Specificity and sensitivity of 99mTc-EDDA/HYNIC-Tyr³-octreotide (99mTc-TOC) for imaging neuroendocrine tumors.

OBJECTIVES: Gastroenteropancreatic neuroendocrine tumors (NETs) are cancers originating from neuroendocrine organs such as the pancreas, pituitary, thyroid, and adrenal glands and tumors arising from the diffuse neuroendocrine cells that are widely distributed throughout the body. NETs express somatostatin (SS) and contain a high density of SS receptors; therefore, they can be specifically targeted with SS-based radiopharmaceuticals. The aim of this research was to determine the validity in terms of specificity, sensitivity, and the agreement beyond chance with the biopsy (gold standard) of the 99mTc-EDDA-HYNIC-Tyr³octreotide (99mTc-TOC) to image and localize NETs and their metastases. MATERIALS AND METHODS: Freeze-dried kits containing 0.0125 mg HYNIC-octreotide and co-ligands were easily labeled and quality controlled within the hospital radiopharmacy. Fifty-six consecutive Mexican patients with a previous presumptive diagnosis of NETs underwent several clinical and laboratory studies and were referred to the Nuclear Medicine Department for a routine scan with 99mTc-TOC. The patients were injected with 500-600 MBq 99mTc-TOC, and whole-body images were obtained 2 h later with a SPECT or a SPECT/CT camera. Two nuclear medicine physicians observed the images and classified them as 17 negative and 39 positive. After correlating the image of each patient with our 'gold standard' (biopsy, clinical history, morphological images, and tumor marker assays), the 99mTc-TOC images were classified by the same two physicians as 12 true negatives, five false negatives, 38 true positives and one false positive. RESULTS: The validity of 99mTc-TOC in terms of relative frequencies with corresponding 95% confidence intervals were as follows: 92.3% (64-100%) specificity; 88.4% (78-97%) sensitivity; and the agreement beyond chance was 73% (60-84%). The positive predictive value was 97.4% (87-100%); the negative predicted value was 70.6% (48-93%); the accuracy was 89.3% (89-97%); and the prevalence was 76.8% (64-87%). CONCLUSION: Because of these high values, we strongly recommend scintigraphy with the Mexican-produced 99mTc-TOC for the localization of NETs and their metastases, and we conclude that it is a good tool for detecting neuroendocrine disease in a Mexican population.

Radiopharmacokinetic and dosimetric parameters of 188Re-lanreotide in athymic mice with induced human cancer tumors.

Radiolabeled peptides, like the somatostatin analogs, have been used for peptide receptor-mediated radionuclide therapy (PRMRT) in metastatic neuroendocrine tumors. The eight amino acid peptide 3-(2-naphthalenyl)-D-alanyl-L-cysteinyl-L-tyrosyl-D-tryptophyl-L-lysyl-L-valyl-L-cysteinyl-L-threoninamide,cyclic(2-->7)-disulfide (9Cl) (lanreotide) was found to bind to the five somatostatin tumor receptors. Lanreotide has been labeled via the bifunctional chelating agent, DOTA, to (111)In, and (90)Y. A direct labeling method was used to label lanreotide with (188)Re. Athymic mice with implanted human cancer tumors (uterine-cervix, renal, and neuroblastoma) were injected with radiochemically pure (188)Re-lanreotide (1.11 MBq). The percent injected activity (%IA/g) from serial blood samples was the input data for the WinNonlin computer program to obtain radiopharmacokinetic parameters. The organs' percent injected activity per gram of tissue (%IA/g) was extrapolated to the weights of a 70 kg male model organs and the number of nuclear transitions (N) were the input for the OLINDA/EXM program to obtain dosimetry estimates. Induced uterine-cervix tumors (HeLa cells) show a mean 2.4 %IA/g uptake up to 24 h and the tumor/blood ratio was over 1.85 (1.5-24 h post-injection) confirming (188)Re-lanreotide remains bound to the tumor. The estimated tumor absorbed dose was 460 mGy/MBq. Human effective dose was 0.0182 mSv/MBq. Therefore, (188)Re-lanreotide is a good candidate for PRMRT and a clinical trial is being planned in order to acquire individual dosimetric data.

Cytotoxic and genotoxic effect of the [166Dy]Dy/166Ho-EDTMP in vivo generator system in mice.

Multiple myeloma and other hematological malignancies have been treated by myeloablative radiotherapy/chemotherapy and subsequent stem cell transplantation. [(166)Dy]Dy/(166)Ho-ethylenediaminetetramethylene phosphonate (EDTMP) forms a stable in vivo generator system with selective skeletal uptake in mice; therefore, it could work as a potential and improved agent for marrow ablation. Induced bone marrow cytotoxicity and genotoxicity are determined by the reduction of reticulocytes (RET) and elevation of micronucleated reticulocyte (MN-RET) in peripheral blood and ablation by bone marrow histological studies. The aim of this study was to determine the bone marrow cytotoxic and genotoxic effect of the [(166)Dy]Dy/(166)Ho-EDTMP in vivo generator system in mice and to evaluate by histopathology its myeloablative potential. Enriched (166)Dy(2)O(3) was irradiated and [(166)Dy]DyCl(3) was added to EDTMP in phosphate buffer (pH 8.0) in a molar ratio of 1:1.75. QC was determined by TLC. Dy-EDTMP complex was prepared the same way with nonirradiated dysprosium oxide. A group of BALB/c mice were intraperitoneally injected with the radiopharmaceutical and two groups of control animals were injected with the cold complex and with 0.9% sodium chloride, respectively. A blood sample was taken at the beginning of the experiments and every 48 h for 12 days postinjection. The animals were sacrificed, organs of interest taken out and the radioactivity determined. The femur was used for histological studies. Flow cytometry analysis was used to quantify the frequency of RET and MN-RET in the blood samples. The MCNP4B Monte Carlo computer code was used for dosimetry calculations. Radiochemical purity was 99% and the mean specific activity was 1.3 MBq/mg. The RET and MN-RET frequency were statistically different in the treatment at the end of the 12-day period demonstrating cytotoxicity and genotoxicity induced by the in vivo generator system. The histology studies show that there was complete, or almost complete, acellularity, which means significant suppression of the bone marrow activity. Bone marrow absorbed dose was 18-23 Gy. [(166)Dy]Dy/(166)Ho-EDTMP induces cytotoxicity, genotoxicity and severe myelosuppression in mice. Potentially, it is a good agent for use in humans.

Uptake of 153Sm-DTPA-bis-biotin and 99mTc-DTPA-bis-biotin in rat as-30D-hepatoma cells.

Labeled biotin has been used mainly for pretargeted therapy, an approach for increasing the amount of radioactivity delivered to a cancer cell. The aim of this investigation was to prepare (153)Sm-DTPA-bis-biotin and (99m)Tc-DTPA-bis-biotin in order to study their in vitro and in vivo uptake in rat AS-30D hepatoma cells found in ascites and in implanted tumor. DTPA-bis-biotin (pH 8) was (153)Sm labeled with (153)SmCl(3) and (99m)Tc-DTPA-bis-biotin was prepared via SnCl(2) reduction. Radiochemical purity was >98% in both cases. AS-30D hepatoma cells were obtained from ascites of a rat with hepatoma and were propagated in the peritoneum cavity of normal rats. In vitro ascites cell (153)Sm-DTPA-bis-biotin uptake was compared with (153)SmCl(3) cell uptake. The ratio cell (153)Sm-DTPA-bis-biotin/(153) SmCl(3) was 39.6 and when avidin was added it increased to 50. The ratio (99m)Tc-DTPA-bis-biotin/TcO(4)Na was 8.7. Concentration of (153)Sm-DTPA-bis-biotin in tumor 2, 3 and 24 h after administration, was 5, 15 and 3 times higher than in normal muscle (T/nT). Biodistribution in a 0.083-24 h time period showed that (153)Sm-DTPA-bis-biotin was taken up only by ascites tumor cells and hepatoma cells. Two and 3 h ratio ascites/liver (As/Lv) was 6.4 and 6.0. For (99m)Tc-DTPA-bis-biotin 2 and 3 h T/nT was 15.7 and 4.7 and 2 h As/Lv was 1.4. In conclusion, both radiopharmaceuticals show high uptake in rat AS-30D hepatoma cells in ascites and in implanted tumor. Since lung, thyroid, kidney, liver or pancreas carcinomas are ascites producing cancers (153)Sm-DTPA-bis-biotin would be an adequate therapeutic radiopharmaceutical for these patients whose life quality would be enhanced with control of ascites, and a reduction of the primary tumor and its metastases.