Unresolved pulmonary embolism: the role of fibrinolysis.

A minority of patients with acute pulmonary embolism (PE) show failure of resolution when assessed by serial ventilation/perfusion (V/Q) radionuclide lung imaging. The fibrinolytic systems were studied in six such patients (group I), and in 11 patients in whom PE had resolved (group II), together with 17 healthy control subjects. Assays of the fibrinolytic system included euglobulin clot lysis times (ECLT), tissue plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1). Euglobulin clot lysis times were not prolonged in the unresolved PE group, but were significantly longer in patients in group II when compared to control subjects (P < 0.03). This could not be explained either on the basis of tPA levels, which were higher in group II when compared to group I (P < 0.05) and control subjects (P < 0.02), or on the basis of PAI-1 levels which did not differ significantly between the three groups. Our inability to demonstrate derangements of fibrinolysis in the patients with unresolved PE makes defective fibrinolysis an unlikely aetiological factor in the persistence of thrombosis in these patients.

The treatment of resistant neuroblastoma with 131I-mIBG: alternative methods of dose prescription.

A UK multi-centre study has been carried out to collect medical and dosimetry data from treatments with 131I-metaiodobenzylguanidine (mIBG) for patients suffering from resistant neuroblastoma. All data have been acquired in a standardised way, following strict physics and clinical protocols. The accuracy of three different methods of dose prescription was studied. The results show that the most accurate method involved the use of an initial tracer study to determine the therapeutic activity required to deliver a predetermined absorbed whole-body (WB) dose.

Radiolabelled metaiodobenzylguanidine targeted radiotherapy for malignant phaeochromocytoma.

Metaiodobenzylguanidine (MIBG) targeted radiotherapy is a promising treatment for malignant phaeochromocytoma. It is an effective palliative therapy and may influence prognosis by reducing tumour metabolic function and preventing excessive catecholamine secretion. Repeated treatments are necessary to achieve tumour arrest and disease regression, and it is essential that patients are followed closely for life. Toxicity is limited to myelosuppression but is cumulative. Bone marrow harvesting is recommended for all patients who are likely to undergo repeated treatments. Heightened clinical awareness and easier diagnosis of malignancy using MIBG scintigraphy are likely to result in an increasing number of referrals for treatment. It is essential, therefore, that experience is pooled from individual centres and that patients are treated according to agreed protocols, so that results can be directly compared.

Strontium-89 chloride for pain palliation in prostatic skeletal malignancy.

In a multi-centre study strontium-89 was shown to be effective in relieving bone pain from prostatic carcinoma in patients who had failed conventional therapies. Of 83 patients assessed at 3 months, following the administration of a dose of at least 1.5 MBq/kg, 75% derived benefit and 22% became pain free. Symptomatic improvement usually occurred within 6 weeks and continued for between 4 and 15 months (mean 6 months). Based on the dose estimation part of this study the recommended dose of strontium-89 is 150 MBq. Toxicity was low, provided platelet levels were above 100 x 10(9) l-1 at the time of treatment. Repeat treatments with strontium-89 may be given at intervals of not less than 3 months. Strontium-89 is administered intravenously on an out-patient basis with no special radiological protection precautions.

Association of hypovolemia after subarachnoid hemorrhage with computed tomographic scan evidence of raised intracranial pressure.

Hypovolemic patients are more likely to suffer delayed cerebral ischemia and infarction after a subarachnoid hemorrhage (SAH). Prompt recognition and correction of hypovolemia may improve the outcome. We have identified computed tomographic (CT) scan findings that increase the probability of a patient presenting with hypovolemia soon after an SAH. The plasma volume (PV) of 25 patients admitted within 96 hours of an SAH was measured using radioiodinated serum albumin. The normal PVs were measured in an outpatient setting 6 months later or predicted from their total body water. Nine patients (36%) were found to be hypovolemic, defined as a fall in PV exceeding 10% of the normal PV (mean fall, 18 +/- 2%). Sixteen patients were normovolemic or hypervolemic (mean PV, +9 +/- 2%). The basal cisterns were compressed or obliterated on the CT scans of all hypovolemic patients compared with 12.5% of normovolemic patients (chi-square, 14.52; P less than 0.01). The probabilities of a patient being hypovolemic if the CT scan indicated raised intracranial pressure were high: hydrocephalus, P = 0.80; compression of the basal cisterns, P = 0.82; and compression of the basal cisterns associated with intracerebral hematoma or midline shift, P = 1.00. Patients with an SAH and radiological evidence of raised intracranial pressure should be considered at particular risk for systemic hypovolemia.

Comparison of radionuclide estimation of glomerular filtration rate using technetium 99m diethylenetriaminepentaacetic acid and chromium 51 ethylenediaminetetraacetic acid.

Simultaneous measurements of the clearance rates of technetium 99m diethylenetriaminepentaacetic acid (99mTc-DTPA) and chronium 51 ethylenediaminetetraacetic acid (51Cr-EDTA) were performed in 30 patients with a range of renal function (glomerular filtration rates between 9 and 120 ml/min). Using multiple blood samples, the two clearance values correlated well (r = 0.991, standard error 3.9 ml/min), but DTPA clearance was systematically higher by 7.6%. For each radiopharmaceutical, an equation was derived to correct clearance values obtained using only plasma samples taken at 2 and 4 h for the systematic error inherent in this technique compared with analysis of the complete plasma concentration-time curve. The root mean square error remaining after application of these equations was 1.9 ml/min for both the EDTA and DTPA data. The corresponding errors obtained using the equation derived by Brochner-Mortensen for EDTA plasma clearance were 2.2 ml/min and 1.9 ml/min, respectively, these values were not significantly different from those obtained using the equations derived in this study.

A prospective, randomised double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone.

The palliative efficacy of strontium-89 chloride has been evaluated in a prospective double-blind crossover study comparing it with stable strontium as placebo in 32 patients with prostate cancer metastatic to bone. Response was assessed 5 weeks after each treatment. 26 patients were evaluable. Complete pain relief was only reported following strontium-89 injection. Statistical comparison between placebo and strontium-89 showed clear evidence of a therapeutic response to strontium-89 compared with only a limited placebo effect (P less than 0.01).

The enzyme-inhibitor approach to cell-selective labelling--II. In vivo studies with pIBS in small animals and man.

p-Iodobenzenesulphonamide (pIBS), a potent red cell carbonic anhydrase inhibitor, was used as a carrier for radioiodine in the enzyme-inhibitor approach to cell-specific blood labelling. Radioactivity distribution was monitored in rats and man following i.v. administration of the radiolabelled carrier or of pre-labelled red cells. Rat blood activity fitted a two compartment model; the half-life for overall elimination was 69 +/- 27 h. At 24 h most activity remained associated with red cells, but there was a significant uptake in the large intestine (10 +/- 6%). In man there was no significant accretion by gut or any other organ over 93 h, and the blood clearance was mono-exponential (t1/2 = 9.8 +/- 1.5 days).

Late noninvasive evaluation of cardiac performance in mildly symptomatic older patients with Ebstein's anomaly of tricuspid valve: role of radionuclide imaging.

Ten patients 8 to 54 years of age with isolated Ebstein's anomaly of the tricuspid valve were evaluated by electrocardiography, maximal exercise treadmill testing, 24 h electrocardiographic (ECG) monitoring, echocardiography and rest radionuclide imaging of the left ventricle. The patients presented after the 1st year of life and had not undergone surgical intervention. All except one were in functional class II. No patient had preexcitation on the surface ECG, but abnormal tachyarrhythmias or bradyarrhythmias were seen in five patients on 24 h ECG monitoring. Subnormal exercise performance was observed in five patients. Echocardiography demonstrated typical variable tricuspid valve displacement and paradoxic interventricular septal motion. Left ventricular end-diastolic dimensions were normal in all patients, but posterior wall motion was reduced in two. Moderate to severe tricuspid regurgitation with a Doppler jet velocity less than 2.5 m/s was demonstrated in eight patients. Left ventricular radionuclide scintigraphy revealed a subnormal ejection fraction (less than 50%) in 5 of 10 patients; these 5 had previously shown suboptimal exercise performance. The two youngest patients (less than 15 years) had no arrhythmia, normal exercise performance and normal left ventricular ejection fraction. There was no correlation between the degree of tricuspid valve displacement or regurgitation and the presence of rhythm disturbance, exercise performance or radionuclide left ventricular function. Late evaluation of patients with Ebstein's anomaly may demonstrate significant unsuspected abnormalities in cardiac rhythm, exercise performance and left ventricular function. Radionuclide scintigraphy is a useful noninvasive technique for assessing left ventricular dysfunction in these patients.

A comparison of three indices of relative hepatic perfusion derived from dynamic liver scintigraphy.

Data from dynamic radiocolloid liver scintigraphy (DLS) have been analysed to calculate three indices of relative arterial to total hepatic perfusion. Ninety subjects have been studied, comprising 21 normals, 62 patients with metastatic liver disease and 7 patients with cirrhosis. Correlation coefficients above 0.81 were found in all patient groups between an index based on rates of liver uptake (the hepatic perfusion index, HPI) and a method based on quantitative liver uptake (the mesenteric fraction, MF). A further method employing the spleen to model arterial inflow (hepatic arterial ratio, HAR) had less agreement with both HPI and MF, with correlation coefficients below 0.76. Posterior images have previously been used to calculate HAR, and greater errors are expected in HAR from the anterior images acquired in this study. Receiver operating characteristic analysis showed that the diagnostic performance of HPI and MF indices in metastatic disease were not significantly different. For anterior image data analysis both HPI and MF were superior to HAR.

Regional indices of relative hepatic arterial perfusion from dynamic liver scintigraphy: the variability of indices and the use of parametric imaging.

Regional indices of relative arterial hepatic perfusion have been studied in 21 control subjects following dynamic radiocolloid scintigraphy of the liver (DLS). Three different indices have been calculated: the hepatic perfusion index (HPI); the hepatic arterial ratio (HAR) and the mesenteric fraction (MF). Three regions were defined in the upper, mid and lower right hepatic lobes and the three indices were calculated for each region. There was reasonable agreement between regional values of the same index with inter-regional correlation coefficients above 0.7 and standard errors in straight line fits of less than 0.093. There were significant regional differences for (1-MF) and HPI indices, but not for HAR. The index (1-MF) was calculated for each pixel and presented as a parametric image in 16 control subjects. The parametric images indicated the raised regional arterial indices due to overlying lung, right kidney and aorta. Parametric images may be of value to show the hepatic area free of significant overlying tissue and therefore available for analysis by DLS. However, the results suggest that the observed variability of single pixel indices limit the potential of parametric imaging for the localization of small focal lesions.

Functional assessment of colonic interposition with 99Tcm-labeled milk.

A prospective study was performed to evaluate the use of radionuclide imaging in the assessment of patients who have undergone esophageal reconstruction. Dynamic radionuclide imaging was performed on ten patients aged 11 months to 11 years who had undergone colon interposition via the normal esophageal route for esophageal atresia. Patients were considered clinically unsatisfactory if at the time of imaging feeding was troubled, or if weight gain had fallen to below the third centile before operation and remained below after operation. Each patient underwent erect imaging with a small milk feed labeled with 10 to 20 MBq (250 to 500 muCi) 99Tcm DTPA adjusted according to body surface area; supine studies were subsequently performed on five patients. All five clinically unsatisfactory patients showed conduit emptying delayed beyond 45 minutes and/or spontaneous reflux, significantly different from the clinically satisfactory patients (X2 = 6.4, P less than .02). Conduit complications were subsequently identified in three of the five clinically unsatisfactory patients. Radionuclide imaging with radiolabeled milk was found to be well tolerated, and obtained results that were clinically useful. These results suggest that dynamic radionuclide imaging can be more widely applied in the assessment of esophageal substitutes.

Strontium-89: treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone.

Two hundred and two patients with bone pain from metastatic cancer were treated with 40 microCi/kg of Sr-89. Patients were followed with pain diaries, records of medication taken, sleep patterns, serial bone scans and a Karnofsky Index. One hundred and thirty-seven patients with adequate followup survived at least 3 months, including 100 with prostate and 28 with breast carcinoma. Eighty of the 100 patients with prostate cancer responded, and 25 of the 28 breast cancer patients improved. Ten patients with prostate cancer and five with breast cancer became pain free. Little hematologic depression was noted. Sr-89 kinetic studies showed that strontium taken up in osteoblastic areas remained for 100 days. The tumor-to-marrow absorbed dose ratio was 10:1.

Glomerular filtration rate and the kinetics of 123I-metaiodobenzylguanidine.

We have recently reported evidence that the calcium antagonist nifedipine can improve the tumour retention of 131I-metaidobenzylguanidine (131I-MIBG) in patients with malignant phaeochromocytoma. During studies of the pharmacological modification of tumour MIBG kinetics, it is important to distinguish clearly between a direct effect on MIBG cellular retention by a pharmaceutical, and secondary effects due, for example, to a change in glomerular filtration rate (GFR). In order to provide the fundamental kinetic data required for the numerical modelling of the effect of nifedipine on tumour MIBG kinetics, we have investigated the influence of GFR on MIBG plasma and renal kinetics. The 123I-MIBG plasma curve and MIBG renal plasma clearance rate were studied in ten patients, ranging from subjects without biochemical or scintigraphic evidence of phaeochromocytoma to individuals with widely disseminated metastatic disease. GFR was measured using the 99mTc-DTPA plasma clearance method. In four cases, the studies were repeated with the patients taking oral nifedipine. Statistically significant correlations were found between GFR and the MIBG plasma concentration. MIBG renal plasma clearance rate and the early (0 to 5 min) renal excretion of MIBG. The data permit the evaluation of the plasma integral during the first few min following bolus injection, a quantity important in the numerical modelling of tumour kinetics. GFR was found to have a major influence on whole-body MIBG kinetics, but there was also evidence of the effect of the metastatic tumour burden.

A comparison of methods to measure the percentage hepatic replacement with colorectal metastases.

The percentage hepatic replacement (PHR) with liver metastases has been recognised as an important factor for patient management, prognosis, and clinical trial evaluation. The PHR can be assessed by various methods including ultrasound, radioisotope, or computed tomography (CT) imaging, or by inspection and palpation at laparotomy. We report a prospective study comparing these methods of PHR assessment in 56 consecutive patients with colorectal liver metastases. When all four methods were used complete agreement was achieved in only 35% of cases (9/26). The three imaging techniques agreed in only 37% of cases (14/38). Overall, the correlation between different methods was poor with a tendency for surgery to underestimate the PHR. However, CT and surgery agreed in 81% of cases (21/26), and CT gave a higher estimate than surgery in each of the other five patients. With such variability in the estimates of PHR derived from these different techniques, consideration must be given to which technique is used. It is concluded that CT is probably the most accurate for PHR assessment at present.

Strontium-89 therapy: measurement of absorbed dose to skeletal metastases.

We report measurements of absorbed dose to vertebral metastases in ten patients referred for 89Sr therapy for disseminated prostatic carcinoma. Patients received a tracer dose of 85Sr at the time of 89Sr treatment and metastatic strontium retention was monitored scintigraphically for 6 mo. Metastatic 85Sr activity corrected for tissue attenuation was measured using the conjugate view principle, with special care taken to eliminate errors due to the selection of the metastatic region of interest. Metastatic volume was determined from high resolution CT images, and density inferred from Hounsfield number using the QCT bone mineral calibration of Genant and Cann. The mean absorbed dose was 850 rad/mCi (23 cGy/MBq) with a range from 220-2260 rad/mCi (6 to 61 cGy/MBq). The wide range found was consistent with the variation expected to arise due to differences in strontium renal plasma clearance (range 0.1-11.81/day) and extent of skeletal metastatic disease (varying from two small metastases to a superscan on [99mTc]MDP images) among the patients studied.

Modification by nifedipine of 131I-meta-iodobenzylguanidine kinetics in malignant phaeochromocytoma.

Following a case report that oral nifedipine can suppress the secretion of noradrenaline by phaeochromocytoma, we examined the effect of nifedipine on the tumour kinetics of tracer 131I-meta-iodobenzylguanidine (131I-mIBG) in five patients referred for mIBG radionuclide therapy for disseminated malignant phaeochromocytoma. In one subject a striking modification of mIBG kinetics was found that resulted in a doubling of the absorbed dose to tumour while the patient was taking nifedipine. At the same time, urinary excretion of noradrenaline was suppressed by a factor of three. The effect of nifedipine in this patient was confirmed when tracer studies were repeated nine months later. The changes in tumour kinetics were shown to be due to prolonged retention of mIBG rather than increased tumour blood flow or alteration of the curve of mIBG plasma concentration as a function of time.