Development of patient-specific molecular imaging phantoms using a 3D printer.

PURPOSE: The aim of the study was to investigate rapid prototyping technology for the production of patient-specific, cost-effective liquid fillable phantoms directly from patient CT data. METHODS: Liver, spleen, and kidney volumes were segmented from patient CT data. Each organ was converted to a shell and filling holes and leg supports were added using computer aided design software and prepared for printing. Additional fixtures were added to the liver to allow lesion inserts to be fixed within the structure. Phantoms were printed from an ultraviolet curable photopolymer using polyjet technology on an Objet EDEN 500V 3D printer. RESULTS: The final print material is a clear solid acrylic plastic which is watertight, rigid, and sufficiently durable to withstand multiple assembly and scanning protocols. Initial scans of the phantoms have been performed with Tc-99m SPECT and F-18 PET/CT. CONCLUSIONS: The organ geometry showed good correspondence with anatomical references. The methodology developed can be generally applied to other anatomical or geometrical phantoms for molecular imaging.

Clinical applications of dosimetry for mIBG therapy.

Metaiodobenzylguanidine (mIBG), developed 30 years ago, is taken up by tumours expressing the noradrenaline transporter. Radiolabelled with I-123 or I-131, mIBG has become a gold standard for diagnostic imaging of pediatric and adult neuroendocrine cancer. Within a few years of its clinical introduction, I-131 mIBG was found to be an effective palliative treatment with minimal toxicity that in some cases could produce a complete response. The importance of internal dosimetry for I-131 mIBG therapy has been demonstrated by a number of studies showing that absorbed doses delivered to tumours and organs-at-risk from standard and weight-based activities can vary by an order of magnitude. However, significant correlations between the whole-body absorbed dose and myelotoxicity have been demonstrated and studies based on this relationship have enabled treatments to be tailored to the individual. Ongoing developments include patient-specific treatment planning based on tumour dosimetry and cocktails of radionuclides and radiosensitisers.

High activity Rhenium-186 HEDP with autologous peripheral blood stem cell rescue: a phase I study in progressive hormone refractory prostate cancer metastatic to bone.

We tested the feasibility and toxicity of high activities Rhenium-186 hydroxyethylidene diphosphonate, with peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. Twenty-five patients received between 2500 and 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate followed 14 days later by the return of peripheral blood peripheral blood stem cells. Activity limiting toxicity was defined as grade III haematological toxicity, lasting at least 7 days, or grade IV haematological toxicity of any duration or any serious unexpected toxicity. Activity limiting toxicity occurred in two of six who received activities of 5000 MBq and maximum tolerated activity was defined at this activity level. Prostate specific antigen reductions of 50% or more lasting at least 4 weeks were seen in five of the 25 patients (20%) all of whom received more than 3500 MBq of Rhenium-186 hydroxyethylidene diphosphonate. The actuarial survival at 1 year is 54%. Administered activities of 5000 MBq of Rhenium-186 hydroxyethylidene diphosphonate are feasible using autologous peripheral blood peripheral blood stem cell rescue in patients with progressive hormone refractory prostate cancer metastatic to bone. The main toxicity is thrombocytopaenia, which is short lasting. A statistically significant activity/prostate specific antigen response was seen. We have now commenced a Phase II trial to further evaluate response rates.

Value of protein-bound radioactive iodine measurements in the management of differentiated thyroid cancer treated with (131)I.

Measurement of the protein-bound radioactive iodine level (PBI(131)) in the plasma of patients following (131)I-iodide administration for thyroid cancer has been re-examined in a retrospective study of 171 patient episodes. It is shown that whereas the previously used threshold value for the measurement at 6 days does not correlate well with the 3-day whole body scan, there is good agreement between the scan and the temporal changes in PBI(131) from 1-6 days: an increasing PBI(131) correlates with a positive scan, and a decreasing PBI(131) with a negative scan. The area under the curve (AUC) for the PBI(131)-time curve is related to the absorbed dose for the tumour. For a small group of 11 patients, dosimetry estimates were made from serial scans, quantified with phantoms; these absorbed doses correlated with the AUC and the 6-day PBI(131). Therefore, it is suggested that these parameters may be useful in predicting absorbed radiation dose in these patients.

Three-dimensional dosimetry for intralesional radionuclide therapy using mathematical modeling and multimodality imaging.

UNLABELLED: A method of dosimetry is described that quantifies the three-dimensional absorbed-dose distribution resulting from an intralesional administration of a radiolabeled monoclonal antibody, allowing for both spatial and temporal heterogeneity of distribution of the radionuclide and without the need for a calibration scan. METHODS: A mathematical model was developed to describe the distribution of activity as a function of time resulting from infusion at a single point within the solid component of a tumor. The parameters required for this model are either known directly or may be obtained from SPECT image data registered to computed tomography. Convolution of this distribution with a point-source dose kernel enabled the three-dimensional absorbed-dose distribution to be obtained. RESULTS: This method was applied to a set of patient data acquired in the course of a clinical study performed at our center, and dose profiles and dose-volume histograms were produced. It was shown that the three-dimensional distribution of dose was significantly nonuniform. CONCLUSION: Initial results suggest that this method offers a means of determining the absorbed dose distribution within a tumor resulting from intralesional infusion. This method extends the Medical Internal Radiation Dose computation, which, in these circumstances, would make erroneous assumptions. Furthermore, it will enable individual patient treatment planning and optimization of the parameters that are within the clinician's control.

Absolute 99Tcm-DMSA renal uptake in children: a study of 321 kidneys.

Absolute 99Tcm-dimercaptosuccinic acid (DMSA) uptake was measured in 160 children ranging in age from 3 months to 15 years. In total, 108 pairs of kidneys were normal and the mean uptake for the left and right kidneys was 24.0 and 23.4%, respectively. The mean summed uptake for the left and right kidneys was 47.3%. A method of calculation based on the geometric mean of the anterior and posterior views was used to allow for radiation attenuation. DMSA uptake did not vary significantly with the age of the child. The value of the method in the assessment of abnormal kidneys is presented. The effect of using a supine or prone position for the anterior view was also investigated.

Absolute 99Tcm-DMSA renal uptake in children: optimum time to scan.

Absolute renal uptake was measured at 2, 4 and 6 h in 27 patients in order to determine a more convenient time for uptake compared with the 6-h measurement proposed by other authors. Measurements made at 2 and 4 h would need to be increased by 20 and 6%, respectively, to convert to the value at 6 h. Measurements at 4 h are a reasonable compromise to achieve a high-count/low-background image in a reasonable time and to obtain a good estimate of the predicted 6 h uptake at a single scanning session. The percent renal uptake at 6 h, U(6), can be derived from the percent uptake measured at t hours after injection, U(t), using the following formula: U(6) = U(t) x CF(t), where CF(t) = 1.0 + 0.03 (6 - t) for 4 < or = t < or = 6.

Microangiopathy of the skin and the effect of leg compression in patients with chronic venous insufficiency.

PURPOSE: The reasons for the efficacy of leg compression in the treatment of chronic venous insufficiency are not clear. We have used laser Doppler fluxmetry to assess the effect of external compression on the skin microcirculation. METHODS: Fifteen patients with lipodermatosclerosis caused by chronic venous insufficiency and 15 control subjects were studied in the supine and sitting positions. The laser Doppler probe, incorporated in a polyethylene chamber, was applied to the lower leg underneath a blood pressure cuff. Pressures were applied from 10 to 100 mm Hg in increments of 10 mm Hg. A computer data logging system recorded laser Doppler flux blood cell velocity, and concentration of moving blood cells. RESULTS: In patients in the supine position, 20 mm Hg compression resulted in a median increase of 33% in laser Doppler flux, and a median increase of 79% in blood cell velocity, but higher pressures caused a progressive decrease in laser Doppler flux and blood cell velocity. With the patient in the sitting position, compression up to 60 mm Hg caused an increase in laser Doppler flux (median percentage increase at 20 mm Hg compression 84%) and blood cell velocity (median percentage increase at 20 mm Hg compression 22%). At 20 mm Hg compression, the concentration of moving blood cells decreased in the supine position (median percentage fall 27%) but did not change significantly in the dependent position. The effects of compression in control subjects were similar to those in patients, but to a lesser degree. CONCLUSION: Our study suggests that compression treatment may achieve part of its effect by causing an increase in the microcirculatory flow velocity.

Microvascular investigations in diabetes mellitus.

This paper reviews the current literature concerning the different investigative modalities available to assess the microcirculation in diabetic microangiopathy. The advantages and disadvantages of the different invasive and noninvasive methods available are presented objectively. We have concentrated on the tests that provide a quantitative assessment of the microcirculation, including laser Doppler fluxmetry, capillary microscopy, plethysmography, transcutaneous oximetry and radioactive isotope clearance. Some of the invasive methods described are now being replaced by noninvasive equivalents, providing similar information with less discomfort and risk to the patient.

Hyperaemic response in the skin microcirculation of patients with chronic venous insufficiency.

The capacity of the microcirculation in the liposclerotic skin of patients with chronic venous insufficiency to vasodilate in response to pilocarpine electrophoresis was assessed using laser Doppler fluxmetry. Pilocarpine induces vasodilation by direct action on capillaries; other methods of vasodilatation, such as heating of the skin, act by a number of pathways including a neurogenic one. Thirty patients with lipodermatosclerosis and chronic venous insufficiency and 20 control subjects were studied. There was no difference in peak vasodilatation following pilocarpine electrophoresis in the two groups. The median (interquartile range) peak flux in patients was 665 (382-1025) units and in controls 765 (452-975) units (95 per cent confidence interval of difference--270 to 150 units, P = 0.5). This suggests that the capillaries in the liposclerotic skin of patients with chronic venous insufficiency have a normal capacity to vasodilate.

Vasomotion in the leg skin of patients with chronic venous insufficiency.

The characteristics of vasomotor activity in patients with lipodermatosclerosis (LDS) were studied using Laser Doppler fluxmetry and frequency analysis. Laser Doppler flux in the skin was recorded in the goiter region in 17 patients with LDS due to venous disease and in 16 normal control subjects. The Laser Doppler signals were analysed to give mean levels of flux and the frequency and amplitude of vasomotion were found using a fast Fourier transform (FFT). The results show significantly greater basal flow (p less than .001), and vasomotor frequency (p less than .001) and amplitude (p less than .001) in venous disease. The altered vasomotor activity is not due simply to the increased flow in LDS since increasing the flow in normal skin using the vasodilator pilocarpine does not produce as noticeable a difference.

Microangiopathy in diabetes mellitus: II. Features, complications and investigation.

This paper reviews the current literature on the morphological, physiological, pathological and rheological features of microangiopathy in diabetes mellitus. The current theories explaining the development of these features as well as complications resulting from them are discussed. In the first section the morphological changes including capillary basement membrane thickening as well as physiological changes such as increased permeability and reduced diffusion of oxygen across capillary endothelium are discussed. Rheological factors and functional changes in blood flow as well as capillary proliferation and degeneration are addressed. The second section of this paper deals with the complications suffered by diabetics such as retinopathy, nephropathy, neuropathy, cardiovascular disease and skin ulceration. The role of microangiopathy in the pathogenesis of these complications is reviewed. The last section discusses the investigative techniques available to the clinician and researcher in the study of micro-angiopathy. These include various methods of blood flow measurement such as plethysmography, LASER Doppler flowmetry, capillary microscopy and clearance of tracers from the skin microcirculation.

Microangiopathy in diabetes mellitus: I. Causes, prevention and treatment.

Microangiopathy is the major cause of death in Insulin Dependent Diabetes Mellitus. However, the pathogenesis of microangiopathy is still far from clear. This paper is a review of the literature on diabetic microangiopathy and discusses the current theories concerning its causes, prevention and treatment. The roles of abnormal glucose metabolism, protein glycosylation, genetic factors and puberty as well as the changes in vascular endothelium, capillary permeability and blood constituents, in the development of microangiopathy are discussed. The benefits of strict control of blood glucose concentrations are discussed along with the action of various pharmaceutical preparations such as aldose reductase inhibitors, hydroxyrutosides, pentoxifylline and free radical scavengers currently assessed in the prevention or treatment of diabetic microangiopathy.

The effect on skin blood flow of short-term venous hypertension in normal subjects.

Plugging of skin capillaries by activated white blood cells is one of the proposed mechanisms by which skin damage may be initiated in chronic venous insufficiency. The aim of this study was to determine whether a microcirculatory deficit was induced in the skin by raising the venous pressure proximally for thirty minutes. Seventeen subjects with no evidence of venous or arterial disease had laser Doppler velocimetry performed in the goiter region of the leg; 8 different subjects had the measurement done on the dorsum of the hand. Peak hyperemic response following three minutes of ischemia was measured before and after a thirty-minute period of sustained venous hypertension applied by a proximal tourniquet inflated to 80 mm Hg. A decrease in the peak flow: baseline flow ratio (median ratio 2.25 before, 1.70 after, p less than 0.02) and an increase in the time taken to reach maximal hyperemia (median time ten seconds before, twenty seconds after, p less than 0.01) were observed after the period of venous hypertension in the lower limb. The second parameter, but not the first, was significantly affected in the upper limb. The authors conclude that a microvascular deficit in the skin is demonstrable after a short period of venous hypertension. This is consistent with the white-cell-trapping theory, but other possible explanations are discussed.