Localization and prediction of malignant potential in recurrent pheochromocytoma/paraganglioma (PCC/PGL) using 18F-FDG PET/CT.

BACKGROUND: To our knowledge, data are lacking on the role of 18F-FDG PET/CT in the localization and prediction of neuroendocrine tumors, in particular the pheochromocytoma/paraganglioma (PCC/PGL) group. PURPOSE: To evaluate the role of 18F-FDG PET/CT in localizing and predicting the malignant potential of PCC/PGL. MATERIAL AND METHODS: Twenty-three consecutive patients with a history of PCC/PGL, presenting with symptoms related to catecholamine excess, underwent 18F-FDG PET/CT. Final confirmation of the diagnosis was made using the composite references. PET/CT findings were analyzed on a per-lesion basis and a per-patient basis. Tumor SUVmax was analyzed to predict the dichotomization of patient endpoints for the local disease and metastatic groups. RESULTS: We investigated 23 patients (10 men, 13 women) with a mean age of 46.43 ± 3.70 years. Serum catecholamine levels were elevated in 82.60% of these patients. There were 136 sites (mean SUVmax: 16.39 ± 3.47) of validated disease recurrence. The overall sensitivities for diagnostic CT, FDG PET, and FDG PET/CT were 86.02%, 87.50%, and 98.59%, respectively. Based on the composite references, 39.10% of patients had local disease. There were significant differences in the SUVmax distribution between the local disease and metastatic groups; a significant correlation was noted when a SUVmax cut-off was set at 9.2 (P<0.05). CONCLUSION: In recurrent PCC/PGL, diagnostic 18F-FDG PET/CT is a superior tool in the localization of recurrent tumors. Tumor SUVmax is a potentially useful predictor of malignant tumor potential.

68Ga-DOTA-TOC uptake in neuroendocrine tumour and healthy tissue: differentiation of physiological uptake and pathological processes in PET/CT.

PURPOSE: We wanted to establish the range of (68)Ga-DOTA-TOC uptake in liver and bone metastases of patients with neuroendocrine tumours (NET) and to establish the range of its uptake in pancreatic NET. This would allow differentiation between physiological uptake and tumour-related somatostatin receptor expression in the pancreas (including the uncinate process), liver and bone. Finally, we wanted to test for differences in patients with NET, either treated or not treated with peptide receptor radionuclide therapy (PRRT). METHODS: In 249 patients, 390 (68)Ga-DOTA-TOC PET/CT studies were performed. The clinical indications for PET/CT were gastroenteropancreatic NET (194 studies), nongastroenteropancreatic NET (origin in the lung and rectum; 46 studies), NET of unknown primary (111 studies), phaeochromocytoma/glomus tumours (18 studies), and radioiodine-negative metastatic thyroid carcinoma (21 studies). RESULTS: SUVmax (mean ± standard deviation) values of (68)Ga-DOTA-TOC were 29.8 ± 16.5 in 162 liver metastases, 19.8 ± 18.8 in 89 bone metastases and 34.6 ± 17.1 in 43 pancreatic NET (33.6 ± 14.3 in 30 tumours of the uncinate process and 36.3 ± 21.5 in 13 tumours of the pancreatic tail). A significant difference in SUVmax (p < 0.02) was found in liver metastases of NET patients treated with PRRT. There were significant differences in SUVmax between nonmalignant and malignant tissue for both bone and liver metastases and for pancreatic NET including the uncinate process (p < 0.0001). At a cut-off value of 17.1 the specificity and sensitivity of SUVmax for differentiating tumours in the uncinate process were 93.6 % and 90.0 %, respectively (p < 0.0001). CONCLUSION: (68)Ga-DOTA-TOC is an excellent tracer for the imaging of tumours expressing somatostatin receptors on the tumour cell surface, facilitating the detection of even small tumour lesions. The noninvasive PET/CT approach by measurement of regional SUVmax can offer important clinical information to distinguish between physiological and pathological somatostatin receptor expression, especially in the uncinate process. PRRT does not significantly influence SUVmax, except in liver metastases of patients with NET.

Diagnostic value of software-based image fusion of computed tomography and F18-FDG PET scans in patients with malignant lymphoma.

AIM: The purpose of this study was to evaluate the accuracy of 2-deoxy-2-[fluorine-18]fluoro-D-glucose (FDG) positron emission tomography (PET), computed tomography (CT), and software-based image fusion of both modalities in the imaging of non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD). METHODS: 77 patients with NHL (n = 58) or HD (n = 19) underwent a FDG PET scan, a contrast-enhanced CT, and a subsequent digital image fusion during initial staging or followup. 109 examinations of each modality were evaluated and compared to each other. Conventional staging procedures, other imaging techniques, laboratory screening, and follow-up data constituted the reference standard for comparison with image fusion. Sensitivity and specificity were calculated for CT and PET separately. RESULTS: Sensitivity and specificity for detecting malignant lymphoma were 90% and 76% for CT and 94% and 91% for PET, respectively. A lymph node region-based analysis (comprising 14 defined anatomical regions) revealed a sensitivity of 81% and a specificity of 97% for CT and 96% and 99% for FDG PET, respectively. Only three of 109 image fusion findings needed further evaluation (false positive). CONCLUSION: Digital fusion of PET and CT improves the accuracy of staging, restaging, and therapy monitoring in patients with malignant lymphoma and may reduce the need for invasive diagnostic procedures.

Nephrotoxicity and hematotoxicity one year after four cycles of peptide receptor radionuclide therapy (PRRT) and its impact on future treatment planning. A retrospective analysis. / Nefrotoxicidad y hematotoxicidad un año después de cuatro ciclos de terapia con péptidos marcados con radionúclidos (PRRT) y su impacto en la planificación del tratamiento futuro. Un análisis retrospectivo.

INTRODUCTION: Nephro- and hematotoxicity after peptide receptor radionuclide therapy (PRRT) have been described in multiple studies with heterogeneous cumulative activities, number of cycles or radiolabelled peptides. Though highly differentiated metastasized neuroendocrine tumours (NET) have long progression free survival, they may progress. We analysed long-term side effects in a homogenous treatment schedule in PRRT-patients and their impact on future oncologic treatment in case of progression. METHODS: From our database 89/384 patients receiving the same PRRT (Lu-177-DOTATATE or Y-90-DOTATOC) 4 times every 10 to 12 weeks and a follow-up at 12 months were analysed. One patient had three and 11 patients had two times four PRRT-cycles resulting in 102 cases. eGFR, Hb, WBC and platelets before the first and one year after the fourth therapy cycle were compared. eGFR-Grading was done according to chronic kidney disease classification (CKD) and grading of hematotoxicity according to Common Terminology Criteria for Adverse Events (CTCAE). Impact of age, gender, cumulative activity, type of PRRT on long-term-toxicity was also assessed. RESULTS: eGFR grade 1-2 dropped from 87/102 at the baseline to 71 cases at follow-up (p<0.001). Before treatment grade 3a was found in 13, grade 3b in 2 cases, and at follow-up grade 3a in 25, grade 3b in 5, and grade 4 in 1 case. Anaemia prior to PRRT and at follow-up was grade 0 in 63 versus 48 (p<0.001), grade 1 in 36 versus 48, and grade 2 in three versus six cases. In white blood cell count and platelets, there were no significant changes in grading occurring. Subgroup analysis revealed that only in the age group 65 and older was there a higher incidence for anaemia (p=0.006). CONCLUSIóN: In roughly 20% of cases an increase in grading of nephro- or hematotoxicity is observed. In those patients, except in one, toxicity findings were mild or moderate one year after completion of four cycles of PRRT with either Y-90- or Lu-177-SST-analogues. In terms of safety, PRRT has no critical impact on further oncologic treatment options in the case of disease progression.

Interleukin 10 inhibits growth and granulocyte/macrophage colony-stimulating factor production in chronic myelomonocytic leukemia cells.

Autonomous release of hematopoietic growth factors may play a crucial role in the pathogenesis of certain hematological malignancies. Because of its cytokine synthesis-inhibiting action, interleukin 10 (IL-10) could be a potentially useful molecule to affect leukemic cell growth in such disorders. Chronic myelomonocytic leukemia (CMML) cells spontaneously form myeloid colonies (colony-forming units-granulocyte/macrophage) in methylcellulose, suggesting an autocrine growth factor-mediated mechanism. We studied the effect of recombinant human IL-10 (rhIL-10) on the in vitro growth of mononuclear cells obtained from peripheral blood or bone marrow of patients with CMML. IL-10 specifically binding to leukemic cells had a profound and dose-dependent inhibitory effect on autonomous in vitro growth of CMML cells. IL-10 significantly inhibited the spontaneous growth of myeloid colonies in methylcellulose in 10/11 patients, and autonomous CMML cell growth in suspension in 5/5 patients tested. Spontaneous colony growth from CMML cells was also markedly reduced by addition of antigranulocyte/macrophage colony-stimulating factor (GM-CSF) antibodies, but not by addition of antibodies against G-CSF, IL-3, or IL-6, IL-10-induced suppression of CMML cell growth was reversed by the addition of exogenous GM-CSF and correlated with a substantial decrease in GM-CSF production by leukemic cells, both at the mRNA and protein levels. Our data indicate that IL-10 profoundly inhibits the autonomous growth of CMML cells in vitro most likely through suppression of endogenous GM-CSF release. This observation suggests therapeutic evaluation of rhIL-10 in patients with CMML.

68Ga-DOTATOC PET/CT in the localization of metastatic extra-adrenal paraganglioma and pheochromocytoma compared with 18F-DOPA PET/CT. / Comparación entre la PET/TC con 18F-DOPA y la PET/TC con 68Ga-DOTATOC para la localización del paraganglioma maligno extra-adrenal y el feocromocitoma.

OBJECTIVE: 18F-Fluoro-L-dihydroxyphenylalanine (18F-DOPA) PET offers high sensitivity and specificity in the imaging of non-malignant extra-adrenal paraganglioma (PGL) and pheochromocytoma (PHEO) but lower sensitivity in metastatic disease. These tumours are of neuroendocrine origin and can be detected by 68Ga-DOTA-Tyr3-octreotide (68Ga-DOTA-TOC) PET. Therefore, we compared 68Ga-DOTA-TOC and 18F-DOPA as radiolabels for PET/CT imaging for the diagnosis of metastatic extra-adrenal PGL and PHEO. Combined cross-sectional imaging was the reference standard. METHODS: A total of 6 men and 4 women (age range 22-72 years) with anatomical and/or histologically proven metastatic PGL and PHEO were included in this study. Of these patients, 2 male patients suffered from PHEO, while the remaining 8 patients were diagnosed as metastatic extra-adrenal PGL disease. Comparative evaluation included morphological imaging with CT and functional imaging with 68Ga-DOTA-TOC and 18F-DOPA PET. The imaging results were analyzed on a per-lesion basis. The maximum standardized uptake value (SUVmax) of each functional imaging modality in concordant tumour lesions was measured. RESULTS: Compared with anatomical imaging, the per-lesion detection rate of 68Ga-DOTA-TOC was 100% (McNemar, P<0.01), and that of 18F-DOPA PET was 82.3% (McNemar, P<0.8) in metastatic extra-adrenal PGL and PHEO. Overall, 68Ga-DOTA-TOC PET identified 67 lesions; anatomical imaging identified 62 lesions, and 18F-DOPA PET identified 56 lesions. The SUVmax (mean±SD) of all concordant lesions was 29.3±19.9 for 68Ga-DOTA-TOC PET and 12.3±9.1 for 18F-DOPA PET (Mann-Whitney U test, P<0.0001). CONCLUSION: 68Ga-DOTA-TOC PET offers the highest detection rate in metastatic extra-adrenal PGL and PHEO compared to 18F-DOPA PET and even to diagnostic CT, particularly in bone lesions. Combined functional/anatomical imaging (68Ga-DOTA-TOC PET/CT) enables exact tumour extension to be detected in these rare tumour entities, especially in the case of unclear anatomical correlation.

A rare case of a 123I-MIBG SPECT/CT positive, but 68Ga-DOTA-TOC PET/CT negative pheochromocytoma of the bladder. / Caso infrecuente de feocromocitoma vesical positivo en la SPECT/TC con 123I-MIBG, pero negativo en la PET/TC con 68Ga-DOTA-TOC.

Pheochromocytoma (PHEO) is rare and belongs to the group of neuroendocrine tumours (NETs). These tumours can be found anywhere from the neck to the pelvis associated with sympathetic ganglia. Morphological imaging, for example CT, provides excellent anatomical detail and high sensitivity but lacks specificity as difficulties may occur when distinguishing between tumours derived from the sympathetic nervous system and other tumour entities. In contrast to anatomical imaging, functional imaging (123I-MIBG, 68Ga-DOTA-TOC PET) provides high sensitivity and specificity in detecting NETs. Early detection of PHEO is crucial and has a major effect on treatment and prognosis. This case report describes the important role of anatomical and functional imaging in a patient with a neuroendocrine tumour of unusual origin.

Physiology of upward transport in the human female genital tract.

The uterus and fallopian tubes represent a functionally united peristaltic pump under the endocrine control of ipsilateral ovary. We have examined this function by using hysterosalpingoscintigraphy (HSS), recording of intrauterine pressure, electrohysterography, and Doppler sonography of the fallopian tubes. An uptake of labeled particles into the uterus was observed during the follicular and luteal phases of the cycle after application into the vagina. Transport into the oviducts, however, could only be demonstrated during the follicular phase. Furthermore, the predominant transport was into the tube ipsilateral to the ovary containing the dominant follicle. The pregnancy rate following spontaneous intercourse or insemination was higher in those women in whom ipsilateral transport could be demonstrated. The amount of material transported to the ipsilateral tube was increased after oxytocin administration, as demonstrated by radionuclide imaging and by Doppler sonography following instillation of ultrasound contrast medium. An increase in the basal tone and amplitude of contractions was observed after oxytocin administration. These results support the idea that the uterus and fallopian tubes act as a peristaltic pump, which increases transport of sperm into the oviduct ipsilateral to the ovary bearing the dominant follicle. Oxytocin appears to play a critical role in this peristaltic pump. A failure of the peristaltic mechanism is possibly responsible for infertility. We propose the term tubal transport disorder (TTD) as a nosological entity. Results from HSS could be a useful adjunct for choosing treatment modalities in patients with patent fallopian tubes suffering from infertility. These patients may be better served with in vitro fertilization (IVF).

Cross-competition between vasoactive intestinal peptide and somatostatin for binding to tumor cell membrane receptors.

Vasoactive intestinal peptide (VIP) is a 28-amino acid peptide with a wide range of biological activities. Recent data suggest that functional VIP receptors are expressed on various tumor cells. Somatostatin (SST) and its long-acting analogue octreotide (OCT) are potent inhibitors of tumor cell growth and secretion. In the present study, the interactions between VIP and SST/OCT on primary tumors (insulinomas, n = 3; VIPomas, n = 2; intestinal adenocarcinomas, n = 5; neuroblastomas, n = 5; papillary thyroid cancers, n = 7; carcinoids, n = 5; ductal breast cancers, n = 8; small cell lung cancers, n = 3; ACTH-producing hypophyseal adenomas, n = 5; pheochromocytomas, n = 5) as well as on tumor cell lines (A431, HT29, PANC1, COLO320, HMC1, and KU812 cells) were analyzed by use of 123I-labeled VIP and 123I-labeled Tyr-3-OCT. Cross-competition between VIP and SST/OCT for binding to tumor cells was observed. The rank-order of potency for displacement of 123I-labeled VIP binding to intact A431 cells was VIP [concentration causing half-maximal inhibition (IC50) = 2.9 +/- 1.9 (SD) nM] > OCT (IC50 = 9.3 +/- 1.7 nM) = SST > substance P = secretin (IC50 = 1 microM). Binding of 123I-labeled Tyr-3-OCT to A431 cells, in turn, was inhibited by OCT = Tyr-3-OCT (IC50 = 1.5 +/- 0.3 nM) = SST > VIP (IC50 = 4.9 +/- 1.1 nM). This rank-order of potency was also obtained for primary tumors and tumor cell lines. Furthermore, SST and OCT inhibited VIP-induced [3H]thymidine incorporation, cyclic AMP formation, and tyrosine kinase activity with IC50 values < 10 nM. Together, these data provide evidence for functional interactions between SST and VIP on various tumor cells. These interactions may involve peptide cross-competition at cellular binding sites and may have implications for the biology and pathophysiology of respective cells and disease states.

Somatostatin receptor subtype specificity and in vivo binding of a novel tumor tracer, 99mTc-P829.

Recent data suggest that somatostatin receptors (SSTRs) are expressed on various tumor cells. High-level expression of SSTR on the tumor cell surface provides the basis for the successful clinical use of radiolabeled ligands for the in vivo localization of tumor sites. We have characterized the in vitro binding properties of the novel SSTR ligand 99mTc-P829 using primary human tumors (carcinoids, breast cancers, intestinal adenocarcinomas, pheochromocytomas, small cell and non-small cell lung cancer, and melanomas; n = 28), various tumor cell lines, and COS7 cells transfected with the human SSTR (hSSTR) subtypes 1, 2, 3, 4, and 5. 99mTc-P829 bound to primary tumor cells and tumor cell lines with high affinity and high capacity. The dissociation constants (Kd) ranged between 1 and 20 nM. 99mTc-P829 also bound with high affinity to the transfected hSSTR2 (Kd, 2.5 nM), hSSTR5 (Kd, 2 nM), and hSSTR3 (Kd, 1.5 nM). Binding of 99mTc-P829 to hSSTR3 was found to be displaceable by unlabeled P829/([ReO]-P829), SST-14, and vasoactive intestinal peptide (VIP; IC50, 2 nM) and, less effectively, by Tyr3-octreotide (IC50, 20 nM). In contrast, the binding of 99mTc-P829 to hSSTR2 and hSSTR5 could be displaced by P829/([ReO]-P829) and Tyr3-octreotide but not by VIP. 99mTc-P829 scintigraphy revealed in vivo binding to primary or metastatic tumor sites in seven of eight patients with breast cancer and six of six patients with melanoma. In summary, our data show that 99mTc-P829 binds with high affinity to many different types of primary and cloned tumor cells. Furthermore, our data identify hSSTR2, the VIP acceptor hSSTR3, and hSSTR5 as the respective target receptors. Because these receptors are frequently expressed at high levels on primary tumor cells, 99mTc-P829 appears to be a promising novel peptide tracer for tumor imaging.

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.

[Treatment of patients with radioiodine refractory, differentiated thyroid carcinoma. A Consensus Statement]. / Therapie des Patienten mit Radioiod-refraktärem, differenziertem Schilddrüsenkarzinom. Ein Konsensusstatement.

There is no clear standard therapy for patients with radioactive iodine (131I)-refractory locally advanced or metastatic differentiated thyroid cancer. The therapeutic options for this indication have expanded with the recently approved multiple kinase inhibitor sorafenib. Recommendations for the definition and the management of iodine refractory patients were worked up by an interdisciplinary expert panel, consisting of endocrine surgeons, medical oncologists and nuclear medicine specialists.

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.

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.

Etofibrate increases binding of low and high density lipoprotein to human platelets of patients with type II hyperlipoproteinemia.

Previous work suggested an influence of etofibrate, a diester of nicotinic acid and clofibric acid, on lipoprotein receptors. Besides its beneficial effects on plasma lipoprotein levels of decrease in total cholesterol, LDL-cholesterol and triglycerides and increase in HDL-cholesterol, etofibrate was shown to inhibit platelet function. In order to further evaluate platelet-lipoprotein interactions, the effects of etofibrate on plasma lipids and lipoproteins on the specific binding of normal [111In]LDL and [111In]HDL onto platelets as well as its effect on platelet function were evaluated in 8 patients affected by Type II hyperlipoproteinemia (HLP). In all patients binding was saturable and indicated high affinity binding sites capable of binding 927 +/- 233 ng protein of [111In]LDL/10(9) platelets (Kd 12 +/- 3 micrograms protein/ml) and 1496 +/- 435 ng protein of [111In]HDL/10(9) platelets (Kd 14 +/- 3 micrograms protein/ml). The capacity of native LDL (HDL) to displace bound [111In]LDL ([111In]HDL) by half (IC50) amounted to 22 +/- 9 micrograms protein/ml (26 +/- 8 micrograms protein/ml). Following a 6-week treatment period with etofibrate (500 mg twice daily), decrease in plasma total cholesterol, LDL-cholesterol and apolipoprotein (apo) B and increase in HDL-cholesterol and apo AI was correlated to a significant (P < 0.01) increase in LDL- as well as HDL-receptor binding. The platelet binding capacity increased to 1085 +/- 212 ng protein/10(9) platelets (Kd 8 +/- 3 micrograms protein/ml) for [111In]LDL and to 1867 +/- 266 ng protein/10(9) platelets for [111In]HDL (Kd 11 +/- 3 micrograms protein/ml). Platelet function studies demonstrated significantly (P < 0.01) reduced platelet aggregation in response to ADP and thromboxane formation after 6 weeks of etofibrate therapy. These findings in patients with HPL Type II indicate in vivo upregulation of specific [111In]LDL as well as [111In]HDL binding sites on human platelets associated with reduced platelet activation following etofibrate therapy.

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.

Indium-111-labeled low-density lipoprotein binds with higher affinity to the human liver as compared to iodine-123-low-density-labeled lipoprotein.

The interaction of 111In-low-density lipoprotein (LDL) and 123I-LDL with human liver-plasma membranes was investigated and compared. LDLs were isolated by sequential ultracentrifugation and radiolabeled either with 123I (using lodogen or iodine-monochloride) each followed by purification with gel-chromatography or dialysis) or 111In (using cyclic DTPA-anhydride). LDL concentrations of 0.1 to 32 micrograms protein/ml were used for direct binding assays investigating the specific binding of labeled LDL (in the presence of a 50-fold excess of unlabeled LDL) to human liver apoB-receptors. In separate experiments, displacement of bound 111In-(123I)-LDL by unlabeled LDL was studied. Human liver plasma membranes bound 239 +/- 26 ng protein of 111In-LDL/mg protein and 148 +/- 18 ng protein of 123I-LDL/mg protein specifically (p less than 0.001). The corresponding dissociation constants were 0.6 +/- 0.2 and 1.2 +/- 0.7 micrograms protein/ml, respectively (p less than 0.001). The capacity of unlabeled LDL to displace bound 111In-LDL was four times higher than that for 123I-LDL (IC50: 1.7 +/- 0.7 versus 7.7 +/- 1.0 micrograms protein/ml). No significant differences among the different methods of iodination of LDL were found. The findings show that 111In-labeled lipoproteins might be a better ligand for lipoprotein-receptor binding studies as compared to radioiodinated lipoprotein products.

Vasoactive intestinal peptide and somatostatin receptor scintigraphy for differential diagnosis of hepatic carcinoid metastasis.

We report a case of a hepatic carcinoid metastasis mimicking a hemangioma on ultrasound and on CT. Indium-111-DTPA-D-Phe-1-octreotide (111In-OCT) and 123I-vasoactive intestinal peptide (123I-VIP) receptor images suggested a carcinoid metastasis of the liver. The final diagnosis was established histopathologically. The differential diagnosis of liver lesions is discussed.

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).

Vasoactive intestinal peptide receptor scintigraphy.

UNLABELLED: This study presents the biodistribution, safety and absorbed dose of 123I-VIP administered to 18 patients with intestinal adenocarcinomas or endocrine tumors. METHODS: To achieve high-specific activity, 123I-VIP was purified by HPLC. Following intravenous administration of 123I-VIP (172 +/- 17 MBq (4.65 +/- 0.5 mCi); < 300 pmole ( < 1 microgram)/patient), sequential images were recorded during the initial 30 min. Thereafter, whole-body images were acquired in anterior and posterior views at various time points. Dosimetry calculations were performed on the basis of gamma camera data, urine, feces and blood activities. RESULTS: After injection of labeled peptide, the lung was the primary site of 123I-VIP uptake. Peak lung activity represented 40% +/- 7% of the injected dose at 0.7 hr and declined to 21% +/- 7% at 3.5, to 14% +/- 3% at 7 and to 8% +/- 4% 22 hr postinjection. Radioactivity was excreted into the urine and amounted to 37% +/- 16% of the injected dose within 4, 68% +/- 12% within 8, 82% +/- 16% within 16 and 93% +/- 8% within 24 hr postinjection. The mean effective half-life of 123I-VIP in the lungs was 2.2 and 6 hr in the urinary bladder. The highest radiation absorbed doses were calculated for the lungs [67 muGy/MBq (248 mrad/mCi)], urinary bladder [77 muGy/MBq (284 mrad/mCi)] and thyroid gland [104 muGy/MBq (386 mrad/mCi)]. The effective dose was 28 muSv/MBq (104 mrem/mCi). CONCLUSION: HPLC-purified 123I-VIP shows favorable dosimetry and is a safe and promising peptide tracer for localization of tumors expressing receptors for VIP.