Gamma Camera Scintigraphy Research Articles

Current Status of Radiolabeled Monoclonal Antibodies Targeting PSMA for Imaging and Therapy.

Prostate cancer (PCa) is one of the most prevalent cancer diagnoses among men in the United States and in several other developed countries. The prostate specific membrane antigen (PSMA) has been recognized as a promising molecular target in PCa, which has led to the development of specific radionuclide-based tracers for imaging and radiopharmaceuticals for PSMA targeted therapy. These compounds range from small molecule ligands to monoclonal antibodies (mAbs). Monoclonal antibodies play a crucial role in targeting cancer cell-specific antigens with a high degree of specificity while minimizing side effects to normal cells. The same mAb can often be labeled in different ways, such as with radionuclides suitable for imaging with Positron Emission Tomography (β+ positrons), Gamma Camera Scintigraphy (γ photons), or radiotherapy (β- electrons, α-emitters, or Auger electrons). Accordingly, the use of radionuclide-based PSMA-targeting compounds in molecular imaging and therapeutic applications has significantly grown in recent years. In this article, we will highlight the latest developments and prospects of radiolabeled mAbs that target PSMA for the detection and treatment of prostate cancer.

Head-to-Head Comparison of Tc-99m-sestamibi SPECT/CT and C-11-L-Methionin PET/CT in Parathyroid Scanning Before Operation for Primary Hyperparathyroidism.

The preferred nuclear medicine method for identification of hyperfunctioning parathyroid glands in hyperparathyroidism (HPT) develops continuously in relation to the technological progress. Diagnostic methods based on PET/CT have during recent years evolved with new tracer possibilities competing with traditional scintigraphic methods. This investigation is a head-to-head comparison of Tc-99m-sestamibi SPECT/CT gamma camera scintigraphy (sestamibi SPECT/CT) and C-11-L-methionin PET/CT imaging (methionine PET/CT) for preoperative identification of hyperfunctioning parathyroid glands. The study is a prospective cohort study including 27 patients diagnosed with primary hyperparathyroidism (PHPT). Two nuclear medicine physicians assessed all examinations independently and blinded. All scanning assessments were matched to the final surgical diagnosis as confirmed by histopathology. Biochemical monitoring of the therapeutical effects was performed preoperatively by PTH-measurements and followed postoperatively for up to 12 months. Comparisons were made for differences in sensitivity and positive predictive value (PPV). Twenty-seven patients (18 females, 9 males; mean age (range): 58.9 years (34.1-79)) were enrolled into the study. The 27 patients had a total of 33 identified sites of lesions of which 28 (85%) turned out to be histopathological verified hyperfunctioning parathyroid glands. The sensitivity and PPV for sestamibi SPECT/CT were 0.71 and 0.95; that of methionine PET/CT was 0.82 and 1, respectively. Both sensitivity and PPV were slightly lower for sestamibi SPECT/CT than for methionine PET PET/CT (-0.11, 95% confidence interval (95% CI): -0.29 to 0.08; -0.05, 95% CI: -0.14 to 0.04, respectively), but not to a statistically significant extent (p=0.38 and p=0.31). The sensitivity and PPV for diagnostic CT were 0.64 (95% CI: 0.44 to 0.81) and 1 (95% CI: 0.81 to 1). Methionine PET/CT performed comparable to sestamibi SPECT/CT with respect to identification and localization of hyperfunctioning parathyroid glands prior to surgery.

Effect of Polar Head Group Modifications on the Tumor Retention of Phospholipid Ether Analogs: Role of the Quaternary Nitrogen.

We have previously described the remarkable capacity of radioiodinated alkyl phospholipids to be sequestered and retained by a variety of tumors in vivo. We have already established the influence of certain structural parameters of iodinated alkyl phospholipids on tumor avidity, such as stereochemistry at the sn-2 carbon of alkylglycerol phosphocholines, meta-or para-position of iodine in the aromatic ring of phenylalkyl phosphocholines, and the length of the alkyl chain in alkyl phospholipids. In order to determine the additional structural requirements for tumor uptake and retention, three new radioiodinated alkylphospholipid analogs, 2-4, were synthesized as potential tumor imaging agents. Polar head groups were modified to determine structure-tumor avidity relationships. The trimethylammonio group in 1 was substituted with a hydrogen atom in 2, an ammonio group in 3 and a tertiary butyl group in 4. All analogs were separately labeled with iodine-125 or iodine-124 and administered to Walker 256 tumor-bearing rats or human PC-3 tumor-bearing SCID mice, respectively. Tumor uptake was assessed by gamma-camera scintigraphy (for [I-125]-labeled compounds) and high-resolution micro-PET scanning (for [I-124]-labeled compounds). It was found that structural modifications in the polar head group of alkyl phospholipids strongly influenced the tumor uptake and tissue distribution of these compounds in tumor-bearing animals. Phosphoethanolamine analog 3 (NM401) displayed a very slight accumulation in tumor as compared with phosphocholine analog 1 (NM346). Analogs 2 (NM400) and 4 (NM402) lacking the positively charged nitrogen atom failed to display any tumor uptake and localized primarily in the liver. This study provided important insights regarding structural requirements for tumor uptake and retention. Replacement of the quaternary nitrogen in the alkyl phospholipid head group with non-polar substituents resulted in loss of tumor avidity.

Monte Carlo simulation study of performance evaluation for sensitivity and scatter fraction in gamma camera scintigraphy with TlBr pixelated semiconductor detector with different parallel-hole collimator designs

Thallium bromide (TlBr) semiconductor materials are widely used to detect gamma rays. They have excellent detection efficiency owing to their high stopping and effective atomic number. The purpose of this study was to compare image quality using TlBr and conventional detector materials according to parallel-hole collimator geometry in gamma camera scintigraphy. The Geant4 application for tomographic emission (GATE) simulation tool was used. Cadmium telluride (CdTe), cadmium zinc telluride (CZT), and TlBr semiconductor materials were used; the parallel-hole collimator lengths were designed as 0.4, 0.6, 0.8, and 1.0 cm. For qualitative analysis, images were acquired using a quadrant-bar phantom with different bar thicknesses. Quantitative analyses, such as sensitivity (cps/MBq) and scatter fraction using a point source with 99mTc of 1 mCi, were conducted. The sensitivity with TlBr material with collimator lengths of 0.4, 0.6, 0.8, and 1.0 cm was 2.38, 2.39, 2.39, and 2.36 times greater than with CdTe and CZT materials, and the scatter fraction with TlBr material was 1.26, 1.25, 1.24, and 1.31 times less than the scatter fraction with CdTe and CZT materials with the same collimator length, respectively. There was no significant difference in sensitivity and scatter fraction between CdTe and CZT materials. Thus, we confirmed that TlBr is a potential detector material with improved sensitivity and scatter fraction in gamma camera scintigraphy.

Monoclonal antibody based radiopharmaceuticals for imaging and therapy

The concept of personalized medicine has been steadily growing for the past decades. Monoclonal antibodies (mAbs) are undoubtedly playing an important role in the transition away from conventional medical practice to a more tailored approach to deliver the best therapy with the highest safety margin to a specific patient. In certain instances, mAbs and antibody drug conjugates (ADCs) may represent the preferred therapeutic option for several types of cancers due to their high specificity and affinity to the antigen. Monoclonal antibodies can be labeled with specific radionuclides well-suited for PET (Positron Emission Tomography) or gamma camera scintigraphy. The use of radiolabeled mAbs allows the interrogation of specific biomarkers and assessment of tumor heterogeneity in vivo by a single diagnostic imaging scan that includes the whole-body in the field-of-view. Moreover, the same mAb can then be radiolabeled with an analogous radionuclide for the delivery of beta-minus radiation or alpha-particles as part of a radioimmunotherapy (RIT) approach. However, the path to develop, validate, and implement mAb-based radiopharmaceuticals from bench-to-bedside is complex due to the extensive pre-clinical experiments and toxicological studies required, and the necessity of labor-intensive clinical trials that often require multi-time-point imaging and blood draws for internal radiation dosimetry and pharmacokinetics. As more mAb-based radiopharmaceuticals have been developed and evaluated, the opportunities and limitations offered by mAbs have become better defined. Our aim with this manuscript is therefore to provide an overview of the recent advances in the development of mAb-based radiopharmaceuticals and their clinical applications in Oncology.

Guide du bon usage de la TDM en médecine nucléaire. Introduction

Nuclear medicine hybrid imaging is a technological evolution of gamma camera scintigraphy or positron emission tomography imaging methods that are now often coupled with an anatomical imaging device, essentially a CT scanner. Following a large demand from the nuclear physicians themselves, but also from the French Nuclear Safety Authority, this guide is intended for the entire nuclear medicine community to integrate both the aspects of radiation protection related to coupled CT and those related to the quality of the CT images according to the clinical context.

Is there an additional benefit of Tc-99m-PSMA-guided gamma probe use for salvage lymph node dissection in recurrent prostate cancer.

e591 Background: PSMA-PET/CT is the most sensitive diagnostic tool in biochemical recurrent prostate cancer to detect minimal metastatic disease. However, it may be difficult to localize small PSMA-positive lymph nodes intraoperatively. Therefore, it was the aim to investigate whether preoperative Tc-99m-PSMA targeting may improve intraoperative tumor localization by use of a gamma probe. Methods: In 13 Patients Ga-68-PSMA-PET/CT identified iliac lymph nodes in patients suitable for salvage lymph node dissection. On the day before operation a mean activity of 480 MBq Tc-99m-PSMA was injected and gamma camera scintigraphy + SPECT was performed 4-5 hours after tracer application. About 24 hours after tracer application a salvage lymph node dissection was performed on the side of initial suspicious lymph node metastases. Sensitivity, specifity, pos and neg. predictive values were calulated for PSMA-PET/CT and gamma probe use to analyse the additional use. Results: In 9 / 13 patients PSMA-positive metastatic lymph nodes were identified in Ga-68 PSMA-PET/CT. A total of 156 lymph nodes were removed with 14 lymph nodes in 9 patients being positive in histopathologic examination. Sensitivity, specifity, pos and neg. predictive values for PSMA PET/CT and gamma probe were 85% and 79%, 99% and 100%, 85% and 100% and 99% and 98% respectively. In one patient only gamma probe use identified a pathologic lymph node. Conclusions: Gamma probe guided salvage lymph node dissection in PSA recurrent prostate cancer is feasible and had a high concordance with PSMA-PET/CT. However, the additional diagnostic benefit is limited compared to PSMA-PET/CT because in only one patient (7%) a positive lymph node could be identified with the use of the gamma probe outside the standard operative area in salvage lymph node dissection.

Proximal and Overall Gastric Emptying of Solids in Patients with Reduced Gastric Volume Accommodation Compared to Matched Controls

Interventions such as gastric surgery and erythromycin result in displacement of solids to the distal stomach and acceleration of overall and proximal gastric emptying. The effect of non-surgical impairment of gastric accommodation on gastric emptying is unclear. Non-surgical impairment of gastric accommodation is associated with accelerated gastric emptying. To compare measurements of proximal and overall gastric emptying in patients with reduced postprandial gastric volume accommodation with the emptying rates in age- and gender-matched controls with normal postprandial gastric volume accommodation. We evaluated overall and proximal gastric emptying in nine patients with impaired gastric accommodation and age-equivalent and gender-matched controls. Gastric volumes and emptying were measured using validated SPECT and dual gamma camera scintigraphy, respectively. We compared group differences in overall and proximal gastric emptying t (1/2) by t test. Patients with impaired postprandial gastric volume accommodation had greater fasting gastric volume. The proportion of food emptied from the proximal stomach immediately after meal ingestion was lower and t (1/2) of proximal gastric emptying correspondingly longer in the group with reduced postprandial gastric accommodation. In contrast, differences were not detected in overall gastric emptying in the two groups, and the ratio of overall to proximal gastric emptying t (1/2) was greater in the group with impaired volume accommodation. Proximal stomach emptying is reduced in patients with impaired postprandial volume accommodation; this difference occurs predominantly during the time of meal ingestion. Compensatory mechanisms that result in normal overall gastric emptying require further elucidation.

Pre-therapeutic 124I PET(/CT) dosimetry confirms low average absorbed doses per administered 131I activity to the salivary glands in radioiodine therapy of differentiated thyroid cancer

Salivary gland impairment following high activity radioiodine therapy of differentiated thyroid cancer (DTC) is a severe side effect. Dosimetric calculations using planar gamma camera scintigraphy (GCS) with (131)I and ultrasonography (US) provided evidence that the average organ dose per administered (131)I activity (ODpA) is too low to account for observed radiation damages to the salivary glands. The objective of this work was to re-estimate the ODpA using (124)I PET(/CT) as a more reliable approach than (131)I GCS/US. Ten DTC patients underwent a series of six (or seven) PET scans and one PET/CT scan after administration of approximately 23 MBq (124)I-iodide. Volumes of interest (VOIs) drawn on the CT and serial PET images were used to determine the glandular volumes and the imaged (124)I activities. To enable identical VOIs to be drawn on serial PET images, each PET was co-registered with the CT image. To correct for partial volume effect and for the artificial bias in the activity concentration due to cascading gamma coincidences occurring in (124)I decay, the imaged activity was effectively corrected using isovolume recovery coefficients (RCs) based on recovery phantom measurements. A head-neck phantom, which contained (124)I-filled spheres, was manufactured to validate the isovolume recovery correction method with a realistic patient-based phantom geometry and for a range of activity concentration regimes. The mean+/-standard deviation (range) ODpA projected for (131)I was calculated using the absorbed dose fraction method. The ODpAs (in Gy/GBq) for the submandibular and parotid glands were 0.32 +/- 0.13 (0.18-0.55) and 0.31 +/- 0.10 (0.13-0.46), respectively. No significant differences (p> 0.2) in the mean ODpA between (124)I PET(/CT) and (131)I GCS/US dosimetry was found. The validation experiment showed that the percentage deviations between RC-corrected and true activity concentrations were <10%. (124)I PET(/CT) dosimetry also corroborates the low ODpAs to the salivary glands. A voxel-based calculation taking into account the nonuniform activity distributions in the glands is necessary to possibly explain the radiation-induced salivary gland damage.

The red cell mass, plasma erythropoietin and spleen size in apparent polycythaemia.

It has been shown previously that measurement of the spleen size and plasma erythropoietin (EPO) concentration are valuable adjuncts in the diagnostic work-up of patients with polycythaemia vera. The aim of the present work was to evaluate their value in the assessment of apparent polycythaemia (AP). Therefore, over a 24-month period we routinely performed bone marrow biopsies, measurement of red cell mass (RCM) and plasma volume (PV), spleen size determination by gamma camera scintigraphy and determination of the plasma EPO concentration in consecutive patients referred to us because of elevated values for packed cell volume (>0.48 in females and >0.51 in males). After having excluded patients with clonal and secondary polycythaemias we were left with 38 patients (27 males and 11 females) with AP. In all of them the measured RCM was within normal range, i.e. <36 ml/kg for males and <32 ml/kg for females. The subjects were characterized by moderate increase in RCM and a concomitant moderate decrease in PV. Thus, as an average the measured RCM exceeded the predicted values by 14% in males and by 12% in females; conversely, as compared to the predicted values the average measured value for PV was reduced by 17% in males and by 8% in females. The average RCM for males was 29+/-3 ml/kg; the corresponding figure for females was 23+/-4 ml/kg. It was shown that 86% of the subjects had plasma EPO concentrations within the control range; the remaining had values slightly above or below the control range. The mean posterior spleen scan area was 57+/-16 cm2 and mean left lateral area 57+/-17 cm2; the reference value for spleen scan area (for both projections) is 57+/-12 cm2. Of the patients 35/38 (92%) had a spleen scan area within the mean+2SD for controls and 38 subjects (100%) had values within the mean+3SD. It is concluded that measurement of plasma EPO and a careful assessment of the spleen size should always be considered in the evaluation of patients with elevated values for venous packed cell volume.

SPECT Imaging for Radioaerosol Deposition and Clearance Studies

Planar gamma camera scintigraphy is well established for measuring the deposition and clearance of radioaerosols. Single photon emission computed tomography (SPECT) provides threedimensional (3D) reconstructions of the radioactivity distribution, thus avoiding the compression of 3D data into two-dimensional (2D) images and potentially offering superior assessment of aerosol deposition patterns. However, SPECT has traditionally been associated with long imaging times, making it unsuitable for measuring deposition and clearance of radioaerosols with fast clearance. Multi-detector SPECT systems can collect complete SPECT studies in <1 min, allowing both initial deposition and clearance over time to be assessed by dynamic SPECT. Simultaneous transmission measurement with an external source provides attenuation correction for absolute activity quantification as well as aiding in the definition of the lung volume of interest. A dynamic SPECT imaging protocol has been developed to allow fast imaging from the oropharynx to the abdomen using gamma cameras with limited axial field of views. This allows activity quantification not only in the lungs, but also in areas outside the thorax. However, fast dynamic SPECT imaging is technically and computationally more demanding and provides less scope for reducing the radioactivity administered to the subjects. It has been shown that dynamic SPECT, compared to planar imaging, is more sensitive in detecting changes in deposition as measured by the Penetration Index (PI). Thus, SPECT can better differentiate between large and small airways, which is important for lung regional analysis.

The detection of skeletal metastases from mammary cancer by gamma camera scintigraphy.

The detection of skeletal metastases from mammary cancer by gamma camera scintigraphy.

153. Adenoviral Gene Therapy Vectors Expressing the Adenovirus Death Protein Demonstrate Increased Transgene Expression In Vivo as Demonstrated by Dose-Volume Histogram Analysis of Reporter Gene Activity

A current limitation of cancer gene therapy is the lack of significant efficacy in the clinic. To improve the effectiveness of adenovirus-delivered gene therapy for the treatment of cancer, we have evaluated various methods to increase transgene expression in vivo. One such method was to co-express the adenoviral death protein (ADP) in a replication-competent adenovirus (Ad5-hNISrep-ADP) also expressing the human sodium iodide symporter (hNIS) as a reporter gene. The ADP gene product has been shown by others to increase cell lysis and adenovirus spread in vitro. The hNIS gene product enables adenovirus-infected cells to uptake the radioactive tracer, 99mpertechnetate (99mTcO4-), which can be imaged non-invasively using gamma camera scintigraphy, and the volume of transgene expression can be quantified in thin tissue sections using dose-volume histogram (DVH) analysis. To study the possible effect of ADP on transgene expression in vivo, the volume of transgene expression was compared following direct injection of replication-competent adenoviruses lacking (Ad5-hNISrep) or containing (Ad5-hNISrep-ADP) ADP into contralateral lobes of the na|[iuml]|ve canine prostate and into human tumor xenografts implanted bilaterally in the hind legs of Balb/c mice. Following injection of 1|[times]|1011 vp (0.1 ml) in the canine prostate, the volume of hNIS-dependent uptake of 99mTcO4- with Ad5-hNISrep-ADP was on average 3-fold greater than with Ad5-hNISrep (5.0%|[plusmn]|1.3% vs. 1.5%|[plusmn]|0.5% of the prostate volume, respectively; n=3). Similarly, following injection of 1|[times]|1010 vp (0.05 ml) in human tumor xenografts (150 mm3), the extent of hNIS activity as a percentage of the tumor volume was 16.2%|[plusmn]|9.5% for Ad5-hNISrep-ADP versus 5.8%|[plusmn]|2.5% for Ad5-hNISrep (n=6), representing a 2.3-fold increase in transgene expression when ADP was present. These results indicate that inclusion of ADP in adenoviral gene therapy vectors can significantly improve the volume of transgene expression in vivo, which may translate into improved therapeutic efficacy when used in a clinical setting.

Functional imaging techniques for evaluation of sarcomas

Sarcomas are often characterised by significant histopathologic heterogeneity, both between and within tumours. This heterogeneity reflects physiologic, biochemical and genetic processes that are amenable to characterisation by functional imaging. Although anatomically based imaging modalities such as plain radiography, X-ray computed tomography (CT) and magnetic resonance imaging (MRI) remain the primary diagnostic modalities for staging sarcomas, nuclear medicine approaches including gamma camera scintigraphy and positron emission tomography (PET) are being used increasingly to provide complementary information in specific clinical situations. These include biopsy guidance within anatomically complex masses, staging, therapeutic response assessment and evaluation of residual mass lesions after treatment. This review aims to address the range of nuclear medicine techniques available for evaluation of bone and soft tissue sarcomas. A subsequent review discusses the clinical application of these techniques with a particular focus on PET.

Noninvasive radiological imaging of pulmonary gene transfer and expression using the human sodium iodide symporter

In this study we investigated the application of the human sodium iodide symporter (hNIS) as a reporter gene to noninvasively image in vivo gene transfer and expression in lung tissue in real time. Human NIS-expressing adenoviruses (Ad-hNIS) or empty adenoviruses (Ad-Bgl II) were instilled into the lungs of Cotton rats via the nostrils. After 3, 10, and 17 days post infection, gamma camera scintigraphy with 99mTcO4- was performed to observe the distribution and duration of gene transfer. At 20 days after infection, reverse transcription polymerase chain reaction was performed to detect hNIS gene expression. Dual expressing vector Ad-hNIS-eGFP was used to detect transgene expression by fluorescence photomicroscopy in infected lung tissue. Positron emission tomography (PET) imaging of gene transfer to the lungs was performed using 124I- as tracer. Finally, hNIS transfer to a polarized human airway epithelial cell layer was evaluated by phosphorimaging. Lungs in animals infected with Ad-hNIS were clearly visible on scintigraphy and PET scans, while those infected with Ad-Bgl II were undetectable. Lungs in Ad-hNIS infected animals could still be visualized at 17 days but were no longer detectable at 20 days. Fluorescence microscopy showed that lung tissue infected with Ad-hNIS-eGFP had significantly higher GFP signal intensity than that infected with Ad-Bgl II. It is feasible to use the hNIS gene as a reporter gene to monitor the location, magnitude, and timing of expression of genes delivered during pulmonary gene therapy. The ability to noninvasively visualize gene expression tomographically in real time has significant translational implications in human gene therapy.

Impaired hepatosplenic elimination of circulating cryoglobulins in patients with essential mixed cryoglobulinaemia and hepatitis C virus (HCV) infection

SUMMARY The pathogenic mechanisms that lead to renal deposition of the cryoprecipitable IgM rheumatoid factor–IgG complexes in essential mixed cryoglobulinaemia (EMC) are unknown. Defective removal of cryoprecipitable complexes from the circulation has been postulated in EMC-associated nephritis. To test this hypothesis, the kinetics and fate of a trace dose of 123I-radiolabelled autologous cryoglobulins were analysed in 13 patients with EMC grouped according to renal involvement. The time course of radioactivity distribution in the blood and organ uptake were measured by gamma camera scintigraphy. In blood sampled 30–300 s after injection, only a minor fraction (&amp;lt; 15%) of the circulating cryoglobulins bound to the erythrocytes, suggesting the elimination mechanisms are independent of binding to CR1 on erythrocytes. The overall blood disappearance curve showed a fast (≤ 1 min) and slow (&amp;gt; 4 h) biphasic pattern. In patients with quiescent or mild nepthritis, the liver and to a lesser extent the spleen were the major organs that mediated the rapid uptake and processing of the cryoglobulins from the circulation. In contrast, patients with active mesangiocapillary glomerulonephritis showed significantly (P &amp;lt; 0.001) less hepatic uptake, low liver-to-precordium ratio, and slower processing of cryoglobulins, prolonged liver mean transit time, than quiescent patients or mild nephritis patients. To elucidate the role and influence of HCV infection in the pathogenesis of EMC-nephritis, sera and cryoglobulins from all patients were assayed for HCV. None of the control group cases without nephritis showed any evidence of HCV-RNA in serum or cryoglobulin pellet. In contrast, all 10 EMC-nephritis patients' sera, and eight corresponding cryoglobulin pellets contained HCV-RNA. Collectively, these findings suggest an impaired reticuloendothelial system removal of IgM–IgG–HCV complexes may underlie their renal deposition.

GENIS: gene expression of sodium iodide symporter for noninvasive imaging of gene therapy vectors and quantification of gene expression in vivo

With the goal of optimizing adenovirus-mediated suicide gene therapy for prostate cancer, we have developed a method based on the human sodium iodide symporter (hNIS) that allows for noninvasive monitoring of adenoviral vectors and quantification of gene expression magnitude and volume within the prostate. A replication-competent adenovirus (Ad5-yCD/mutTKSR39rep-hNIS) coexpressing a therapeutic yeast cytosine deaminase (yCD)/mutant herpes simplex virus thymidine kinase (mutTKSR39) fusion gene and the hNIS gene was developed. Ad5-yCD/mutTKSR39rep-hNIS and a replication-defective hNIS adenovirus (rAd-CMV-FLhNIS) were injected into contralateral lobes of the dog prostate and hNIS activity was monitored in live animals following administration of Na99mTcO4 using gamma camera scintigraphy. Despite the close proximity of the urinary bladder, 99mTcO4− uptake was readily detected in the prostate using viral dose levels (1010 to 1012 viral particles) that have been safely administered to humans. Due to its rapid clearance and short physical half-life (6 h), it was possible to obtain daily measurements of 99mTcO4− uptake in vivo, allowing for dynamic monitoring of reporter gene expression within the prostate as well as biodistribution throughout the body. High-resolution autoradiography of prostate sections coupled with 3D reconstruction of gene expression demonstrated that the magnitude and volume of gene expression could be quantified with submillimeter resolution. Implementation of the GENIS (gene expression of Na/I symporter) technology in the clinic will facilitate optimization of future human gene therapy trials.

Bile acid malabsorption or disturbed intestinal permeability in patients treated with enzyme substitution for exocrine pancreatic insufficiency is not caused by bacterial overgrowth.

In some patients with severe exocrine pancreatic insufficiency, enzyme replacement therapy will not lead to clinical improvement or reduction of steatorrhea. Therefore, other mechanisms separately or in interplay with reduced enzyme secretion might be responsible for malabsorption in these patients. To evaluate the prevalence of bacterial overgrowth, bile acid absorption capacity, and intestinal permeability in a group of patients with well-characterized exocrine pancreatic insufficiency. Eleven men with severe exocrine pancreatic insufficiency, of whom 10 were receiving enzyme replacement therapy, were studied. The prevalence of bacterial overgrowth was evaluated by means of a hydrogen and methane breath test with glucose. Gamma camera scintigraphy after intake of 75Se-homocholic acid taurine (75Se-HCAT) was used to evaluate bile acid absorption capacity. Intestinal permeability was assessed from urine excretion of ingested 14C-mannitol and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA), and these data were compared with results for 10 age-matched healthy men. No patients had abnormal breath hydrogen or methane concentrations after glucose intake. Abdominal retention of 75Se-HCAT was reduced in three of the patients. The patients had lower urine excretion of 14C-mannitol than the control subjects, whereas no difference was revealed in urine excretion of 99mTc-DTPA. Bile acid absorption and small intestinal permeability might be affected in patients with exocrine pancreatic insufficiency who receive treatment with enzyme supplementation. The prevalence of bacterial overgrowth seems to be low among these patients and does not explain the findings.

Circulation and biodistribution profiles of long-circulating PEG-liposomes of various sizes in rabbits

To determine the largest size of liposomes that can retain stealth behavior conferred by poly(ethylene glycol)-DSPE, neutral liposomes were studied in rabbits for their circulation and distribution. Five sizes (136.2, 165.5, 209.2, 275 and 318 nm) of liposomes (DSPC, Cholesterol, PEG-DSPE and α-tocopherol, 90:80:4.5:3.9 molar ratio) were made by extrusion technique and radiolabeled with technetium-99m (Tc-99m) to follow their distribution through 24 h. Although all liposomes showed prolonged circulation in blood, the amount still in circulation at 24 h was dependent on their size. Radioactivity accumulation in spleen progressively increased with increase in size of the liposomes. In the size range of ∼160–220 nm, liver uptake was minimum, spleen uptake was moderate while the amount of circulating liposomes was maximum. Gamma camera scintigraphy corroborated the distribution pattern of liposomes on necropsy. Images within 1 h showed high blood pool activities for liposomes of all sizes. However, at 24 h, the blood pool activity was diminished for 275 nm and negligible for 308 nm liposomes; the smaller sized liposomes (136.2–209.2 nm) continued to show high blood pool activity. The amounts of radioactivity still circulating at 24 h were 46.4, 50.4, 46.8, 36.2 and 14.5% for 136.2, 165.5, 209.2, 275 and 318 nm liposomes, respectively. Corresponding circulation T 1/2s were 21.7, 26.5, 24.9, 18.7 and 8.9 h, respectively. Thus, the optimum size of PEG-liposomes for prolonged circulation in rabbits is 160–220 nm. Beyond this range, the stealth property of PEG-liposomes is significantly compromised and the distribution is characterized by high RES accumulation.

A transporter gene (sodium iodide symporter) for dual purposes in gene therapy: imaging and therapy.

Radioiodide uptake (RAIU) in thyroid follicular epithelial cells, mediated by a plasma membrane transporter, sodium iodide symporter (NIS), provides a first step mechanism for thyroid cancer detection by radioiodide injection and effective radioiodide treatment for patients with invasive, recurrent, and/or metastatic thyroid cancers after total thyroidectomy. NIS gene transfer to tumor cells may significantly and specifically enhance internal radioactive accumulation of tumors following radioiodide administration, and result in better tumor control. NIS gene transfers have been successfully performed in a variety of tumor animal models by either plasmid-mediated transfection or virus (adenovirus or retrovirus)-mediated gene delivery. These animal models include nude mice xenografted with human melanoma, glioma, breast cancer or prostate cancer, rats with subcutaneous thyroid tumor implantation, as well as the rat intracranial glioma model. In these animal models, non-invasive imaging of in vivo tumors by gamma camera scintigraphy after radioiodide or technetium injection has been performed successfully, suggesting that the NIS can serve as an imaging reporter gene for gene therapy trials. In addition, the tumor killing effects of 131I after NIS gene transfer have been demonstrated in in vitro clonogenic assays and in vivo radioiodide therapy studies, suggesting that NIS gene can also serve as a therapeutic agent when combined with radioiodide injection. Better NIS-mediated tumor treatment by radioiodide requires a more efficient and specific system of gene delivery with better retention of radioiodide in tumor. Results thus far are, however, promising, and suggest that NIS gene transfer followed by radioiodide treatment will allow non-invasive in vivo imaging to assess the outcome of gene therapy and provide a therapeutic strategy for a variety of human cancers.