The clinical impact of a combined gamma camera/CT imaging system on somatostatin receptor imaging of neuroendocrine tumours.

AIM: With a combined gamma camera/CT imaging system, CT images are obtained which are inherently registered to the emission images and can be used for the attenuation correction of SPECT and for mapping the functional information from these nuclear medicine tomograms onto anatomy. The aim of this study was to evaluate the clinical impact of SPECT/CT using such a system for somatostatin receptor imaging (SRI) of neuroendocrine tumours. MATERIALS AND METHODS: SPECT/CT imaging with (111)In-Pentetreotide was performed on 29 consecutive patients, the majority of whom had carcinoid disease. All SPECT images were first reported in isolation and then re-reported with the addition of the CT images for functional anatomical mapping (FAM). RESULTS: Fifteen of the 29 SPECT images were reported as abnormal, and in 11 of these abnormal images (73%) FAM was found to either establish a previously unknown location (7/11) or change the location (4/11) of at least one lesion. The revised location could be independently confirmed in 64% of these cases. Confirmation of location was not possible in the other patients due to either a lack of other relevant investigations, or the fact that lesions seen in the SPECT images were not apparent in the other investigations. FAM affected patient management in 64% of the cases where the additional anatomical information caused a change in the reported location of lesions. CONCLUSION: These results imply that FAM can improve the reporting accuracy for SPECT SRI with significant impact on patient management.

Evaluation of whole blood serotonin and plasma and urine 5-hydroxyindole acetic acid in diagnosis of carcinoid disease.

BACKGROUND: Carcinoid disease is an uncommon disorder resulting from tumours of the enterochromaffin cells. Current biochemical investigation usually involves the measurement of 5-hydroxyindole-3-acetic acid (5-HIAA) in 24-h urine collections. Because of the problems associated with urine collections (i.e. inconvenience, accuracy of collection and requirement for preservatives) two alternative markers, fasting plasma 5-HIAA and whole blood serotonin (5-hydroxytryptamine), have been studied. METHODS AND RESULTS: Whole blood serotonin concentration and plasma and urine 5-HIAA concentrations were measured by high-performance liquid chromatography in 31 patients suspected of having carcinoid and 26 known carcinoid patients. Receiver operator characteristic curve analysis of the data showed no statistical difference between the three markers (P>0.01) with regard to their discriminating function. However, fasting plasma 5-HIAA assay showed greater stability than whole blood serotonin assay and is more convenient for the patient than a 24-h urine collection. At a cut-off value of 118 nmol/L plasma 5-HIAA assay showed a sensitivity of 89%, a specificity of 97% and a test efficiency of 93%. Whole blood serotonin assay was further limited by its saturation in platelets at 40 nmol/10(9) platelets which made it less suitable for monitoring the treatment of carcinoid disease. CONCLUSION: Fasting plasma 5-HIAA concentration provides a more convenient screening test for carcinoid and overcomes the problems associated with 24-h urine collections, without any loss of diagnostic precision.

Identifying core skills for the medical curriculum.

A survey was undertaken at the University of Sheffield Medical School to identify clinical and other professional skills which are required on graduation and to assess whether and when these skills have been acquired. The purpose of the survey was to identify core practical skills, defined as skills which the majority of clinical firms require and which, in addition, were used by the majority of Pre-registration house officers (PRHOs). The survey ws conducted by questionnaires which were circulated to the following four sample groups (number in sample: % response rate): (1) consultants in clinical firms taking undergraduates and post-graduates from Sheffield Medical School (63: 75%); (2) house officers starting their pre-registration year (118; 52%); (3) house officers ending their pre-registration year (120: 43%); and (4) undergraduates starting their final year (110: 65%). The questionnaire contained a stimulus list of 31 clinical and four personal skills with an opportunity for respondents to list other skills they felt to be important. Of the 35 skills listed on the questionnaire, 26 were identified as core practical skills. Fifteen of the core skills had been acquired by the majority of students by the time they graduated, 13 of which were acquired prior to the final undergraduate year. Core skills not acquired as an undergraduate were acquired as a PRHO. The survey acted as a quality control mechanism for teaching at both undergraduate and post graduate levels and provided the basis of a medical school core of practical skills on the basic medical education continuum.

Clinical manifestations of carcinoid disease.

Carcinoid tumors are relatively uncommon tumors and their presentation is varied. For these reasons, a high index of suspicion is necessary in order to consider the diagnosis. It is important to separate the "syndrome" from the primary tumor. It is obviously more effective to diagnose the tumor itself before the syndrome manifests itself, usually as a result of metastatic disease. Since the tumors are characteristically slow-growing, the physician may be misled into thinking the patient has functional problems rather than a tumor. Some data and guidelines are given for focusing on the signs and symptoms of carcinoid disease.

The use of new somatostatin analogues, lanreotide and octastatin, in neuroendocrine gastro-intestinal tumours.

In an open phase III study, octastatin was given as a continuous subcutaneous (s.c.) infusion to 35 patients (mean age 62 years) with malignant neuroendocrine gastro-intestinal tumours and the carcinoid syndrome. The wash-out was often incomplete because of the advanced stage of disease. The starting dose of 1.5 mg/24 h was increased up to 3.0 mg/24 h at 3 months in some patients. The carcinoid syndrome disappeared in 20% of patients at 3 months and in 23% at 6 months, with 43 and 45% of patients, respectively, experiencing an improvement. The mean Karnovsky index increased by > 10% in 40% of patients at 3 and 6 months. Urinary 5-hydroxyindoleacetic acid (U-5-HIAA) levels at 3 months normalised in 1 patient, fell in 20% (by > 50%; p = 0.0021) and stabilised in 66%. The respective values at 6 months were 1, 17% (p = 0.023) and 60%. There was also a significant decrease in plasma chromogranin levels at 3 months (p = 0.042), which did not persist at 6 months. Tumour size fell (by > 50%) in 1 patient by 6 months but this patient had undergone chemoembolisation one month prior to the start of the study. Most patients had tumour size stabilisation (76 and 68%) or progression (20 and 24%) at 3 and 6 months, respectively. Dose escalation from 1.5 to 3.0 mg did not significantly improve clinical, biochemical or tumour responses. The treatment was well tolerated with minor adverse events. In an open pilot phase II study of 19 patients (mean age 58 years), patients were given high dose somatuline with a maintenance dose of 12,000 mg/day in 4 divided s.c. injections. U-5-HIAA, which was elevated in 13 patients with a mean of 444 mumol/day before the start, was reduced to 58% of baseline at 3 months, 68% at 6 months (p = 0.04), 66% at 9 months and 75% at 12 months (p = 0.14). P-chromogranin was elevated in 18 patients, with a mean of 5,300 micrograms/l before the start, and was reduced to 52, 55, 63 and 64% of the baseline at 3, 6 (p = 0.039), 9 and 12 (p = 0.013) months, respectively. In the responding patients, apoptosis was induced.

Octreotide therapy in carcinoid disease.

Octreotide therapy is expensive, but at present it and other somatostatin analogues appear to offer the best opportunity of controlling the symptoms of flushing and diarrhoea. It may also have other properties affecting general well-being. The question of whether it changes tumour growth remains unanswered and there is no convincing evidence that it alters survival. In all published studies the numbers of patients are small and there have been no control groups. However, since no other drug has yet proved effective against flushing, the somatostatin analogues, including octreotide, remain the treatment of choice for the symptomatic control of the carcinoid syndrome. Octreotide is of great therapeutic value pre-operatively and intra-operatively and it is essential that all operating theatres have this drug available for immediate use. Surgical debulking, if feasible, provides the best outcome potential in carcinoid disease. Present evidence suggests that the place of octreotide and other somatostatin analogues is in controlling the symptoms of the disease rather than its progress and in ensuring cardiovascular and respiratory stability during surgical procedures.

Indocyanine green elimination in patients with liver disease and in normal subjects.

1. The validity of a two-compartment pharmacokinetic model for the estimation of the hepatic extraction ratio of Indocyanine Green was tested in six patients with cirrhosis of the liver. 2. No agreement was found between the value of the hepatic extraction ratio measured directly and that calculated using the two-compartment model. 3. To investigate the reasons for the failure of the model, an extended sampling period was used to define the time course of Indocyanine Green in plasma in six healthy subjects and in six patients with cirrhosis of the liver after a bolus injection of the dye. 4. Indocyanine Green was measurable in the plasma for up to 10 h after injection in healthy subjects, and up to 48 h after injection in the patients. The plasma elimination curve in both groups was best described by a triexponential function. 5. The clearance of Indocyanine Green calculated using data collected in the first 20 min after injection overestimated that calculated using data collected for as long as Indocyanine Green was measurable in the plasma. In the patients with cirrhosis the mean overestimate was 87%. 6. Thus, a two-compartment pharmacokinetic model was inappropriate for the description of the disposition of Indocyanine Green and estimates of the hepatic extraction ratio obtained using this model in patients with cirrhosis were inaccurate.

Communication skills and clinical methods: a new introductory course.

In the revised medical curriculum at Sheffield University, a new 4-week introductory clinical course has been introduced to teach communication skills, clinical history-taking and physical examination. There is no formal examination for the course, which has been evaluated by feedback from students and tutors with questionnaires and group discussion.

Elderly patients' understanding of their drug therapy: the effect of cognitive function.

The relationship between cognitive function and knowledge about drug therapy and its risks was examined in 207 elderly patients attending a geriatric outpatient clinic. The patients' reports of their therapy were compared with those of their clinic doctor. Patient-doctor agreement on the number of drugs taken per patient fell with increasing age independently of change in cognitive function. However, knowledge about drugs was related to cognitive function. Many patients taking some of the potentially more dangerous drugs were ignorant of possible side-effects of their treatment. Doctors need to be trained more effectively in communicating with elderly patients about their treatment and its risks.

Abdominal carcinoid tumours in Sheffield.

The incidence, presentation, and treatment strategies of abdominal carcinoid tumours are discussed. In the Trent Region of the UK, carcinoid tumours have an incidence of 0.7 cases/100,000 population. The small bowel is the commonest site (36%) followed by the lung (22%) and appendix (13%). Analysis of the presenting symptoms and signs in 24 cases of small bowel cancer demonstrated diarrhoea in 17, pain in 17, and flushing in 12. Treatment strategies comprise surgery and drug therapy. Sandostatin has a role in preventing the release of pharmacologically active tumour products. A long-term trial of Sandostatin in patients with carcinoid syndrome is underway. Experience to dat indicates Sandostatin is indicated: where surgery and drugs (cyproheptadine and codeine phosphate) in combination have failed to control symptoms; where the patient is unfit for surgery; and to cover anaesthesia and surgery as prophylaxis against the risks of carcinoid crisis.

Direct and indirect measurement of the hepatic extraction ratio of indocyanine green in the rat.

1. In order to estimate liver blood flow in the rat, the extraction ratio of Indocyanine Green was determined using a two-compartment model fitted to the plasma concentration time data after a single intravenous bolus dose and compared with values obtained directly by transhepatic sampling, both in the intact rat and in an isolated perfused rat liver preparation. 2. There was no agreement between estimates of the extraction ratio obtained by using the kinetic model and the directly measured values. 3. Elimination curves for Indocyanine Green were simulated to yield varied clearance values. Despite a 250% variation in clearance, extraction ratios derived using the two-compartment model were all greater than 0.9 and varied by less than 6%. 4. Estimates of liver blood flow obtained by deriving a value of the extraction ratio of Indocyanine Green using the two-compartment model are inaccurate.

Irreversible binding and metabolism of propranolol by human liver microsomes--relationship to polymorphic oxidation.

Studies were performed to investigate the irreversible binding and oxidative metabolism of propranolol in human liver microsomes and the relationship of binding and metabolism to the polymorphic oxidation of debrisoquine. Incubation of microsomes with 14C-labelled propranolol in the presence of a NADPH-generating system gave rise to irreversible binding which increased linearly with time and became saturated at high substrate concentrations. The extent of binding was decreased by the exclusion of cofactors, boiling, anaerobic conditions, and the addition of reduced glutathione and SKF-525A. Trichloropropene oxide had a negligible effect on cofactor-dependent binding. However, debrisoquine, antipyrine and phenacetin decreased binding to a considerable extent. The latter compound abolished cofactor-dependent binding completely at the concentration used (1 mM). Electrophoresis of microsomes which had been incubated with tritiated propranolol revealed that binding was probably occurring to a large number of proteins particularly in the 40,000-90,000 molecular weight range. Glutathione, debrisoquine and antipyrine did not inhibit the 4'-hydroxylation and N-deisopropylation of propranolol. In contrast, phenacetin exerted a very potent inhibitory action on both routes of metabolism. It is concluded that a product or products of propranolol oxidation bind irreversibly but non-selectively to human liver microsomal protein, the enzyme system responsible for the activation of propranolol appears to be related more closely to the cytochrome P-450 system which metabolizes phenacetin than to that metabolising debrisoquine, and radiolabelled propranolol is not a sufficiently specific probe for studying these cytochrome P-450 systems.

The impairment of lignocaine clearance by propranolol--major contribution from enzyme inhibition.

To account for a 40% lowering of the systemic clearance of lignocaine by propranolol treatment it has been proposed that propranolol reduces liver blood flow by 25% and causes a 50% decrease in the intrinsic clearance of lignocaine by enzyme inhibition. In theory, the contribution of direct enzyme inhibition is best evaluated using oral administration of lignocaine when models of hepatic drug clearance predict that propranolol could increase the AUCpo of lignocaine by 100-140%. This hypothesis was tested in six healthy men who received 200 mg lignocaine HCl X H2O orally with and without propranolol pre-treatment (80 mg twice daily for 3 days). Propranolol treatment increased the mean plasma AUCpo of lignocaine by 113 +/- 58 s.d.% (P less than 0.005); it increased the peak plasma lignocaine concentration by 79 +/- 50 s.d.% (P less than 0.025) and it prolonged the elimination half-life of lignocaine by 20 +/- 13 s.d.% (P less than 0.05). Propranolol treatment lowered indocyanine green clearance by 11 +/- 15 s.d.%, but this change was not significant statistically. These experimental results are in accord with the theoretical predictions suggesting that propranolol lowers the systemic clearance of lignocaine mainly by direct inhibition of its metabolism rather than by a lowering of the hepatic blood flow.

Penbutolol and propranolol: a comparison of their effects on antipyrine clearance in man.

The effects of two beta-adrenoceptor antagonists, penbutolol (administered on separate occasions as (+/-)- and (-)-forms) and propranolol, on the kinetics of antipyrine were studied in eight normal subjects. At the same degree of beta-adrenoceptor blockade, as assessed by the lowering of exercise tachycardia, propranolol decreased antipyrine clearance by 31 +/- 11 s.d.% (P less than 0.001) whereas neither of the two penbutolol formulations had a significant effect. The volume of distribution of antipyrine was unchanged following any of the beta-adrenoceptor antagonist treatments. The lack of effect of penbutolol on oxidative drug metabolism is not consistent with in vitro data suggesting a relationship between the lipid solubility of beta-adrenoceptor antagonists and inhibition of metabolism.

The effect of beta-adrenoceptor antagonists on the pharmacokinetics and pharmacodynamics of warfarin after a single dose.

The effects of three beta-adrenoceptor antagonists (propranolol, metoprolol and atenolol) on the serum kinetics and pharmacodynamics of warfarin given in a single oral dose (15 mg) were studied in six normal subjects. At the same degree of beta-adrenoceptor blockade, as assessed by the decrease of exercise tachycardia, propranolol increased the area under the serum warfarin concentration time curve (AUC) by 16.3 +/- 14.2 s.d.% (P less than 0.01) and the maximum serum warfarin concentration by 23.0 +/- 14.3 s.d.% (P less than 0.001). Atenolol increased the maximum serum warfarin concentration by 12.5 +/- 12.3% s.d. (P less than 0.05) but was without effect on warfarin AUC. Metoprolol had no effect on warfarin kinetics. The extent of changes in the prothrombin time and the plasma clotting Factor VII activity caused by warfarin were not altered by any of the beta-adrenoceptor antagonists.