Biomedical subjects
A J Coakley
Publications and source records attributed to A J Coakley.
Pentavalent rhenium-188 dimercaptosuccinic acid for targeted radiotherapy: synthesis and preliminary animal and human studies.
Pentavalent rhenium-188 dimercaptosuccinic acid [188Re(V)DMSA] is a beta-emitting analogue of 99mTc(V)DMSA, a tracer that is taken up in a variety of tumours and bone metastases. The aim of this study was to develop the kit-based synthesis of the agent on a therapeutic scale, to assess its stability in vivo, and to obtain preliminary biodistribution and dosimetry estimates, prior to evaluation of its potential as a targeted radiotherapy agent. The organ distribution of 188Re in mice was determined 2 h after injection of 3 MBq 188Re(V)DMSA prepared from eluate from a 188W/188Re generator. Three patients with cancer of the prostate and three with cancer of the bronchus, all with bone metastases confirmed with a standard 99mTc-hydroxymethylene diphosphonate (99mTc-HDP) scan, were given 370 MBq 188Re(V)DMSA and imaged at 3 h and 24 h using the 155-keV gamma-photon (15%). Blood and urine samples were collected to determine clearance and to analyse the speciation of 188Re. Organ residence times were estimated from the scans, and used to estimate radiation doses using MIRDOSE 3. In mice, 188Re(V)DMSA was selective for bone and kidney. In patients, it showed selectivity for bone metastases (particularly those from prostate carcinoma) and kidney, but uptake in normal bone was not significantly greater than in surrounding soft tissues. Of the normal tissues the kidneys received the highest radiation dose (0.5-1.3 mGy/MBq). The images were strongly reminiscent of 99mTc(V)DMSA scans in similar patients. High-performance liquid chromatography analysis of blood and urine showed no evidence of 188Re in any chemical form other than 188Re(V)DMSA up to 24 h. In conclusion, 188Re(V)DMSA and its 186Re analogue warrant further clinical assessment as generator/kit-derived agents for treatment of painful bone metastases. These agents should also be assessed in medullary thyroid carcinoma and other soft tissue tumours which have been shown to accumulate 99mTc(V)DMSA.
Therapeutic implications of thymic uptake of radioiodine in thyroid carcinoma.
The management of 38 consecutive patients with differentiated thyroid carcinoma in the period 1991-1996, who each received at least one therapy dose of iodine-131, was reviewed, looking in particular at those in whom anterior mediastinal uptake was demonstrated on scans taken 3 and 7 days post-therapy. Such activity was noted in ten patients. On the basis of clinical follow-up, thyroglobulin measurement and radiological and other scintigraphic imaging, in nine of the ten patients the anterior mediastinal activity was attributed to physiological thymic uptake. Of those nine, all were under 50 years of age; seven were considered disease free, one had residual disease in the neck and one had distant metastases. Physiological uptake by the thymus was more prominent on the 7-day scans and in patients with low tumour volumes. For appropriate patient management it is essential to recognise that physiological uptake of 131I by the thymus in patients under 50 years of age is a potential cause of false-positive therapy scans.
Drug therapy alternatives in the treatment of thyroid cancer.
Therapy of thyroid cancers is based on the removal of the primary disease by surgery, replacement of the hormonal deficiencies and subsequent therapy of the recurrent and metastatic disease. The metabolic characteristics of many thyroid tumors mean that radionuclide techniques have been used in the identification of sites of tumour and their subsequent therapy. Differentiated thyroid cancers, papillary, follicular and mixed papillary follicular, are treated by surgery--usually a total or subtotal thyroidectomy. Postoperatively, patients have thyroxine as a replacement therapy and to suppress thyroid-stimulating hormone production. Radioiodine therapy is often given to ablate the thyroid remnant. This allows (a) adequate follow-up of patients using thyroglobulin measurements and assessment scans as necessary, and (b) further therapy with radioiodine for metastatic disease. Patients with a short effective half-life of radioiodide may require higher activities or pharmacological methods of prolonging the retention half-times of iodine. The use of chemotherapy in this group of tumors is limited and at best provides palliation. The overall prognosis is good for differentiated thyroid cancer; papillary carcinomas have an 80 to 90% 10-year survival, whereas follicular tumors are associated with a 65 to 75% 10-year survival. Medullary carcinomas may be sporadic or familial, and some of the latter form part of a multiple endocrine neoplasia syndrome (MEN). Primary treatment is surgery, and total thyroidectomy is usually recommended since tumours are often multifocal. The use of radiolabelled metaiodobenzylguanidine (MIBG) and 111In octreotide as potential therapeutic agents has been explored and may be potentially useful in palliative care. Chemotherapy is of limited benefit. The 10-year survival for medullary carcinomas is 60 to 70%. Anaplastic tumours of the thyroid are usually aggressive, with a high mortality. Treatment is palliative by surgical debulking; some patients may benefit from local radiotherapy or occasionally chemotherapy. The use of therapeutic doses of radionuclides is well tolerated, although it may be associated with a variety of mostly transient adverse effects, including gastritis, thyroiditis and sialadenitis. Therapy with high activities of radioiodine require radiation protection precautions. Despite retreatment with radioiodine there appear to be no long term effects on the fertility of patients, and healthy children are born to women receiving this treatment. 131I remains perhaps the most specific cancer therapy available today and has few adverse effects. It is difficult to see any marked improvement being developed for differentiated thyroid cancer, with the possible exception of targeted gene therapy.
Out-of-hours weekend scintigraphy: luxury or necessity?
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The effects of standardization and reference values on patient classification for spine and femur dual-energy X-ray absorptiometry.
The effect of two methods for standardizing dual-energy X-ray absorptiometry (DXA) measurements on patient classification by the T-score has been determined for a group of over 2000 patients. The methods proposed by the International DXA Standardization Committee and the European Community's COMAC-BME group were used in conjunction with young reference data from the major DXA manufacturers, the COMAC-BME group and the third US National Health and Nutrition Examination Survey (NHANES III). The two standardization techniques produced dissimilar classifications as measured by the kappa statistic (kappa = 0.34-0.90), especially for the femoral neck, with up to 24.3% of patients reclassified from osteopenic to normal and 18.6% reclassified from osteoporotic to osteopenic when the standardization method was changed. Considering the effects of both reference data and standardization techniques together, there was a wide variation of patient classification, with the number of patients classified as osteoporotic varying from 9.6% to 21.1% for the postero-anterior spine L2-4 region and from 2.3% to 27.6% for the femoral neck. The agreement between different classifications ranged widely, from very poor to excellent (kappa = 0.02-0.98). The creation of standardized reference data must be an important priority in order to harmonize patient management using standardized BMD measurements. The choice of standardization technique, however, must be addressed in light of the results presented here.
Pentavalent 99Tcm-DMSA imaging in patients with bone metastases.
Pentavalent 99Tcm-dimercaptosuccinic acid (99Tcm-(V)DMSA) has an established role in imaging medullary thyroid carcinoma. There have been case reports of uptake in bone metastases. Our aims were to compare 99Tcm-(V)DMSA with 99Tcm-hydroxymethylene diphosphonate (99Tcm-HDP) in bone metastases, to assess its value in imaging of bone metastases, and to assess the prospects of the beta-emitting analogues 186/188Re-(V)DMSA as palliative agents for painful bone metastases. Ten patients confirmed by a 99Tcm-HDP bone scan to have bone metastases secondary to carcinoma of the prostate, lung or breast were injected with 99Tcm-(V)DMSA (600 MBq). Whole-body scans acquired at 3 and 24 h were compared with the 99Tcm-HDP bone scans. 99Tcm-(V)DMSA showed high soft tissue background, kidney retention and avid uptake in most bone metastases: 86% of bone lesions identified on bone scans were detected with 99Tcm-(V)DMSA. The lesion-to-normal ratios were comparable to or lower than those for 99Tcm-HDP at 3 h, but increased by 24 h. Instances of abnormal uptake in liver, primary lung tumour, lymph nodes and pleural effusion were observed. We conclude that 99Tcm-(V)DMSA is a tracer for bone metastases (with lower sensitivity than 99Tcm-HDP) and soft tissue tumours. If 186/188Re-(V)DMSA behave similarly, they may find use in therapy for soft tissue tumours and bony metastases.
Radiation dose rates from patients receiving iodine-131 therapy for carcinoma of the thyroid.
Patients treated with radioiodine present a radiation hazard and precautions are necessary to limit the radiation dose to family members, nursing staff and members of the public. The precautions advised are usually based on instantaneous dose rates or iodine retention and do not take into account the time spent in close proximity with a patient. We have combined whole-body dose rate measurements taken from 86 thyroid cancer patients after radioiodine administration with published data on nursing and social contact times to calculate the cumulative dose that may be received by an individual in contact with a patient. These dose estimates have been used to calculate restrictions to patients behaviour to limit received doses to less than 1 mSv. We have also measured urinary iodide excretion in 19 patients to estimate the potential risk from the discharge of radioiodide into the domestic drainage system. The dose rate decay was biexponential for patients receiving radioiodine to ablate the thyroid after surgery (the ablation group, A) and monoexponential for these receiving subsequent treatments for residual or recurrent disease (the follow-up group, FU). The faster clearance in the follow-up patients generally resulted in less stringent restrictions than those advised for ablation patients. For typical activities of 1850 MBq for the ablation patients and 3700 MBq or 7400 MBq for the follow-up patients, the following restrictions were advised. Patients could travel in a private car for up to 8h on the day of treatment (for an administered activity of 1850 MBq in group A) or 4 and 2h (for activities of 3700 or 7400 MBq in group FU) respectively. Patients should remain off work for 3 days (1850 MBq/group A) or 2 days (up to 7400 MBq/group FU). Partners should avoid close contact and sleep apart for 16 days (1850 MBq/group A) or 4-5 days (3700 or 7400 MBq/group FU). Contact with children should be restricted according to their age, ranging from 16 days (1850 MBq/group A) or 4-5 days (3700 or 7400 MBq in group FU) for younger children, down to 10 days (1850 MBq/group A) or 4 days (up to 7400 MBq/group FU) for older children. The cumulative dose to nursing staff for the week after treatment was dependent on patient mobility and was estimated at 0.08 mSv for a self-caring patient to 6.3 mSv for a totally helpless patient (1840 MBq/group A). Corresponding doses to nurses looking after patients in group FU were 0.18-12.3 mSv (3700 MBq) or 0.36-24.6 mSv (7400 MBq). Sensible guidelines can be derived to limit the dose received by members of the public and staff who may come into contact with cancer patient treated with radioiodine to less than 1 mSv. The rapid clearance of radioiodine in patients treated on one or more than one occasion means that therapy could be administered at home to selected patients with suitable domestic circumstances. In most cases the restriction times, despite the high administered activities, are less than those for patients treated for thyrotoxicosis. The concentration of radioiodide in domestic drainage systems should not pose a significant risk.
Assessment of changes in dual-energy X-ray absorptiometry performance following a system upgrade.
System upgrades are a constant feature of many highly technical specialties and are normally assumed to have a negligible effect on patient data. We report on the assessment of an upgrade made to a Norland XR-26 dual-energy X-ray absorptiometry (DXA) system. The upgraded version (2.3) consisted of new hip positioning aids, hip image analysis software and updates to the normal ranges. Measurements of femoral neck and trochanteric bone mineral density correlated well between versions (r = 0.969 and r = 0.971), those for femoral neck and trochanteric bone mineral content less well (r = 0.956 and r = 0.911), and Ward's triangle values and femoral neck area measurements were poorly correlated (r = 0.719-0.881). The upgrade was claimed to improve precision while reducing analysis and imaging time. Improved precision was not demonstrated, with good precision found both before and after the upgrade. Correlation between femoral neck Z-scores were good for the European normal range (r = 0.970), but unacceptable for the UK range (r = 0.769). These correlations were not close enough to allow patients scanned with the old version to be followed up with scans using the upgrade. The upgrade was, however, preferred for new attenders because of the improved speed and automation of hip analysis, without loss of precision. The most important implication in terms of patient management was the change made to the UK normal range, which had a very large effect on the number of patients deemed to be at risk from osteoporosis. It is essential that any upgrade introduced to an existing DXA system is carefully evaluated, since it may affect system performance and patient results.
RCP guidelines: the use of radioiodine in the management of hyperthyroidism.
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Bone mineral densitometry in clinical practice. Differences in reference values are important.
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Timing of VQ ventilation perfusion scanning.
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Ventilation and perfusion lung imaging--which nebulizer?
Three commercially available 99Tcm-diethylenetriamine pentaacetate (99Tcm-DTPA) aerosol delivery nebulizers for lung ventilation imaging were investigated. Two were air-jet systems, 'Optimist' (Medicaid) and 'Microcirrus' (Amersham), and one was an ultrasonic device (Europlus). Altogether, 112 consecutive patients were scanned, 37 using the Optimist, 40 using the Microcirrus and 35 the Europlus. The age mix, FEV1, FVC and PEFR measurements of the patients in each group were similar. Each contained a proportion of patients with poor respiratory function, with PEFR rates ranging from 30 to 582 l min-1 for patients studied with all systems. Ease of use, image quality and cost were evaluated as well as radioactive and microbiological contamination. The Optimist system gave the best combination of image quality and cost, and was associated with the lowest level of radioactive contamination. It also proved the most popular. Airborne contamination for all nebulizers was lower than previously reported and was largely dependent on patient compliance. With poorly compliant patients, the contamination levels are sufficient to warrant an extraction device. There was no evidence of bacterial contamination of the nebulizers or tubing on repeated use over 5 days.
Parathyroid imaging.
Developments in technology mean that it is now possible to localize abnormal parathyroid glands by a variety of imaging methods. There remain a number of unresolved issues. With all commonly used methods (radionuclide imaging, ultrasound, computed tomography and magnetic resonance imaging), there are wide variations in sensitivity of detection of glands, and in many cases this variation is not explained satisfactorily. The necessity for imaging is questioned by many parathyroid surgeons, particularly before a first operation. However, parathyroid surgery is itself changing, with a trend towards more limited neck exploration, which requires localization of the glands pre-operatively. This review describes the methods available for localizing parathyroid glands, with their advantages and limitations, and discusses the role of the techniques prior to surgery.
A survey of dual-energy X-ray absorptiometry (DEXA) normal reference ranges used within the UK and their effect on patient classification.
Differences between dual-energy X-ray absorptiometry (DEXA) normal ranges can lead to patients being characterized as osteoporotic using one range and normal using another. To investigate the diversity of normal ranges used within the UK, a survey of all DEXA sites was carried out with a 60.6% response rate. The effect of the different ranges was evaluated by translating each range to an equivalent range for a Norland XR-26 system and applying the ranges to stratify a representative sample of over 1000 patients into grades of bone density based on percentages of age-matched mean BMD, Z-scores and T-scores. The effect of femoral neck and P/A spine L2-L4 regions was considered both separately and jointly. Large differences between the normal ranges were apparent, which resulted in the classification of the number of patients with a Z-score of less than -2.0 varying by a factor of more than 20 for the femoral neck and more than 3 for the spine. The number of patients defined as osteoporotic by a T-score less than -2.5 varied from none to over one-third of patients for the hip and by a factor of almost 3 for the spine. The exclusion criteria used for construction of the normal ranges varied markedly with none constructed using population-based sampling. Smoothing of normal ranges was carried out by DEXA manufacturers, while local normal ranges made use of raw unprocessed data. There is reason to question the validity of such processing. We recommend the construction of a unified UK normal range applicable to all UK DEXA systems in order to harmonize patient management and care.
Home reporting for the nuclear clinician?
The computer-based 'home office' is becoming a widely accepted mode of operation for modern businesses. It is implausible to believe that a nuclear medicine department can be covered permanently at a distance by a single physician, but it should be possible to provide cover for colleagues during sickness or at night or weekends. We have used a 486 PC with a high-resolution screen and software provided by LINK Medical Ltd to obtain images from hospital sites using a modem link to ADAC, Bartec and Nuclear Diagnostic SUN workstations. The data were transferred via standard telephone lines to the homes of two of the authors. During a trial period lasting several months, 60 lung scans, 20 bone scans, 1 gastrointestinal bleeding study, 4 leukocyte scans, 5 bone tomograms, 9 renograms, 6 myocardial perfusion tomograms and 2 gated cardiac studies were transferred. The system allowed transfer of a 128 x 128 eight-view lung scan to be completed in approximately 2 min. The program on the PC allowed alteration of individual image contrast, image rotation, cine display and a variety of colour scales to enhance image interpretation. A system to transfer chest X-rays has been developed and typical transfer times are approximately 3.5 min. Within the viewing protocol on the PC, a reporting window was available with the ability to fax the report directly to the hospital. The system allowed consultants who live at a distance from their nuclear medicine departments to provide cover and is now used as an integral part of our out-of-hours service. The system also allows cover of satellite units or to provide cover for junior staff at night or weekends.
Dual energy X-ray absorptiometry normal reference range use within the UK and the effect of different normal ranges on the assessment of bone density.
The number of different normal ranges used on dual energy X-ray absorptiometry (DEXA) machines in the United Kingdom was determined by means of a postal questionnaire. Both femoral neck and posteroanterior spine L2-L4 regions were considered. It was clear from this survey that a variety of normal ranges were in use for all manufacturers of DEXA systems. The effects of four normal ranges supplied by Norland for use within the UK on the stratification of over 1000 consecutive patients into different grades of bone mineral density (BMD) and Z-score were examined. The main outcomes measure the number of patients with BMD less than 80% of mean age-matched BMD and Z-score less than -1.5 over the femoral neck and spine for each normal range. The percentage of patients for each normal range with BMD less than 80% of mean for the femoral neck were 24.6%, 7.4%, 17.5% and 11.1% and for the spine 12.1%, 7.4%, 16.5% and 14.4%, respectively. For the femoral neck, 21.2%, 5.0%, 12.9% and 12.1% of patients had Z-scores of less than -1.5, for the spine this was 7.9%, 8.1%, 14.2% and 13.6% of patients. These differences between ranges are large enough to influence patient management--patients may be diagnosed as osteoporotic using one range and normal using another. The relationship between hip and spine measurements was also studied as some therapeutic agents do not affect BMD equally at all anatomical sites. The number of patients with a lower hip than spine BMD grade varied from 12.3% to 34.4%, and with a lower hip than spine Z-score from 14.0% to 43.4%. Choice of normal range thus has a critical effect on the categorization of osteoporotic patients using DEXA. The wide variety of normal ranges indicates that there are likely to be differences in patient management throughout the country. This will be an increasing problem due to the ability of NHS purchasers to switch contracts from one provider to another.