Imaging of highly malignant osteosarcoma with iodine-123-vascular endothelial growth factor.

OBJECTIVE: Vascular endothelial growth factor (VEGF) is an important angiogenic factor, and its receptors have been shown to be overexpressed in various human carcinomas. In this study, we investigated the role of scanning with iodine-123 ((123)I)-labelled VEGF(165) in patients with highly malignant osteosarcoma. METHODS: Two patients (a 15-year-old female and a 14-year-old male) with osteosarcoma were injected with 140 MBq [<130 pmol (<5 µg) VEGF(165) per patient] of (123)I-VEGF(165). Dynamic acquisition was initiated immediately after administration and carried out until 30 min after injection. Whole-body images were done in anterior and posterior views at various time points. All patients underwent single-photon emission tomography imaging. RESULTS: (123)I-VEGF(165) scans were positive in these patients. Sequential images clearly showed increased (123)I-VEGF(165) activity in osteosarcoma lesions. The tumour lesions were still visualized in whole-body images and single-photon emission tomography examinations 2 h after injection. Intravenous injection of (123)I-VEGF(165) did not cause any side effects. CONCLUSION: Our results suggest that (123)I-VEGF(165) receptor scintigraphy may be useful for the visualization of highly malignant osteosarcoma and/or metastasis and the angiogenic activity of the tumour.

Improved quality of life in patients treated with Peptide radionuclides.

Peptide receptor radionuclide therapy (PRRT) has recently been established as an important treatment modality for somatostatin receptor (SSTR)-positive tumors. The purpose of this study was to evaluate the clinical response, side-effects as well as the quality of life following (90)Y-DOTA-lanreotide (DOTALAN) and/or (90)Y-DOTA-Tyr (3)-DPhe(1)-octreotide (DOTATOC) therapy in patients with progressive metastatic disease during a 6-year follow-up period. Following dosimetric evaluation with (111)In-DOTALAN and (111)In-DOTATOC, 13 patients with estimated absorbed tumor doses of >5 Gy/GBq (carcinoid, n = 5; radioiodine-negative thyroid cancer, n = 4; gastrinoma, n = 1; insulinoma, n = 1; glucagonoma, n = 1; glomus jugularis tumor, n = 1) were assigned for PRRT. A dose of 925 MBq of (90)Y-DOTALAN (four patients) or 1.85-3.7 GBq of (90)Y-DOTATOC (10 patients) was administered intravenously and repeated every 4-8 weeks. Tumor dosimetry was performed prior to and under therapy, re-staging every 2-3 months. Pain intensity, Karnofsky score and general symptoms were evaluated in order to determine quality of life. Patients were followed until death. Altogether, 53 infusions of PRRT (1.85-14.1 GBq) were administered. After the first follow-up of 3 months of (90)Y-DOTALAN therapy, stable disease (SD) was observed in one patient and progressive disease (PD) in three patients. With (90)Y-DOTATOC therapy, SD was found in all 10 patients. During the re-evaluation period (4-27 months), one patient had to be shifted from (90)Y-DOTALAN to (90)Y-DOTATOC therapy due to reduced (111)In-DOTALAN uptake after 5.5 GBq. In the first 6 months after PRRT with DOTATOC, SD was found in nine of 10 patients and PD in one patient. Thereafter, SD was observed in two patients and PD in eight patients. Nine of 13 patients after PRRT with either DOTALAN or DOTATOC died. None of the patients had experienced severe acute hematological side-effects. Transient thrombocytopenia or lymphocytopenia was seen in 10 patients after 3.7 GBq, and a skin reaction in one patient. Total accumulated kidney dose ranged between 4 and 64 Gy, with reduced creatinine clearance in two patients. Pain relief was achieved in three of three patients after ~3.7 GBq ERT within 4-6 months. Appetite, weight, Karnofsky score and general well-being had improved in patients with SD during and after therapy. Based on the results of this study conducted on a small group of patients, we conclude that PRRT may offer an alternative treatment option for SSTR-positive tumors, with only mild transient side-effects and a marked improvement in the quality of life.

Uptake of (18)F-FLT and (18)F-FDG in primary head and neck cancer correlates with survival.

UNLABELLED: The aim of the study was to determine the practicability of (18)F-FLT in tumours of the head and neck area in terms of visualization, a possible correlation between FLT uptake and proliferation fraction as determined by Ki-67 immunostaining, and if tumoural FLT-uptake has a prognostic meaning, as determined by a correlation to patient survival time. Results were compared to (18)F-FDG. PATIENTS, METHODS: 20 patients with previously untreated lesions of the head and neck area, which were clinically highly suspicious to be malignant, underwent PET scans with (18)F-FLT and (18)F-FDG, a CT of the head and neck area, and a biopsy. Tumour tracer uptake was determined by standardized uptake value (SUV) normalized to body weight and /non-tumor ratios (T/N). (18)F-FDG and (18)F-FLT uptake were compared with histopathologic and immunohistochemical results. RESULTS: 19 patients had malignant tumours; one patient had a benign cystadenoma (so called Warthin's tumour) of the parotid gland. One negative lesion turned out to be a malignant T1 stage squamous cell carcinoma in both PET scans, the Warthin's tumour was false positive with (18)F-FDG but showed only faint uptake with (18)F-FLT, resulting in a sensitivity of 95 % for both tracers. Of all lesions, maximum SUVs of (18)F-FLT ranged from 1.53 to 11.70 (mean +/- SD 5.81 +/- 2.28) those of FDG from 2.63 to 16.50 (mean +/- SD 8.91 +/- 3.58), p < 0.001. (18)F-FLT-T/N ranged from 0.94 to 5.85 (mean +/- SD, 3.18 +/- 1.21), (18)F-FDG-T/N was from 0.92 to 7.50 (mean +/- SD, 3.6 +/- 1.74), n.s. The mean survival time was 18 months in a maximum follow up time of 36 months. A significant correlation between both PET tracers and survival was detected, but no correlation between the amount of Ki-67 positive cells and FLT. CONCLUSION: In head and neck cancer in the primary setting (18)F-FLT does not provide additional visual information in comparison to (18)F-FDG.(18)F-FLT uptake is inversely correlated with patient survival, as well as (18)F-FDG.

Iodine-123-vascular endothelial growth factor-165 (123I-VEGF165). Biodistribution, safety and radiation dosimetry in patients with pancreatic carcinoma.

AIM: Imaging with radiolabelled vascular endothelial growth factor (VEGF) has been developed for the localisation and diagnosis of a variety of human solid tumors including gastrointestinal tumors. METHODS: In this study we investigated the biodistribution, safety and absorbed dose of iodine-123 radiolabelled VEGF(165) ((123)I-VEGF(165)) in 9 patients with pancreatic carcinoma. Following intravenous administration of (123)I-VEGF(165) (189+/-17 MBq; <130 pmole (<5 microg) VEGF(165) per patient), sequential images were recorded during the initial 30 min PI. Serial whole-body images were acquired in anterior and posterior views at various time points. All patients underwent single-photon emission tomography (SPET) imaging. Dosimetry calculations were performed on the basis of gamma camera data. Estimates of radiation absorbed dose were calculated using the MIRDOSE 3 program. RESULTS: The highest absorbed organ doses were found to be thyroid (0.058+/-0.004 mGy/MBq), spleen (0.046+/- 0.017 mGy/MBq), urinary bladder (0.04+/-0.02 mGy/MBq), lungs (0.034+/-0.009 mGy/MBq) and kidneys (0.033+/-0.005 mGy/MBq). The effective dose was estimated to be 0.017+/-0.002 mSv/MBq. A majority of primary pancreatic tumors and their metastases were visualized by (123)I-VEGF(165) scan. CONCLUSION: In vitro binding results confirmed specific binding of (123)I-VEGF(165) to pancreatic tumor cells and tissues. (123)I-VEGF(165) shows favorable dosimetry and is a safe radiopharmaceutical that may be of potential value for the imaging of VEGF receptor status in vivo.

Imaging gastrointestinal tumours using vascular endothelial growth factor-165 (VEGF165) receptor scintigraphy.

BACKGROUND: Recent studies have shown that vascular endothelial growth factor (VEGF) receptor is overexpressed in vascular endothelial cells of various human tumours as well as in human tumour cells. The aim of this study was to evaluate the usefulness of scanning with VEGF(165) labeled with (123)I for tumor localisation in patients with gastrointestinal tumours. PATIENTS AND METHODS: Human recombinant VEGF(165) was radiolabelled with (123)I by electrophilic radioiodination using the chloramine T method. [(123)I]VEGF(165) was administered intravenously [mean dose 184 +/- 18 MBq (

Experience with indium-111 and yttrium-90-labeled somatostatin analogs.

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide / lanreotide analogs as tumor tracers in nuclear medicine. Other (nontumoral) potential indications for SSTR scintigraphy are based on an increased lymphocyte binding at sites of inflammatory or immunologic diseases such as thyroid-associated ophthalmology. The vast majority of human tumors seem to over-express the one or the other of five distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to overexpress more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to In-DTPA-DPhe(1)-octreotide (OctreoScan(R)) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (K(d) 10-100 nM) and does not bind to hSSTR1 and hSSTR4, (111)In / (90)Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (K(d) 200 nM). Based on its unique hSSTR binding profile, (111)In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and (90)Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to (111)In-DTPA-DPhe(1)-octreotide and (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higherrdquuo; high-affinity binding of (111)In-DOTA-DPhe(1)-Tyr(3)-octreotide to hSSTR2 (K(d) 0.1-1 nM). Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, such as (99m)Tc-depreotide (NeoSpect(R); NeoTect(R)). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or nonsmall cell lung cancer ((99m)Tc-depreotide), indicating high diagnostic cabability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. Beneficial results were reported for high-dose treatment with (111)In-DTPA-DPhe(1)-octreotide, based on the emission of Auger electrons. The Phase IIa study "MAURITIUS" (Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study) showed in progressive cancer patients (therapy entry criteria) with a calculated tumor dose > 10 Gy / GBq (90)Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with peptide receptor imaging agents. In the "MAURITIUS" study, cummulative treatment doses up to 200 mCi (90)Y-DOTA-lanreotide were given as short-term infusion. Overall treatment results in 70 patients indicated stable tumor disease in 35% of patients and regressive tumor disease in 10% of tumor patients with different tumor entities expressing hSSTR. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to (90)Y-DOTA-lanreotide treatment, were reported. (90)Y-DOTA-DPhe(1)-Tyr(3)-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore be superior for treatment in patients with neuroendocrine tumors. However, there is only limited excess to long-term and survival data at present. Potential indications for (90Y-DOTA-lanreotide are radioiodine-negative thyroid cancer, hepatocellular cancer and lung cancer. Besides newer approaches and recent developments of 188)Re-labeled radioligands, no clinical results on the treatment response are yet available. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm their potential use in diagnosis as well as "proof-of-principle" for therapy of cancer patients. However, an optimal radiopeptide formulatioents. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy. Ongoing developments may result in peptides more suitable for this kind of receptor-targeted radionuclide therapy.

Aspects of 6-[18F]fluoro-L-DOPA preparation: precursor synthesis, preparative HPLC purification and determination of radiochemical purity.

A modified method for the synthesis of the intermediate product N-Boc-3,4-di(Boc-O)-6-iodo-L-phenylalanine ethyl ester of the [18F]FDOPA precursor preparation was developed. With the application of bis-(trifluoroacetoxy)-iodobenzene for the iodination step with elemental iodine the yield of the intermediate can be increased from 12% to 50-60%. By replacing silica-gel-based RP HPLC column by a polymer-based column for semi-preparative purification of [18F]FDOPA from the reaction mixture the radiochemical purity of the final product can be increased up to >99%. For the determination of the radiochemical impurity [18F]fluoride a HPLC method using a column with polymer-based RP material was introduced.

Effects of chemotherapeutic agents on expression of somatostatin receptors in pancreatic tumor cells.

UNLABELLED: Specific tumors express high amounts of receptors for somatostatin (SST), providing the basis for imaging and treatment using radiolabeled SST analogs. However, little is known about the potential influence of cytotoxic drugs on SST receptor (SSTR) expression in malignant cells. METHODS: To study the interaction between cytotoxic drugs and SSTR expression, the pancreatic cancer-derived tumor cell lines BxPC-3, Panc-1, Capan-1, and ASPC-1 were exposed to a range of cytotoxic drugs in vitro: Gemcitabine, 5-fluorouracil, cisplatin (cis-diaminedichloroplatinum [II]), camptothecin, mitomycin C, and doxorubicin were checked for changes in binding characteristics of the SSTR ligand (111)In-1,4,7,10-tetraazacyclododecane- N,N',N",N"'-tetraacetic acid-lanreotide (DOTA-LAN). Chemosensitivity was quantitated by measurements of reduction in cell numbers, changes in cell cycle distribution, and appearance of apoptotic subG1 (subG1/0 cell DNA content) cells. RESULTS: Cells were treated with gemcitabine (1.0 or 2.0 microg/mL), 5-fluorouracil (65-520 microg/mL), camptothecin (1.5 or 3 microg/mL), mitomycin C (0.1 or 0.2 microg/mL), and doxorubicin (1.0 or 2.0 microg/mL). Each of the chemotherapeutic agents induced a loss of high-affinity receptors. In addition, gemcitabine caused a reduction of low-affinity receptors in BxPC-3, Panc-1, and ASPC-1 cells. Mitomycin C, camptothecin, and 5-fluorouracil also induced an overexpression of low-affinity receptors. In cells pretreated with cisplatin (2-10 microg/mL), binding of DOTA-LAN was increased. Excluding gemcitabine, the increase in low-affinity binding sites exhibits a weak correlation with apoptosis (r(2) = 0.62). For gemcitabine, these effects were reversed after 4 d of recovery of the cell lines, eventually revealing overexpression of low- and high-affinity sites for BxPC-3 and Panc-1 cells and low-affinity sites for ASPC-1 cells. CONCLUSION: Our results clearly show that the pancreatic tumor lines reduce the expression of high-affinity DOTA-LAN binding sites during application of chemotherapeutic drugs, which is accompanied by variable overexpression of low-affinity binding sites. In the case of gemcitabine, SSTRs are overexpressed during recovery from drug exposure within 4 d. These findings may have implications on the interpretation of scintigraphic results obtained by receptor ligands.

New trends in peptide receptor radioligands.

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide/lanreotide analogs as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress the one or the other of five distinct hSSTR sub-type receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to over-express more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to 111In-DTPA-DPhe1-octreotide (OCTREOSCAN) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (Kd 10-100 nM) and does not bind to hSSTR1 and hSSTR4, 111In/90Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (Kd 200 nM). Based on its unique hSSTR binding profile, 111In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higher" high-affinity binding of 111In-DOTA-DPhe1-Tyr3-octreotide to hSSTR2. Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, including 99mTc-HYNIC-octreotide or 99mTc-depreotide (NEOSPECT; NEOTECT). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or non-small cell lung cancer (99mTc-depreotide), indicating high diagnostic capability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. The study "MAURITIUS" (MulticenterAnalysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study), a Phase IIa study, showed in patients with a calculated tumor dose >10 Gy/GBq 90Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with receptor imaging agents. Overall treatment results in >60 patients indicated stable tumor disease in roughly 35% of patients and regressive disease in 15% of tumor patients with different tumor entities. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to 90Y-DOTA-lanreotide, was reported. 90In-DOTA-DPhe1-Tyr3-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore provide even better treatment results in tumor patients, but there is only limited excess to long-term and survival data at present. Besides newer approaches and recent developments of 188Re-labeled radioligands no clinical results on the treatment response is available yet. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm "proof-of-principle" for their use in diagnosis as well as therapy of cancer patients. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy.

Effects of vasoactive intestinal peptide (VIP) and somatostatin (SST) on lipoprotein receptor expression by A431 tumor cells.

A variety of tumor cells have been shown to express lipoprotein receptors. Recent data suggest that lipoprotein receptors may play a regulatory role in the growth of certain tumor cells. We investigated the effects of vasoactive intestinal peptide (VIP) and somatostatin-14 (SST-14) on the binding of 111Indium-labeled lipoproteins [(111)In-low density lipoprotein ((111)In-LDL), (111)In-high density lipoprotein ((111)In-HDL) and (111)In-very low density lipoprotein ((111)In-VLDL)] onto the epidermoid mammary carcinoma cell line A431. Scatchard analyses of the binding data indicated one class of specific high affinity binding sites for LDL, HDL and VLDL expressed by A431 cells, respectively. VIP increased significantly the binding capacity for (111)In-LDL on A431 cells. The VIP-induced increase of (111)In-LDL binding sites was inhibited by SST-14. Furthermore, SST-14 inhibited VIP-induced 3H-thymidine incorporation and adenosine 3'-5' cyclic monophosphate (cAMP) formation in A431 cells with IC50 values in the range of 5-7 nM. However, SST-14 showed no effect on dibutyryl-cAMP-induced increase of (111)In-LDL binding sites expressed on A431 cells. In contrast to (111)In-LDL binding, no effects of VIP or SST-14 on HDL or VLDL binding to A431 tumor cells were found. Our results suggest a direct effect of VIP and SST-14 on LDL-binding onto tumor cells. The complex interactions between VIP and SST-14 on LDL receptor expression of tumor cells may play a role in tumor cell lipid metabolism.

Characterization of (123)I-vascular endothelial growth factor-binding sites expressed on human tumour cells: possible implication for tumour scintigraphy.

To explore the possibility of vascular endothelial growth factor (VEGF) receptor scintigraphy of primary tumours and their metastases, we analysed the binding properties of (123)I-labelled VEGF(165) ((123)I-VEGF(165)) and (123)I-VEGF(121) to human umbilical vein endothelial cells (HUVECs), several human tumour cell lines (HMC-1, A431, KU812, U937, HEP-1, HEP-G2, HEP-3B and Raji), a variety of primary human tumours (n = 40) and some adjacent non-neoplastic tissues as well as normal human peripheral blood cells in vitro. Two classes of high-affinity (123)I-VEGF(165)-binding site were found on the cell surface of HUVECs. In contrast, one class of high-affinity binding sites for (123)I-VEGF(165) was found on HMC-1, A431, HEP-1, HEP-G2, HEP-3B and U937 cells as well as many primary tumours. For (123)I-VEGF(121), a single class of high-affinity binding site was found on certain cell lines (HUVEC, HEP-1 and HMC-1) and distinct primary tumours (primary melanomas, ductal breast cancers and ovarian carcinomas as well as meningiomas). Tumour cells expressed significantly higher numbers of VEGF receptors compared with normal peripheral blood cells and adjacent non-neoplastic tissues. Immunohistochemical staining revealed that the VEGF receptor Flk-1 is expressed to a much higher extent within malignant tissues compared with neighbouring non-neoplastic cells. We observed significantly greater specific binding of (123)I-VEGF(165) and (123)I-VEGF(121) to a variety of human tumour cells/tissues compared with the corresponding normal tissues or normal peripheral blood cells. In comparison with (123)I-VEGF(121), (123)I-VEGF(165) bound to a higher number of different tumour cell types with a higher capacity. Thus, (123)I-VEGF(165) may be a potentially useful tracer for in vivo imaging of solid tumours.

Comparative somatostatin receptor scintigraphy using in-111-DOTA-lanreotide and in-111-DOTA-Tyr3-octreotide versus F-18-FDG-PET for evaluation of somatostatin receptor-mediated radionuclide therapy.

BACKGROUND: Based on the high number of somatostatin (SST) receptors expressed by neuroendocrine tumors, long-acting SST analogs have been successfully used for tumor detection. New developments point to the potential use of these types of radioligands for tumor-specific radionuclide therapy. PATIENTS AND METHODS: We have comparatively investigated the diagnostic capacity of the SST analog. 111In-DOTA-lanreotide (LAN), as opposed to 111ln-DOTA-DPhe1-Tyr3-octreotide (TOCT) in tumor patients. This article gives an overview of recent scintigraphic results compared to CT/MRI, 18F-FDG-PET, endoscopy and/or surgery in a threshold of 218 tumor patients. RESULTS: As opposed to radiology, previously unknown tumor lesions were demonstrable by either SST radioligand in about one third of patients. In carcinoid patients, the SST scan sensitivity was 64% for LAN (18 of 28) and 87% (34 of 39) for TOCT, whereas the sensitivity was 100% in patients with (radioiodine-negative) thyroid cancer (17 of 17) for LAN and 95% for TOCT (20 of 21). Discordant scintigraphic results between LAN and TOCT (higher tumor uptake and/or visualisation of different lesions in the same patient) were also seen in patients with lymphoma, lung cancer and intestinal adenocarcinoma. In a direct comparison of both SST tracers in 38 tumor patients, LAN gave positive results in 35 of 38, TOCT in 36 of 38 and 18F-FDG-PET in 14 of 22 of the same patients. SST scan results obtained by both tracers were equivocal in 23 of 38 patients, but were better in 10 patients withTOCTand in 5 patients with LAN. CONCLUSIONS: We conclude that both SST radioligands are suitable tracers for tumor imaging, but may give significantly different uptake results for different tumor types. Since the uptake is most important for tumor therapy, using either longacting SSTanalogs, and/or 90Y-labeled analogs, careful evaluation should be made prior to therapy.

New radiopharmaceuticals for receptor scintigraphy and radionuclide therapy.

In vitro data have demonstrated a high amount of receptors for various hormones and peptides on malignant cells of neuroendocrine origin. Among these, binding sites for members of the SST-family (hSSTR1-5) are frequently found, and their expression has led to therapeutic and diagnostic attempts to specifically target these receptors. Receptor scintigraphy using radiolabeled peptide ligands has proven its effectiveness in clinical practice. In addition, initial results have indicated a clinical potential for receptor-targeted radiotherapy. Based on somatostatin (SST) receptor (R) recognition, the novel radiopharmaceuticals 111In/90Y-DOTA-lanreotide developed at the University of Vienna as well as 111In/90Y-DOTA-DPhe1-Tyr3-octreotide (NOVARTIS) both have provided promising data for diagnosis and treatment of hSSTR-positive tumors. SSTR scintigraphy using 111In-DTPA-DPhe1-octreotide has a high positive predictive value for the vast majority of neuroendocrine tumors and has gained its place in the diagnostic work-up as well as follow-up of patients. We have used 111In-DOTA-lanreotide scintigraphy in 166 patients since 1997 and have seen positive results in 93% of patients. In 42 patients with neuroendocrine tumors comparative data were obtained. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of patients concerning both the tumor uptake as well as tumor lesion detection. Initial results both with 90Y-DOTA-lanreotide as well as 90Y-DOTA-DPhe1-Tyr3-octreotide has pointed out the clinical potential of radionuclide receptor-targeted radiotherapy. This new therapy could offer palliation and disease control at a reduced cost. The final peptide therapy strategy is most probably cheaper than conventional radiotherapies or prolonged chemotherapies. Overall, receptor-mediated radiotherapy with 90Y-DOTA-lanreotide/90Y-DOTA-DPhe1-Tyr3-octre otide might also be effective in patients refractory to conventional strategies.

Value of peptide receptor scintigraphy using (123)I-vasoactive intestinal peptide and (111)In-DTPA-D-Phe1-octreotide in 194 carcinoid patients: Vienna University Experience, 1993 to 1998.

PURPOSE: To report our experience with both (123)I-vasoactive intestinal peptide (VIP) and (111)In-DTPA-D-Phe(1)-octreotide for imaging to identify primary and metastatic tumor sites in carcinoid patients. PATIENTS AND METHODS: One hundred ninety-four patients with a verified or clinically suspected diagnosis of a carcinoid tumor were injected with (111)In-DTPA-D-Phe(1)-OCT for imaging purposes, while 133 patients underwent scanning with both (123)I-VIP and (111)In-DTPA-D-Phe(1)-OCT in random order. Imaging results were compared with computed tomography scans, results of conventional ultrasound, endosonography, and endoscopy, and results of surgical exploration in case of inconclusive conventional imaging. RESULTS: Primary or recurrent carcinoid tumors could be visualized with (111)In-DTPA-D-Phe(1)-OCT in 95 (91%) of 104 patients; metastatic sites were identified in 110 (95%) of 116 patients. In 11 (51%) of 21 patients with suggestive symptoms but without identified lesions by conventional imaging, focal tracer uptake located the carcinoid tumor. In addition, metastatic disease was demonstrated in three patients after resection. In a direct comparison in the 133 patients who underwent both imaging modalities, (111)In-DTPA-D-Phe(1)-OCT was found to be superior to (123)I-VIP, with 35 (93%) of 38 versus 32 (82%) of 38 scans being positive in primary or recurrent tumors, 58 (90%) of 65 versus 53 (82%) of 65 being positive in patients with metastatic sites, and seven (44%) of 16 versus four (25%) of 16 being positive in patients with symptoms but otherwise negative work-ups. Overall, additional lesions not seen on conventional imaging were imaged in 43 (41%) of 158 versus 25 (25%) of 103 scans with (111)In-DTPA-D-Phe(1)-OCT and (123)I-VIP, respectively. CONCLUSION: Both peptide tracers have a high sensitivity for localizing tumor sites in patients with ascertained or suspected carcinoid tumors, with (111)In-DTPA-D-Phe(1)-OCT scintigraphy being more sensitive than (123)I-VIP receptor scanning. Both, however, had a higher diagnostic yield than conventional imaging, as verified by surgical intervention or long-term follow-up. The combination of both peptide receptor scans does not seem to further enhance diagnostic information.

Radiation synovectomy using 165Dy ferric-hydroxide and oxidative DNA damage in patients with different types of arthritis.

UNLABELLED: Radiation synovectomy is an effective treatment for chronic synovitis refractory to pharmacological treatment in patients with rheumatoid or seronegative arthritis. Concerns persist about possible radiation-induced cytogenetic damage after radiation synovectomy leading to recommendations to use this technique only in the elderly. Micronucleus (MN) frequency in lymphocytes and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8OHdG) as an indicator of cellular oxidative DNA base damage are biomarkers of radiation-induced cytogenetic damage. The course of both biomarkers was studied in patients with different types of chronic synovitis undergoing radiation synovectomy with very short-lived 165Dy-ferric-hydroxide (DFH). METHODS: Radiation synovectomy of the knee was performed in 13 men and 12 women (mean age, 44+/-15 y) using a mean activity of 9.48+/-1.65 GBq 165Dy-DFH in 27 consecutive treatments. MN frequency in lymphocytes and urinary excretion of 8OHdG, measured by high-performance liquid chromatography, were assessed before and 4 (MN only) and 20 h after radiation synovectomy. RESULTS: Urinary excretion of 8OHdG in patients (in micromol/mol creatinine; pretreatment mean, 3.1+/-3.4; median, 2.27) was not significantly different from that in healthy volunteers (mean, 2.0+/-1.2; median, 1.87) and not altered by radiation synovectomy (post-treatment mean, 2.5+/-1.5; median, 2.04, NS). An increase in 8OHdG levels after radiation synovectomy of more than 1 SD was found in only 1 patient, who experienced leakage to the lymph nodes but who already had elevated urinary 8OHdG levels before treatment. The frequency of MN/500 binucleated cells (BNCs) was slightly lower in patients (pretreatment mean, 4.3+/-2.6; median, 4.25) than in healthy volunteers (mean, 5.4+/-2.3; median, 5.3) and did not significantly change after therapy, either (4-h post-treatment mean, 3.9+/-2.1, median, 3.8; 20-h post-treatment mean, 4.1+/-2, median 3.8 MN/500 BNC). In 22 of 27 treatments, no leakage to nontarget organs could be monitored, whereas leakage to the local lymph nodes and the liver was detected after 5 treatments. CONCLUSION: Radiation synovectomy using 165Dy-DFH causes no significant radiation burden to most patients as indicated by the absence of adverse changes in levels of biomarkers of cytogenetic damage and a low incidence of leakage. These data suggest that the risk of malignancy may not be elevated.

Imaging serotonin and dopamine transporters with 123I-beta-CIT SPECT: binding kinetics and effects of normal aging.

UNLABELLED: [123I]beta-carbomethoxy-3-beta-(4-iodophenyl)-tropane (CIT) is a useful ligand for dopamine transporters (DATs) and serotonin transporters (5-HTTs). Previous SPECT studies have shown a state of sustained equilibrium in the striatum on day 2 after injection that allows quantification of striatal DATs using a simple ratio of specific-to-nondisplaceable binding. The aim of this study was to investigate the kinetics of [123I]beta-CIT uptake in the thalamus, hypothalamus, and midbrain, areas known to contain 5-HTTs in high densities. METHODS: SPECT with a triple-head camera was performed on 16 healthy volunteers (13 women, 3 men; mean age [+/-SD], 32 +/- 11 y) after intravenous bolus injection of 130 +/- 20 MBq (3.5 +/- 0.5 mCi) [123I]beta-CIT. Two individuals were scanned 1, 2, 4, 7, 10, 13, 16, and 24 h after injection, and the remaining 14 were scanned 4, 7, 10, 20, and 24 h after injection. Values from 19 previously examined healthy volunteers (8 women, 11 men; mean age, 52 +/- 20 y) were included in the analysis to study the age dependency of beta-CIT binding in striatal and 5-HTT-rich brain areas in a larger control sample. RESULTS: Peak uptake 4 h after injection, followed by stable uptake until 10 h and a slow decrease until 24 h, was observed in the thalamus-hypothalamus region. Activity in the midbrain-pons region peaked 2 h after injection. Because of a concomitant slow but steady decline of uptake in reference regions starting 4 h after injection, a higher stability of binding ratios for 5-HTT-rich brain areas was observed on day 2, suggesting that a state of transient equilibrium is reached between 20 and 24 h but that conditions are only close to transient equilibrium between 4 and 10 h after injection for 5-HTT-rich brain areas. In addition to an age-related decline of striatal [123I]beta-CIT binding of 6.6% per decade, a significant age-associated decrease of beta-CIT binding of 3-4% per decade was found in 5-HTT-rich brain areas. The decline of beta-CIT binding in these regions may be explained, at least in part, by a loss of monoamine transporters with age but may also be related to age-associated morphologic changes. CONCLUSION: [123I]beta-CIT appears to be a suitable ligand for imaging serotonin transporters with SPECT. However, careful age matching is warranted for [123I]beta-CIT SPECT studies of 5-HTT changes in patients with neuropsychiatric disorders.

"MAURITIUS": tumour dose in patients with advanced carcinoma.

Radioimaging of various human tumours by means of somatostatin analogues and vasoactive intestinal peptide has been introduced into clinical practice in recent years. The finding that human tumours express various subtypes of somatostatin receptors has led to the development and characterization of a novel peptide tracer, termed MAURITIUS. MAURITIUS identifies a broad range of somatostatin receptors with high binding affinity, and somatostatin receptor 1 with low binding affinity. In order to evaluate patients for tumour radiotherapy with 90Y-MAURITIUS, tumour dose calculation is performed with 111In-MAURITIUS [111In-DOTA-lanreotide]. Treatment is initiated in patients presenting a tumour uptake of > or = 10 Gy/GBq (i.e., standard dose for 1 treatment cycle with 90Y-MAURITIUS). In 25 patients with advanced cancer refractory to conventional antineoplastic treatment 111In-MAURITIUS (approximately 150 MBq; 10 nmol/patient), scintigraphy and dosimetry was performed. Dosimetry data were calculated based on scintigraphic results as well as urine, faeces and blood data. In all patients, at least one tumour site was visualized during the initial few minutes of application. Additional tumour sites not seen on conventional imaging (computerized tomography, magnetic resonance imaging bone scan) could be detected in 6 patients with carcinoids, one patient with prostate cancer and one patient with lymphoma. Liver metastases were visualized in all patients with gastrointestinal cancers, while the primary tumour was not detected in 2 patients with pancreatic, and in 1 patient with rectal, cancer. The calculated radiation dose for tumours and/or metastases ranged between 3-60 Gy/GBq for 90Y-MAURITIUS. MAURITIUS is a universal receptor ligand for a large variety of different human tumours, and is suitable for treatment when labelled with 90Y.

DOTA-lanreotide: a novel somatostatin analog for tumor diagnosis and therapy.

Long acting somatostatin-14 (SST) analogs are used clinically to inhibit tumor growth and proliferation of various tumor types via binding to specific receptors (R). We have developed a 111In-/90Y-labeled SST analog, DOTA-(D)betaNal1-lanreotide (DOTALAN), for tumor diagnosis and therapy. 111In-/90Y-DOTALAN bound with high affinity (dissociation constant, Kd, 1-12 nM) to a number of primary human tumors (n = 31) such as intestinal adenocarcinoma (n = 17; 150-4000 fmol/mg protein) or breast cancer (n = 4; 250-9000 fmol/mg protein). 111In-/90Y-DOTALAN exhibited a similar high binding affinity (Kd, 1-15 nM) for the human breast cancer cell lines T47D and ZR75-1, the prostate cancer cell lines PC3 and DU145, the colonic adenocarcinoma cell line HT29, the pancreatic adenocarcinoma cell line PANC1, and the melanoma cell line 518A2. When expressed in COS7 cells, 111In-DOTALAN bound with high affinity to hsst2 (Kd, 4.3 nM), hsst3 (Kd, 5.1 nM), hsst4 (Kd, 3.8 nM), and hsst5 (Kd, 10 nM) and with lower affinity to hsst1 (Kd, approximately 200 nM). The rank order of displacement of [125I]Tyr11-SST binding to hsst1 was: SST (IC50, 0.5 nM) >> DOTALAN (IC50, 154 nM) > lanreotide (LAN) approximate to Tyr3-octreotide (TOCT) approximate to DOTA-Tyr3-octreotide (DOTATOCT) approximate to DOTA-vapreotide (DOTAVAP; IC50, >1000 nM); that to hsst2 was: DOTATOCT approximate to TOCT approximate to DOTALAN approximate to SST approximately LAN approximate to DOTAVAP (IC50, 1.4 nM); that to hsst3 was: SST (IC50, 1.2 nM) > DOTALAN = LAN (IC50, 15 nM) approximate to TOCT (IC50, 20 nM) approximate to DOTAVAP (IC50, 28 nM) > DOTATOCT (IC50, 73 nM); that to hsst4 was: SST (IC50, 1.8 nM) approximate to DOTALAN (IC50, 2.5 nM) > LAN (IC50, 22 nM) >> DOTATOCT approximate to DOTAVAP approximate to TOCT (IC50, >500 nM); and that to hsst5 was: DOTALAN (IC50, 0.45 nM) > SST (IC50, 0.9 nM) > TOCT (IC50, 1.5 nM) > DOTAVAP (IC50, 5.4 nM) >> LAN (IC50, 21 nM) > DOTATOCT (IC50 260 nM). In Sprague Dawley rats (n = 10), 90Y-DOTALAN was rapidly cleared from the circulation and concentrated in hsst-positive tissues such as pancreas or pituitary. Taken together, our results indicate that 111In-/90Y-DOTALAN binds to a broad range of primary human tumors and tumor cell lines, probably via binding to hsst2-5. We conclude that this radiolabeled peptide can be used for hsst-mediated diagnosis (111In-DOTALAN) as well as systemic radiotherapy (90Y-DOTALAN) of human tumors.

Response to treatment with yttrium 90-DOTA-lanreotide of a patient with metastatic gastrinoma.

1,4,7,10-tetraazacyclododecane-N,N',N",N'''-tetraacetic acid (DOTA)-lanreotide is a universal somatostatin (SST) receptor subtype ligand that binds to a large variety of human tumors. We report the case of a patient with metastatic gastrinoma who was treated with 90Y-DOTA-lanreotide. Before treatment, dosimetry with 111In-DOTA-lanreotide (150 MBq, 10 nmol) indicated a dose of 5.8 mGy/MBq for the recurrent abdominal gastrinoma, and a mean dose of approximately 1.0 mGy/MBq for liver metastases (i.e., 56 and approximately 10 mGy/MBq for 90Y-DOTA-lanreotide, respectively). After four infusions of 90Y-DOTA-lanreotide (each 1 GBq, approximately 30 nmol) over a 6-mo period, the 111In-DOTA-lanreotide scintigraphy of the liver had returned to a nearly normal condition and a remarkably decreased uptake by the recurrent gastrinoma was calculated (approximately 5 mGy/MBq for 90Y-DOTA-lanreotide). The imaging results were well-correlated with a 25% regression of the liver metastases as indicated by CT. Blood, urine and whole-body clearances of 111In-DOTA-lanreotide and 90Y-DOTA-lanreotide were very similar. The DOTA-lanreotide promises to be useful for functional tumor diagnosis (111In-DOTA-lanreotide) and receptor-mediated tumor radiotherapy (90Y-DOTA-lanreotide).

Indium-111-DTPA-D-Phe-1-octreotide and technetium-99m-(V)-dimercaptosuccinic acid scanning in the preoperative staging of medullary thyroid carcinoma.

UNLABELLED: The early detection of all tumor sites in patients with medullary thyroid carcinoma (MTC) before primary surgery is important, because MTC tends to metastasize to regional lymph nodes of the neck and mediastinum early during the course of the disease. METHODS: In an approach to localize the primary tumor sites and to detect additional tumor involvement, we have performed in 22 patients with MTC either 99mTc(V)-dimercaptosuccinic acid (DMSA) and/or 111In-diethylenetriamine pentaacetic acid-D-Phe-1-octreotide scintigraphy. RESULTS: Indium-111-octreotide (150-200 MBq) identified the primary tumor in 10 of 14 patients (71%), whereas the primary tumor was visualized by 99mTc-DMSA (300-370 MBq) in 10 of 17 patients (58%). In 8 of 22 patients (36%), lymph node metastases were present at the time of diagnosis, as confirmed by histopathology and histochemistry after surgery (all <2 mm). Preoperatively, neither scan was able to detect lymph node involvement in these patients (0/8). CONCLUSION: Both 99mTc-DMSA and 111In-octreotide studies have similar sensitivity to localize primary MTC; however, these scans are not able to detect small lymph node involvement (micrometastases) before initial surgery. Unfortunately, both scans have no clinical implication for preoperative staging in patients with MTC.