Discrepant salivary gland response after radioiodine and MIBG therapies.

BACKGROUND: A retrospective study using PET/CT imaging with 124I-labeled metaiodobenzylguanidine (124I-MIBG) was performed to estimate the (radiation) absorbed dose to the salivary glands in neuroendocrine cancer patients undergoing 131I-MIBG therapy and to compare these results with those in radioiodine (131I-iodide) therapy. METHODS: Twenty-seven patients received individual 124I-MIBG-PET/CT dosimetries, among whom 18 had not previously undergone any MIBG therapies (patient group before treatment) and 9 had already received MIBG therapies prior to the tracer dosimetries (patient group after treatment). For each patient, three or four 124I-MIBG PET/CT scans were performed at approximately 4 and 24 hours, as well as at approximately 48 or/and ≥96 hours after tracer injection. The absorbed doses per administered 131I-MIBG activity to the submandibular and parotid glands were calculated based on the MIRD concept, with its assumption of a uniform glandular activity distribution. RESULTS: The mean±standard deviation of the (self-)absorbed dose per activity averaged over both patient groups and salivary gland types was 0.53±0.24 Gy/GBq (median, 0.49 Gy/GBq; range, 0.17-1.38 Gy/GBq). The absorbed doses per activity of the patient group before treatment did not significantly deviate from those of the patient group after treatment (P=0.67). In the patient group after treatment, the mean±standard deviation of the cumulative 131I-MIBG activity was 20±12 GBq (median, 16 GBq; range, 10-50 GBq). Among the patient groups, no significant absorbed dose difference was found between the submandibular and parotid glands (P>0.24). In comparison to radioiodine therapy, the estimated absorbed dose per activity in MIBG was significantly higher (P<0.001), on average twice as high, contradicting the relationship between the absorbed dose and clinical observation of glandular side effects. CONCLUSIONS: The discrepant salivary gland responses in MIBG and radioiodine therapies suggest a different radiotherapeutical distribution on microscopic scale within the glandular tissue and prove the clinical relevance of a microdosimetric analysis.

Identification and Tumour-Binding Properties of a Peptide with High Affinity to the Disialoganglioside GD2.

Neuroectodermal tumours are characterized by aberrant processing of disialogangliosides concomitant with high expression of GD2 or GD3 on cell surfaces. Antibodies targeting GD2 are already in clinical use for therapy of neuroblastoma, a solid tumour of early childhood. Here, we set out to identify peptides with high affinity to human disialoganglioside GD2. To this end, we performed a combined in vivo and in vitro screen using a recombinant phage displayed peptide library. We isolated a phage displaying the peptide sequence WHWRLPS that specifically binds to the human disialoganglioside GD2. Binding specificity was confirmed by mutational scanning and by comparative analyses using structurally related disialogangliosides. In vivo, significant enrichment of phage binding to xenografts of human neuroblastoma cells in mice was observed. Tumour-specific phage accumulation could be blocked by intravenous coinjection of the corresponding peptide. Comparative pharmacokinetic analyses revealed higher specific accumulation of 68Ga-labelled GD2-binding peptide compared to 111In-labelled peptide in xenografts of human neuroblastoma. In contrast to 124I-MIBG, which is currently evaluated as a neuroblastoma marker in PET/CT, 68Ga-labelled GD2-specific peptide spared the thyroid but was enriched in the kidneys, which could be partially blocked by infusion of amino acids.In summary, we here report on a novel tumour-homing peptide that specifically binds to the disialoganglioside GD2, accumulates in xenografts of neuroblastoma cells in mice and bears the potential for tumour detection using PET/CT. Thus, this peptide may serve as a new scaffold for diagnosing GD2-positive tumours of neuroectodermal origin.

Assessment of lesion response in the initial radioiodine treatment of differentiated thyroid cancer using 124I PET imaging.

UNLABELLED: (124)I PET/CT images from differentiated thyroid cancer patients were retrospectively analyzed to assess the relationship between absorbed radiation dose (AD) to lesions and their response after radioiodine therapy. METHODS: Patients received serial (124)I PET/CT scans before and after their first radioiodine treatment. The pretherapy PET data were used to segment the lesion volumes and to predict the therapy-delivered ADs after administration of the therapeutic (131)I activity. The segmentation method's lower volume limit of determinability was a sphere of 0.80 mL, which classified the lesions into a known-volume group (>0.80 mL) or a small-volume group (≤0.80 mL) with their respective average and minimum ADs. The posttherapy PET data were used to assess the lesion-based therapy success. In the known-volume group, the response rate was calculated on the basis of lesions that received average ADs above the generally accepted threshold of 85 Gy for metastases and 300 Gy for thyroid remnants (TRs) and was expressed as the percentage of completely responding lesions. In the small-volume group, the metastasis and TR responses were evaluated for 3 minimum-AD groups: 5 to 10 Gy (TR, 5 to 30 Gy), >10 to 85 Gy (TR, >30 to 300 Gy), and >85 Gy (TR, >300 Gy). Their response rates were calculated in terms of the percentage of completely responding lesions in each minimum-AD group. RESULTS: In total, 59 lesions in 17 patients were amenable to reliable volume estimation. The response rates were 63%, 88%, and 90% for lymph node metastases (LMs), pulmonary metastases, and TRs, respectively. The response rates of 168 small lesions in 34 patients were more than 82% for LMs and more than 91% for TRs in each of the 3 minimum-AD groups; all small pulmonary metastases responded completely. CONCLUSION: In the known-volume group, the response rate for TRs matched well with historical data derived using (131)I scintigraphy imaging, whereas the response rate for LMs was not as high as expected, which may be explained by too short a follow-up time for a few LMs and a higher sensitivity of PET imaging. Small lesions were treated effectively, suggesting that they are considerably smaller than 0.80 mL.

Chewing-gum stimulation did not reduce the absorbed dose to salivary glands during radioiodine treatment of thyroid cancer as inferred from pre-therapy (124)I PET/CT imaging.

BACKGROUND: The goal of this prospective study was to estimate the absorbed (radiation) doses to salivary glands in radioiodine therapy of thyroid cancer under chewing-gum stimulation using (124)I positron emission tomography (PET)/computed tomography (CT) imaging. METHODS: Duplex ultrasonography was conducted in three test persons for visual comparison of the glandular blood flow with three different stimulation types (no stimulation, chewing tasteless gum base, sucking on lemon slices). Ten patients with newly diagnosed differentiated thyroid cancer received (124)I PET/CT dosimetry after thyroidectomy and prior to radioiodine therapy. Patients underwent a series of three (124)I PET/CT scans (4, 24, and ≥96 h after administration of 23 MBq (124)I). They were instructed to chew gum base (tasteless) approximately 20 min after ingesting the (124)I-containing capsule in the course of the first day. Absorbed doses per administered (131)I activity to the salivary glands were calculated and compared with the previously published results of the lemon-juice stimulation and non-stimulation groups. RESULTS: The sonograms in the three test persons showed that glandular blood perfusion by lemon-juice stimulation was clearly increased compared with non-stimulation or chewing of gum base. The sonogram comparison between the chewing-gum stimulation and non-stimulation demonstrated a minor increase of blood flow for the gum base-stimulated salivary glands. The mean ± standard deviation of the absorbed dose per activity under chewing-gum stimulation for the submandibular and parotid glands (within parentheses) was 0.22 ± 0.09 Gy/GBq (0.22 ± 0.08 Gy/GBq). Compared with the absorbed doses of the non-stimulation group, 0.24 ± 0.08 Gy/GBq (0.21 ± 0.05 Gy/GBq), those of the chewing-gum stimulation group showed no significant change (P > 0.60), but the absorbed doses of the lemon-juice stimulation group, 0.35 ± 0.14 Gy/GBq (0.33 ± 0.09 Gy/GBq), were significantly higher (P < 0.04) than those of the chewing-gum stimulation group. CONCLUSIONS: The results suggest that salivary flow induced by chewing gum base does not cause a significant reduction of the salivary gland absorbed dose compared with that in the non-stimulation group. The increased blood flow appears to be a decisive factor causing the increased (131)I absorbed doses in the lemon-juice stimulation group.

Differential uptake of (68)Ga-DOTATOC and (68)Ga-DOTATATE in PET/CT of gastroenteropancreatic neuroendocrine tumors.

PURPOSE: Abundant expression of somatostatin receptors (sst) is a characteristic of neuroendocrine tumors (NET). Thus, radiolabeled somatostatin analogs have emerged as important tools for both in vivo diagnosis and therapy of NET. The two compounds most often used in functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both analogs share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in detection of NET lesions, as sst2 is the predominant receptor subtype on gastroenteropancreatic NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same patients with gastroenteropancreatic NET. PATIENTS AND METHODS: Twenty-seven patients with metastatic gastroenteropancreatic NET underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the workup before prospective peptide receptor radionuclide therapy (PRRT). The performance of both imaging methods was analyzed and compared for detection of individual lesions per patient and for eight defined body regions. A region was regarded as positive if at least one lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUV(max)) was compared for concordant lesions and renal parenchyma. RESULTS: Fifty-one regions were found positive with both (68)Ga-DOTATATE and (68)Ga-DOTATOC. Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE in comparison with (68)Ga-DOTATOC (174 versus 179, p < 0.05). Mean (68)Ga-DOTATATE SUV(max) across all lesions was significantly lower compared with (68)Ga-DOTATOC (16.9 ± 6.8 versus 22.1 ± 12.0, p < 0.01). Mean SUV(max) for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.6 ± 2.6 versus 12.6 ± 2.7). CONCLUSIONS: (68)Ga-DOTATOC and (68)Ga-DOTATATE possess similar diagnostic accuracy for detection of gastroenteropancreatic NET lesions (with a potential advantage of (68)Ga-DOTATOC) despite their evident difference in affinity for sst2. Quite unexpectedly, maximal uptake of (68)Ga-DOTATOC tended to be higher than its (68)Ga-DOTATATE counterpart. However, tumor uptake shows high inter- and intraindividual variance with unpredictable preference of one radiopeptide. Thus, our data encourage the application of different sst ligands to enable personalized imaging and therapy of gastroenteropancreatic NET with optimal targeting of tumor receptors.

68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors.

UNLABELLED: Radiolabeled somatostatin analogs represent valuable tools for both in vivo diagnosis and therapy of neuroendocrine tumors (NETs) because of the frequent tumoral overexpression of somatostatin receptors (sst). The 2 compounds most often used in functional imaging with PET are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both ligands share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately 10-fold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in the detection of NET lesions because it is the sst2 that is predominantly overexpressed in NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same NET patients. METHODS: Forty patients with metastatic NETs underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the work-up before prospective peptide receptor radionuclide therapy. The performance of both imaging methods was analyzed and compared for the detection of individual lesions per patient and for 8 defined body regions. A region was regarded positive if at least 1 lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUVmax) was compared for concordant lesions and renal parenchyma. RESULTS: Seventy-eight regions were found positive with (68)Ga-DOTATATE versus 79 regions with (68)Ga-DOTATOC (not significant). Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE than with (68)Ga-DOTATOC (254 vs. 262, P < 0.05). Mean (68)Ga-DOTATATE SUVmax across all lesions was significantly lower than (68)Ga-DOTATOC (16.0 ± 10.8 vs. 20.4 ± 14.7, P < 0.01). Mean SUVmax for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.7 ± 3.0 vs. 13.2 ± 3.3). CONCLUSION: (68)Ga-DOTATOC and (68)Ga-DOTATATE possess a comparable diagnostic accuracy for the detection of NET lesions, with (68)Ga-DOTATOC having a potential advantage. The approximately 10-fold higher affinity for the sst2 of (68)Ga-DOTATATE does not prove to be clinically relevant. Quite unexpectedly, SUVmax of (68)Ga-DOTATOC scans tended to be higher than their (68)Ga-DOTATATE counterparts.

68Ga-DOTATOC PET/CT and somatostatin receptor (sst1-sst5) expression in normal human tissue: correlation of sst2 mRNA and SUVmax.

PURPOSE: By targeting somatostatin receptors (sst) radiopeptides have been established for both diagnosis and therapy. For physiologically normal human tissues the study provides a normative database of maximum standardized uptake value (SUV(max)) and sst mRNA. METHODS: A total of 120 patients were subjected to diagnostic (68)Ga-DOTATOC positron emission tomography (PET)/CT (age range 19-83 years). SUV(max) values were measured in physiologically normal tissues defined by normal morphology, absence of surgical intervention and absence of metastatic spread during clinical follow-up. Expression of sst subtypes (sst1-sst5) was measured independently in pooled adult normal human tissue by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: SUV(max) revealed a region-specific pattern (e.g., mean ± SD, spleen 31.1 ± 10.9, kidney 16.9 ± 5.3, liver 12.8 ± 3.6, stomach 7.0 ± 3.1, head of pancreas 6.2 ± 2.3, small bowel 4.8 ± 1.8, thyroid 4.7 ± 2.2, bone 3.9 ± 1.3, large bowel 2.9 ± 0.8, muscle 2.1 ± 0.5, parotid gland 1.9 ± 0.6, axillary lymph node 0.8 ± 0.3 and lung 0.7 ± 0.3). SUV(max) was age independent. Gender differences were evident within the thyroid (female/male: 3.7 ± 1.6/5.5 ± 2.4, p < 0.001; Mann-Whitney U test) and the pancreatic head (5.5 ± 1.9/6.9 ± 2.2, p < 0.001). The sst mRNA was widely expressed and heterogeneous, showing sst1 to be most abundant. SUV(max) values exclusively correlated with sst2 expression (r = 0.846, p < 0.001; Spearman rank correlation analysis), whereas there was no correlation of SUV(max) with the expression of the other four subtypes. CONCLUSION: In normal human tissues (68)Ga-DOTATOC imaging has been related to the expression of sst2 at the level of mRNA. The novel normative database may improve diagnostics, monitoring and therapy of sst-expressing tumours or inflammation on a molecular basis.

Lesion dose in differentiated thyroid carcinoma metastases after rhTSH or thyroid hormone withdrawal: 124I PET/CT dosimetric comparisons.

PURPOSE: Renal radioiodine excretion is ~50% faster during euthyroidism versus hypothyroidism. We therefore sought to assess lesion dose/GBq of administered 131I activity (LDpA) in iodine-avid metastases (IAM) of differentiated thyroid carcinoma (DTC) in athyreotic patients after recombinant human thyroid-stimulating hormone (rhTSH) versus after thyroid hormone withdrawal (THW). METHODS: We retrospectively compared mean LDpA between groups of consecutive patients (N=63) receiving 124I positron emission tomography/computed tomography (124I PET/CT) aided by rhTSH (n=27) or THW (n=36); we prospectively compared LDpA after these stimulation methods within another individual. Data derived from serial PET scans and one CT scan performed 2-96 h post-124I ingestion. A mixed model analysis of covariance (ANCOVA) calculated the treatment groups' mean LDpAs adjusting for statistically significant baseline intergroup differences: non-IAM were more prevalent, median IAM count/patient lower in cervical lymph nodes and higher in distant sites, median stimulated thyroglobulin higher, mean cumulative radioiodine activity greater and prior diagnostic scintigraphy more frequent in the rhTSH patients. RESULTS: Mean LDpAs were: rhTSH group (n=71 IAM), 30.6 Gy/GBq; THW group (n=66 IAM), 51.8 Gy/GBq. The difference in group means (rhTSH less THW), -21.2 Gy/GBq, was statistically non-significant (p=0.1667). However, the 95% confidence interval of that difference (-51.4 to +9 Gy/GBq) suggested a trend favouring THW. The within-patient comparison found 2.9- to 10-fold higher LDpAs under THW. CONCLUSION: We found some suggestions, but no statistically significant evidence, that rhTSH administration results in a lower radiation dose to DTC metastases than does THW. A large, well-controlled, prospective within-patient study should resolve this issue.

Gold nanoparticles of diameter 1.4 nm trigger necrosis by oxidative stress and mitochondrial damage.

Gold nanoparticles (AuNPs) are generally considered nontoxic, similar to bulk gold, which is inert and biocompatible. AuNPs of diameter 1.4 nm capped with triphenylphosphine monosulfonate (TPPMS), Au1.4MS, are much more cytotoxic than 15-nm nanoparticles (Au15MS) of similar chemical composition. Here, major cell-death pathways are studied and it is determined that the cytotoxicity is caused by oxidative stress. Indicators of oxidative stress, reactive oxygen species (ROS), mitochondrial potential and integrity, and mitochondrial substrate reduction are all compromised. Genome-wide expression profiling using DNA gene arrays indicates robust upregulation of stress-related genes after 6 and 12 h of incubation with a 2 x IC50 concentration of Au1.4MS but not with Au15MS nanoparticles. The caspase inhibitor Z-VAD-fmk does not rescue the cells, which suggests that necrosis, not apoptosis, is the predominant pathway at this concentration. Pretreatment of the nanoparticles with reducing agents/antioxidants N-acetylcysteine, glutathione, and TPPMS reduces the toxicity of Au1.4MS. AuNPs of similar size but capped with glutathione (Au1.1GSH) likewise do not induce oxidative stress. Besides the size dependency of AuNP toxicity, ligand chemistry is a critical parameter determining the degree of cytotoxicity. AuNP exposure most likely causes oxidative stress that is amplified by mitochondrial damage. Au1.4MS nanoparticle cytotoxicity is associated with oxidative stress, endogenous ROS production, and depletion of the intracellular antioxidant pool.

Iodine-124 PET dosimetry in differentiated thyroid cancer: recovery coefficient in 2D and 3D modes for PET(/CT) systems.

PURPOSE: This study evaluated the absolute quantification of iodine-124 ((124)I) activity concentration with respect to the use of this isotope for dosimetry before therapies with (131)I or (131)I-labeled radiotherapeuticals. The recovery coefficients of positron emission tomography(/computed tomography) PET(/CT) systems using (124)I were determined using phantoms and then validated under typical conditions observed in differentiated thyroid cancer (DTC) patients. METHODS: Transversal spatial resolution and recovery measurements with (124)I and with fluorine-18 ((18)F) as the reference were performed using isotope-containing line sources embedded in water and six isotope-containing spheres 9.7 to 37.0 mm in diameter placed in water-containing body and cylinder phantoms. The cylinder phantom spheres were filled with (18)F only. Measurements in two-dimensional (2D) and three-dimensional (3D) modes were performed using both stand-alone PET (EXACT HR(+)) and combined PET/CT (BIOGRAPH EMOTION DUO) systems. Recovery comparison measurements were additionally performed on a GE ADVANCE PET system using the cylinder phantom. The recovery coefficients were directly determined using the activity concentration of circular regions of interest divided by the prepared activity concentration determined by the dose calibrator. The recovery correction method was validated using three consecutive scans of the body phantom under our (124)I PET(/CT) protocol for DTC patients. RESULTS: Compared with that of (18)F, transversal spatial resolution of (124)I was slightly, but statistically significantly degraded (7.4 mm vs. 8.3 mm, P<0.002). Using the body phantom, recovery was lower for (124)I than for (18)F in both 2D and 3D modes. The (124)I recovery coefficient of the largest sphere was significantly higher in 2D than in 3D mode (81% vs. 75%, P=0.03). Remarkably, the (18)F recovery coefficient for the largest sphere significantly deviated from unity (range of 87%-93%, P<0.004) for all scanners but the GE ADVANCE. The maximum range of inaccuracy of the measured (124)I activity concentration under in vivo conditions after applying partial volume correction was +/-10% for spheres > or =12.6 mm in diameter. CONCLUSIONS: Recovery correction is mandatory for (124)I PET quantification, even for large structures. To ensure accurate dosimetry, thorough absolute recovery measurements must be individually established for the particular PET scanner and radionuclide to be used.

Improved synthesis of no-carrier-added p-[124I]iodo-L-phenylalanine and p-[131I]iodo-L-phenylalanine for nuclear medicine applications in malignant gliomas.

This work describes the synthesis and the tumor affinity testing of no-carrier-added (n.c.a.) p-[(124)I]iodo-L-phenyalanine ([(124)I]IPA) and n.c.a. p-[(131)I]iodo-l-phenyalanine ([(131)I]IPA) as radiopharmaceuticals for imaging brain tumors with PET and for radionuclid-based therapy, respectively. Parameters for labeling were optimized with regard to the amount of precursor, temperature and time. Thereafter, n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA were investigated in rat F98 glioma and in primary human A1207 and HOM-T3868 glioblastoma cells in vitro, followed by an in vivo evaluation in CD1 nu/nu mice engrafted with human glioblastoma. No-carrier-added [(124)I]IPA and n.c.a. [(131)I]IPA were obtained in 90+/-6% radiochemical yield and >99% radiochemical purity by iododestannylation of N-Boc-4-(tri-n-butylstannyl)-L-phenylalanine methylester in the presence of chloramine-T, followed by hydrolysis of the protecting groups. The total synthesis time, including the HPLC separation and pharmacological formulation, was less than 60 min and compatible with a clinical routine production. Both amino acid tracers accumulated intensively in rat and in human glioma cells. The radioactivity incorporation in tumor cells following a 15-min incubation at 37 degrees C/pH 7.4 varied from 25% to 42% of the total loaded activity per 10(6) tumor cells (296-540 cpm/1000 cells). Inhibition experiments confirmed that n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA were taken up into tumor by the sodium-independent L- and ASC-type transporters. Biodistribution and whole-body imaging by a gamma-camera and a PET scanner demonstrated a high targeting level and a prolonged retention of n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA within the xenotransplanted human glioblastoma and a primarily renal excretion. However, an accurate delineation of the tumors in mice was not possible by our imaging systems. Radioactivity accumulation in the thyroid and in the stomach as a secondary indication of deiodination was less than 1% of the injected dose at 24h p.i., confirming the high in vivo stability of the radiopharmaceuticals. In conclusion, n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA are new promising radiopharmaceuticals, which can now be prepared in high radiochemical yields and high purity for widespread clinical applications. The specific and high-level targeting of n.c.a. [(124)I]IPA and n.c.a. [(131)I]IPA to glioma cells in vitro and to glioblastoma engrafts in vivo encourages further in vivo validations to ascertain their clinical potential as agent for imaging and quantitation of gliomas with PET, and for radionuclid-based therapy, respectively.

Size-dependent cytotoxicity of gold nanoparticles.

Gold nanoparticles are widely used in biomedical imaging and diagnostic tests. Based on their established use in the laboratory and the chemical stability of Au(0), gold nanoparticles were expected to be safe. The recent literature, however, contains conflicting data regarding the cytotoxicity of gold nanoparticles. Against this background a systematic study of water-soluble gold nanoparticles stabilized by triphenylphosphine derivatives ranging in size from 0.8 to 15 nm is made. The cytotoxicity of these particles in four cell lines representing major functional cell types with barrier and phagocyte function are tested. Connective tissue fibroblasts, epithelial cells, macrophages, and melanoma cells prove most sensitive to gold particles 1.4 nm in size, which results in IC(50) values ranging from 30 to 56 microM depending on the particular 1.4-nm Au compound-cell line combination. In contrast, gold particles 15 nm in size and Tauredon (gold thiomalate) are nontoxic at up to 60-fold and 100-fold higher concentrations, respectively. The cellular response is size dependent, in that 1.4-nm particles cause predominantly rapid cell death by necrosis within 12 h while closely related particles 1.2 nm in diameter effect predominantly programmed cell death by apoptosis.

Segmentation of PET volumes by iterative image thresholding.

UNLABELLED: The segmentation of metastatic volumes in PET is usually performed by thresholding methods. In a clinical application, the optimum threshold obtained from the adaptive thresholding method requires a priori estimation of the lesion volume from anatomic images such as CT. We describe an iterative thresholding method (ITM) used to estimate the PET volumes without anatomic a priori knowledge and its application to clinical images. METHODS: The ITM is based on threshold-volume curves at varying source-to-background (S/B) ratio acquired from a body phantom. The spheres and background were filled either with (18)F-FDG or Na(124)I ((124)I). These calibrated S/B-threshold-volume curves were used in estimating the volume by applying an iterative procedure. The ITM was validated with a PET phantom containing spheres and with 39 PET tumors that were discernable on CT by using whole-body (18)F-FDG (15 patients) and (124)I PET/CT (9 patients): The measured S/B ratios of the lesions were estimated from PET images, and their volumes were iteratively calculated using the calibrated S/B-threshold-volume curves. The resulting PET volumes were then compared with the known sphere inner volume and CT volumes of tumors that served as gold standards. RESULTS: Phantom data analysis showed that the S/B-threshold-volume curves of (18)F-FDG and (124)I were similar. The average absolute deviation (expressed as a percentage of the expected volume) obtained in the PET validation phantom was 10% for volumes larger than 1.0 mL; sphere volumes of 0.5 mL showed a significantly larger deviation. For patients, the average absolute deviation for volumes between 0.8 and 7.5 mL was about 9% (31 lesions), whereas volumes larger than 7.5 mL showed an average volume mismatch of 15% (8 lesions). CONCLUSION: The ITM sufficiently estimated the clinical volumes in the range of 0.8-7.5 mL; volumes larger than 7.5 mL showed greater deviations that were still acceptable. These findings are associated with the limitation of the ITM. The ITM is especially useful for lesions that are only visible on PET. As a consequence, the lesion dosimetry is feasible with sufficient accuracy using PET images only.

Feasibility of central cannabinoid CB1 receptor imaging with [124I]AM281 PET demonstrated in a schizophrenic patient.

We studied central cannabinoid CB1 receptors in a schizophrenic patient using the pyrazole derivative AM281 labelled with the positron-emitting nuclide iodine-124. A dynamic positron emission tomography (PET) acquisition with simultaneous blood sampling was performed up to 1.5 h post-injection. The classical Logan plot analysis was applied to generate a three-dimensional map of distribution volume (DV). The map was spatially normalised into the Montreal Neurological Institute stereotactic space. Using a volume of interest (VOI) template, mean values of DV were extracted from multiple grey matter regions and white matter (as a reference). As a measure of regional receptor availability, ratios of DV in grey matter to DV in white matter minus one (DVR-1) were calculated. The highest receptor binding was observed in the striatum and the pallidum (DVR-1: 0.35-0.37). Binding in basal ganglia regions was lower on the left than the right side. Moderately high binding was seen in the frontal cortex (0.22), the temporal cortex (0.18) and the cerebellum (0.15). In conclusion, 124I-AM281 PET can be used to reveal areas with prominent CB1 receptor binding. Nevertheless, limited image contrast and relatively high radiation exposure (physical half-life of 124I: 4 days) have to be taken into account. Asymmetric receptor binding may possibly reflect pathologic changes in schizophrenia.

Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer.

BACKGROUND: Radionuclide imaging of reporter gene expression may be useful for noninvasive monitoring of clinical cardiac gene therapy. Experience until now, however, has been limited to small animals. METHODS AND RESULTS: To evaluate feasibility in a clinically applicable setting, pigs were studied by conventional positron emission tomography (PET) 2 days after regional intramyocardial injection of control adenovirus or adenovirus carrying herpesviral thymidine kinase reporter gene (HSV1-tk). Myocardial blood flow was quantified by use of [13N]ammonia. Subsequently, kinetics of the reporter substrate [124I]-2'-fluoro-2'-deoxy-5-iodo-1-beta-d-arabino-furanosyluracil (FIAU) were assessed over a period of 2 hours. Areas infected with adenovirus expressing HSV1-tk showed significantly elevated FIAU retention during the first 30 minutes after injection. At later times, washout was observed, and retention was not different from that in areas infected with control virus or remote myocardium. Early in vivo FIAU uptake correlated with ex vivo images, autoradiography, and immunohistochemistry for reporter gene product after euthanasia. After intramyocardial injection of both adenoviruses, myocardial blood flow was mildly elevated compared with that in remote areas, consistent with histological signs of regional inflammation. CONCLUSIONS: In vivo quantification of regional myocardial transgene expression is feasible with clinical PET methodology, the radioiodinated reporter probe FIAU, and the HSV1-tk reporter gene. Radioactivity efflux after specific initial uptake was not observed previously in tumor studies, suggesting that tissue-specific differences in nucleoside metabolism influence reporter probe kinetics. By coregistering reporter gene expression with additional biological parameters such as myocardial blood flow, PET allows for noninvasive characterization of the success of cardiac gene transfer along with its functional correlates.