestine, coeliac disease and tropical malabsorption, most of the T cells expressing TcR gamma/delta use the non-disulfide-linked form. This is especially prominent in untreated coeliac disease where the increase in TcR gamma/delta T cells is mainly restricted to those using the non-disulfide-linked form. In human fetal small intestinal epithelium, however, only cells using the disulfide-linked form are present. These variations in expression of different forms of TcR gamma/delta in the gut epithelium in different conditions suggests that antigen, or some as yet undefined factor may determine the frequency of each subpopulation.

Effect of sustained exercise on plasma amino acid concentrations and on 5-hydroxytryptamine metabolism in six different brain regions in the rat.

Abstract: Sustained exercise to fatigue elicits no major differences either in plasma amino acid levels or in brain 5-hydroxytryptamine (5-HT) metabolism between sedentary and endurance-trained animals. Furthermore, 11 weeks of endurance training did not influence the maximal activity of the enzyme monoamine oxidase in the brain areas which were studied. In both sedentary and endurance-trained rats, sustained running to fatigue caused an increase in the plasma concentration ratio of free tryptophan/other large neutral amino acids and an increase in the concentration of tryptophan in the six brain areas that were studied. The increase was similar in the different regions of the brain and averaged 36%. Exercise caused an increase in the levels of 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) in the brain stem (14 and 44% respectively) and hypothalamus (16 and 17% respectively) and an increase in the level of 5-HIAA in the hippocampus (21%) and striatum (28%). Exercise also caused an increase in the level of dopamine in the brain stem (56%) and hypothalamus (46%) and of nor adrenaline in the striatum (59%). Since the levels of 5-HT and dopamine were both increased in the brain stem and hypothalamus, it is possible that these changes may play important roles in the central effects of exercise, including both physical and mental fatigue and effects on mood.

Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study.

Abstract: OBJECTIVE--To compare the long term effects of short term intravenous infusions of iloprost with those of oral nifedipine in patients with Raynaud9s phenomenon associated with systemic sclerosis. DESIGN--Double blind, placebo controlled, randomised group comparison. SETTING--Dermatology outpatient clinic. PATIENTS--Twenty three patients with Raynaud9s phenomenon associated with well documented systemic sclerosis (American Rheumatism Association criteria) and with typical abnormalities in fingernail folds on capillaroscopy. INTERVENTIONS--Twelve patients were randomised to receive intravenous infusions of iloprost starting at 0.5 ng/kg/min and increased by 0.5 ng/kg/min every 15 minutes to a maximum of 2.0 ng/kg/min for eight hours on three consecutive days with a further single infusion at week 8. Placebo capsules were given concurrently. Eleven patients were randomised to receive nifedipine, starting at 30 mg daily and increased to 60 mg daily after four weeks for another 12 weeks. Infusions of placebo were given in the same manner as the infusions of iloprost. One patient from each group withdrew because of social reasons and three patients receiving nifedipine withdrew because of side effects. END POINT--Reduction in number, duration, and severity of attacks of Raynaud9s phenomenon, reduction in number of digital lesions, increase in digital blood flow. MEASUREMENTS AND MAIN RESULTS--Measurements were taken at 0, 4, 8, 12, and 16 weeks. Both regimens produced a reduction in the number, duration, and severity of attacks of Raynaud9s phenomenon. The mean (SE) number of digital lesions was reduced with iloprost (from 3.5 (1.6) to 0.6 (0.3] and with nifedipine (from 4.3 (0.8) to 1.4 (0.5] after 16 weeks. Hand temperature and digital and microcirculatory blood flow were increased with iloprost but not with nifedipine. CONCLUSION--Both iloprost and nifedipine are beneficial in the treatment of Raynaud9s phenomenon. With nifedipine, however, side effects are common. Short term infusions of iloprost provide longlasting relief of symptoms, and side effects occur only during the infusions and are dose dependent.

Interleukin-1 directly stimulates the release of corticotrophin releasing factor from rat hypothalamus

Abstract: While interleukin-1 (IL-1), a monocyte-derived polypeptide, clearly stimulates the hypothalamo-pituitary-adrenal (HPA) axis, its precise site of action is controversial. In these studies, the possibility of a hypothalamic and/or a pituitary site of action was investigated in vitro, using incubated rat hypothalami and perifused dispersed pituitary cells. Both forms of IL-1, IL-1α and IL-1β, produced a dose-dependent stimulation of CRF-41 release from incubated rat hypothalami in the dose range of 1–100 U/ml (p

Preferred versus actual place of death: a hospital palliative care support team experience

Abstract: A prospective study of the place of death of 160 patients referred to a hospital support team was carried out. Of these patients 62% died in hospital, 26% at home and 12% in a hospice. Overall, 56%...

Anterior and posterior pituitary function in brain-stem-dead donors. A possible role for hormonal replacement therapy.

Abstract: Blood samples were obtained, at the time of organ donation, from 31 consecutive brain-stem-dead (BSD) donors referred to one transplant coordinator during a 9-month period. Twenty-four cases (77%) had clinical diabetes insipidus (DI), which was poorly controlled with marked dehydration in a majority of cases (serum osmolality range 268-357; median 302 mOSM/kg). Serum triiodothyronine (T3) was subnormal in 25 (81%); all had normal or high serum reverse T3; and the serum free thyroxine (T4) index was subnormal in 9 (29%), and TSH was subnormal in 7 (23%). In no case were T4 and TSH both subnormal and results were typical of the sick euthyroid syndrome rather than TSH deficiency. Of 21 cases not receiving corticosteroids, 5 (24%) had a serum cortisol above 550 nmol/L (20 micrograms/dl), excluding ACTH deficiency, and only 1 had undetectable cortisol levels. Those with severe hypotension did not have significantly lower serum cortisol (mean 354 vs. 416; P greater than 0.5). Levels of prolactin, growth hormone, gonadotrophins, and gonadal steroids were variable, but only a minority were frankly deficient in these hormones. BSD donors frequently have DI, which is often managed poorly by nonspecialists and requires appropriate replacement therapy. In contrast most patients are not totally deficient in anterior pituitary hormones. Routine hormonal therapy with cortisol and T3 cannot, therefore, be justified on endocrinological grounds. Widespread introduction of such treatment should only follow controlled trials that clearly demonstrate clinically significant improvement in the transplanted organ function, without detriment to the donor.

Effect of homeopathic treatment on fibrositis (primary fibromyalgia)

Abstract: mens. Several treatments were required for each tumour, and injecting alcohol was often associated with considerable pain, whereas our patients did not report pain. These reports did not mention changes seen on ultrasound scans during or immediately after injection, which we found useful in laser treatment. The most important advantage of the laser is its precision. It is unlikely that it will ever be possible to predict the extent of necrosis around a site at which absolute alcohol has been injected with an accuracy comparable to that already possible with the laser technique. In conclusion, interstitial laser hyperthermia is feasible and seems to be safe. A multiple fibre system makes it feasible to treat tumours of clinically relevant size in the centre of solid organs. The real challenge for the future will be to develop diagnostic techniques that disclose exactly how far individual tumours extend in a wider range of organs (unlike the well defined tumours treated in this pilot study) and to establish the conditions of laser treatment that give complete tumour ablation with safe healing. This combination of technologies may be valuable for treating otherwise untreatable tumours in a range of solid organs and for the primary treatment of small neoplasms such as tumours of the prostate and adrenal glands.

The fate of radioiodinated endothelin-1 and endothelin-3 in the rat.

Abstract: Endothelin-1 (ET-1) has been isolated from cultured endothelial cells and might have a role in cardiovascular regulation. To study the fate of labeled ET-1, we prepared (/sup 125/I)-labeled ET-1 (formerly porcine and human ET) and ET-3 (formerly rat ET). Approximately 0.2 microCi (0.2 pmol) was injected into the left ventricle of anesthetized rats and blood samples analyzed for radioactivity for up to 40 min. The animals were then killed and the distribution of radioactivity determined in various organs. Both ET-1 and ET-3 were rapidly removed from the circulation, with more than 60% of the removal occurring in the first minute. Removal of ET-1 was somewhat faster than that of ET-3. The highest uptake of radioactivity was seen in lung, kidney, and liver. When ET-1 was infused into the isolated perfused lung of the guinea pig, 64 +/- 1.9% of the label was retained. Subcellular fractionation of the lung homogenate following infusion of labeled ET-1 showed that 93% of the label was associated with membranes and intracellular organelles, suggesting internalization of the bound ET-1. Together, the results indicate a high density of ET-1 binding sites in the lung, liver, and kidney and that these organs may be important in removing circulatingmore » ET-1.« less

Rising incidence of IDDM in Europe.

Abstract: A rising incidence of insulin-dependent diabetes mellitus (IDDM) has been reported in many northern European countries, with a rate equivalent to a doubling time of 20-30 yr in some. North American and Japanese studies report a similar trend, although they are less uniform in their findings. Although the number of genetically susceptible individuals within these populations has increased, the rapidity of the change suggests that environmental factors are responsible. If these could be identified, primary prevention might become possible.

Prevention of blindness by screening for diabetic retinopathy: a quantitative assessment.

Abstract: Diabetic retinopathy is an important cause of blindness in the Western World. A review of the randomised trials of laser photocoagulation of the retina as a method of preventing blindness from this disorder showed that this treatment is very effective, reducing the risk of blindness by 61% in a treated eye. As only one eye is needed for sight the reduction in blindness in a population will be greater than 61% because the effect of treatment in one eye is not always identical with the effect in the other eye. For analysis this reduction was taken as 73%, representing the average of the minimum and maximum estimates (61% and 85%). The effectiveness of this treatment suggests that there is the potential for a national screening programme to bring about a major reduction in blindness from this cause. A quantitative assessment of the effect of screening indicated that a programme in which patients with diabetes mellitus are systematically referred to ophthalmic opticians for a retinal examination could detect 88% of all diabetics with serious retinopathy and that 87% of these cases would be treatable. Screening and early treatment of retinopathy would prevent deterioration of visual acuity and could reduce the risk of blindness due to diabetic retinopathy by an estimated 56% (0.73 X 0.88 X 0.87). The findings suggest that an effectively managed community based screening programme encompassing detection, referral, treatment, and follow up would prevent about 260 new cases of blindness in diabetics under the age of 70 each year in England and Wales. This would represent over 10% of all cases of blindness in adults in this age group.

Superoxide anions enhance platelet adhesion and aggregation.

Abstract: 1. Superoxide dismutase (SOD, 60 u ml-1) or ferricytochrome c (70 microM) significantly inhibited thrombin-stimulated platelet adhesion to gelatin-coated plastic, whereas catalase (1000 u ml-1) or mannitol (1 mM) had no effect. 2. The platelet aggregation induced by low concentrations of thrombin (causing less than 45% maximal change in light transmission) was inhibited by SOD. Catalase or mannitol had no effect on platelet aggregation. 3. Pyrogallol (an O2- generator) enhanced both platelet adhesion to gelatin-coated plastic and platelet aggregation induced by thrombin; this enhancement was neutralized by SOD. 4. These results indicate that O2- increase both platelet adhesion and aggregation, whereas other free radicals such as hydrogen peroxide or hydroxyl radicals are not involved.

The natural history of lymphocyte subsets infiltrating the pancreas of NOD mice.

Abstract: A longitudinal study of lymphocytic infiltration in the endocrine pancreas of non-obese diabetic mice was performed to investigate the role of different lymphocyte subsets in the pathogenesis of diabetes. The incidence of insulitis and the percentage of mononuclear cell subsets in the pancreas were evaluated in non-obese diabetic mice of various ages (5, 9, 13, 17, 22, 29 and 36 weeks). Cryostat sections of pancreas were stained with heamatoxilin-eosin or with different monoclonal antibodies against total T lymphocytes, helper T lymphocytes, cytotoxic/suppressor T lymphocytes, activated interleukin 2 receptor positive lymphocytes and B lymphocytes. A monoclonal antibody against Class-II antigens was also used. Positive cells were revealed by the immunoperoxidase technique. Insulitis was found in 5 weeks old mice but to a lesser extent than in adult animals. No significant variation between infiltrating cell subsets was found in different age groups. T lymphocytes ranged between 20.4% and 28.1%, B lymphocytes between 28.8% and 30.8% and Class-II positive cells between 22.8% and 32.2%. Interleukin 2 receptor positive cells ranged between 5.5% and 8.5% as detected with AMT-13 monoclonal antibody which recognise the interleukin 2 binding site. A higher percentage of activated cells was observed using another monoclonal antibody (7D4) directed against a different epitope of the interleukin 2 receptor, suggesting the presence of activated lymphocytes with interleukin 2 receptors saturated by interleukin 2. No insulin-containing cells were found to express Class-II molecules as demonstrated by a double immunofluorescence technique. Most infiltrating mononuclear cells were found to be positive for Class-II and L3T4 antigens or to be Class-II positive and express surface immunoglobulins. We conclude that pancreatic infiltration is an early expression of autoimmune phenomena occurring in these mice and that monocytes and B-lymphocytes predominate in the infiltrate. The role of interleukin 2 and interleukin 2 receptor positive lymphocytes in inducing and maintaining the immune response towards B cells is discussed.

Angiotropic large cell lymphoma (ALCL): morphological, immunohistochemical and genotypic studies with analysis of previous reports.

Abstract: The entity 'angioendotheliomatosis proliferans systemisata' was first described 28 years ago as a cutaneous small vessel neoplasm of presumed endothelial origin. Since then, 101 similar cases have been reported under a variety of different names, most with systemic as well as cutaneous lesions, and a lymphoid histogenesis of the tumour cell is now favoured. Review of these cases has shown a characteristic clinical presentation with predominant neurological and dermatological features, although the diagnosis was made at autopsy in 53 per cent of patients. Most therapeutic regimens have proved ineffective with a median survival of 5 months from date of clinical presentation. Aggressive combination chemotherapy can produce complete and lasting remission and a partial response to steroids is sometimes seen. We have examined a case of this condition showing unusual clinical features. Immunohistochemical studies confirm the lymphoid origin of the tumour cells with B cell phenotype. Antigen receptor gene rearrangement studies indicate the presence of the same clonal population of B cells in multiple sites. We suggest that the term 'angioendotheliomatosis proliferans systemisata' should be dropped and support the use of 'angiotropic large cell lymphoma' to describe this unusual condition.

Megavoltage pituitary irradiation in the management of Cushing's disease and Nelson's syndrome: long-term follow-up.

Abstract: We report the long-term follow-up of the clinical and biochemical effects of megavoltage pituitary irradiation (radiotherapy; RT), administered as primary or secondary therapy, for pituitary Cushing's disease and Nelson's syndrome in 52 patients. Irradiation was administered, from a 4-15 MeV linear accelerator, via a three-field technique (two lateral, one frontal), to a total dose of 4500 cGy (rad) in 25 fractions over 35 days. Twenty-one patients received RT as primary ablative therapy for Cushing's disease and were under follow-up 5.8 to 15.5 years later (median 9.5 years). All were initially treated with metyrapone to induce normal mean plasma cortisol levels, and all achieved clinical remission on this therapy. At latest follow-up, 12 (57%) are off all therapy, in clinical remission, with a normal mean cortisol through the day; however, only two show completely normal plasma cortisol responses to dynamic testing; four remain on medical therapy with metyrapone or op'DDD and all have required a steady dose reduction accompanied by falling plasma ACTH levels; five have required alternative therapy with bilateral adrenalectomy and/or transsphenoidal hypophysectomy. Fifteen patients received RT for Nelson's syndrome, developing after bilateral adrenalectomy, and have been followed up for 1.5 to 17.3 years (median 9.6 years). Fourteen patients showed progressive depigmentation, shrinkage of the pituitary adenoma and fall in plasma ACTH levels to 1-72% (median 16%) of the pre-RT basal value. In the remaining patient an initial fall in plasma ACTH was followed by tumour enlargement at 6 years, leading to death at 11 years after RT. Of the remaining patients, results are assessed in nine who received RT after unsuccessful transsphenoidal surgery, three after transfrontal surgery for aggressive macroadenomas, and four prophylactically after bilateral adrenalectomy. Radiotherapy remains a valuable second-line therapy for Cushing's disease and its complications.