Novel recombinant human thyroid-stimulating hormone in aiding postoperative assessment of patients with differentiated thyroid cancer-phase I/II study.

PURPOSE: Thyroid hormone withdrawal (THW) inevitably induced hypothyroidism in patients with differentiated thyroid cancer (DTC), and we aimed to evaluate the safety and efficacy of a novel recombinant human thyroid-stimulating hormone (rhTSH, ZGrhTSH) as an alternative of THW in China. METHODS: Totally, 64 DTC patients were enrolled with 24 in the dose-escalation cohort equally grouped into 0.9 mg × 1 day, 0.9 mg × 2 day, 1.8 mg × 1 day, and 1.8 mg × 2 day dosage, and 40 further enrolled into 0.9 mg × 2 day dose-expansion cohort. All patients underwent both ZGrhTSH phase and levothyroxine (L-T4) withdrawal phase for self-comparison in terms of TSH levels, the radioactive iodine (RAI) uptake, stimulated thyroglobulin level, and the quality of life (QoL). RESULTS: In ZGrhTSH phase, no major serious adverse events were observed, and mild symptoms of headache were observed in 6.3%, lethargy in 4.7%, and asthenia in 3.1% of the patients, and mostly resolved spontaneously within 2 days. Concordant RAI uptake was noticed in 89.1% (57/64) of the patients between ZGrhTSH and L-T4 withdrawal phases. The concordant thyroglobulin level with a cut-off of 1 µg/L was noticed in 84.7% (50/59) of the patients without the interference of anti-thyroglobulin antibody. The QoL was far better during ZGrhTSH phase than L-T4 withdrawal phase, with lower Billewicz (- 51.30 ± 4.70 vs. - 39.10 ± 16.61, P < 0.001) and POMS (91.70 ± 16.70 vs. 100.40 ± 22.11, P = 0.011) scores which indicate the lower the better. Serum TSH level rose from basal 0.11 ± 0.12 mU/L to a peak of 122.11 ± 42.44 mU/L 24 h after the last dose of ZGrhTSH. In L-T4 withdrawal phase, a median of 23 days after L-T4 withdrawal was needed, with the mean TSH level of 82.20 ± 31.37 mU/L. The half-life for ZGrhTSH clearance was about 20 h. CONCLUSION: The ZGrhTSH held the promise to be a safe and effective modality in facilitating RAI uptake and serum thyroglobulin stimulation, with better QoL of patients with DTC compared with L-T4 withdrawal.

[Feasibility of apoptosis-imaging agent 99mTc-HYNIC-annexin V in early assessment of chemotherapeutic effect on tumor models].

OBJECTIVE: To evaluate if 99mTc-HYNIC-annexin V may be used to detect the early chemotherapeutic effect and to determine the best timing for detecting apoptosis in vivo. METHODS: Annexin V was labeled with 99mTc using HYNIC as a bifunctional agent. Normal Kunming mice received inoculation of Ehrlich ascites cells into the right upper limb. After the tumor reached 1 cm in diameter, the mice were randomly divided into saline treatment group as control and cyclophosphamide (150 mg/kg injected intraperitoneally) treatment group. 99mTc-HYNIC-annexin V was injected intravenously at 1 h and 24 h after treatment. Region of interest technique (ROI) from the SPECT images taken at different time was used to get the ratio of tumor/limb in each group. TUNEL staining was used to detect apoptotic cells and the rates of positive stained cells were calculated. RESULTS: After treatment with saline, only little amount of the radiolabeled tracer could be seen in the tumor and showed weak image of the tumor. But after 24 h of treatment with cyclophosphamide, clear image on the tumor could be seen. 24 h after the treatment of cyclophosphamide, the ratio of tumor/limb was (6.27 +/- 0.24) which was much higher than that at 24 h after treatment with saline (2.36 +/- 0.18) and that at 1 h after cyclophosphamide treatment (4.00 +/- 0.38). At 24 h after cyclophosphamide treatment, TUNEL staining showed a significantly higher rate of apoptotic cells in the mice. CONCLUSION: 99mTc-HYNIC-annexin V can be used as an apoptosis-imaging agent to detect and evaluate the early curative effect after chemotherapy. The effective detection of apoptotic response in tumor with 99mTc-HYNIC-annexin V requires a 24 h interval after chemotherapy. SPECT images can be obtained at 60 min after injection of the imaging agent. It suggests that 99mTc-HYNIC-annexin V may become a promising agent for apoptosis-imaging in clinical application.

[Targeted radionuclide therapy for patients with metastatic medullary thyroid carcinoma].

OBJECTIVE: To evaluate the effect of 90Y-DOTATOC and 131I-MIBG in treatment of metastatic medullary thyroid carcinoma (MTC). METHODS: Twelve histologically confirmed patients with metastatic MTC were included. All patients underwent both 111In-DTPA-octreotide imaging and 131I/ 123I-meta-iodobenzylguanidine (MIBG) imaging. According to the results of the combined imaging, positive patients were selected to be treated with 90Y-DOTA-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) or 131I-MIBG, respectively. The therapeutic procedures of targeted internal radiation were performed with 3.33 GBq 90Y-DOTATOC at 6-week intervals, or 11.1 GBq 131I-MIBG with a minimum interval of three months. RESULTS: The imaging procedure was positive in all 12 patients: 111In-DTPA-octreotide imaging in eight patients, 131I/ 123I-MIBG imaging in six patients. According to the results of combined imaging, we identified four patients to be treated with 90Y-DOTATOC, and five patients with 131 I-MIBG. After three to five sessions of treatment, three patients with partial remission and six with stable disease were observed. The effective rate was 3/9 (33.3%) and the overall tumor response rate was 9/9 (100%). No relevant toxicity was observed. CONCLUSION: The combined imaging technique can be used to identify patients for effective radionuclide treatment. The treatment with 90Y-DOTATOC or 131I-MIBG is well tolerated and may improve the fate of patients with metastatic MTC.

[Use of 99mTc-survivin antisense oligonucleotide in diagnosis of hepatocellular carcinoma: an experiment with mice].

OBJECTIVE: To investigate the possibility of using survivin antisense oligonucleotide (ASON) labeled with radionuclide technetium-99m ((99m)Tc) for diagnosing hepatocellular carcinoma in nude mice bearing human hepatoma. METHODS: A 18 mer single-stranded survivin ASON sequence was synthesized and linked with a primary amine on the 5'-end. Survivin ASON was labeled with (99m)Tc by conjugating the chelator, S-acetyl-NHS-MAG3 (mercaptoacetyltriglycine). The biodistribution, antisense gene imaging and antisense gene inhibition imaging of (99m)Tc-survivin ASON in nude mice bearing human hepatocellular carcinoma (SMMC-7721) were studied. RESULTS: Tumor lesion was early detected with (99m)Tc-survivin ASON and the lesion image showed up at 0.5 h postinjection. The accumulation of (99m)Tc-survivin ASON in tumor tissue gradually increased and reached the top at 4 h postinjection. The %ID/g (percentage of injected dose per gram of tissue) of (99m)Tc-survivin ASON in tumor tissue at 4 h postinjection was 0.69% +/- 0.11%. And the ratios of tumor to muscle were 3.35 +/- 0.57 in biodistribution study and 2.48 +/- 0.44 in antisense imaging study. But the %ID/g of (99m)Tc-survivin SON (sense oligonucleotide) in tumor tissue was only 0.17% +/- 0.01% at 4 h postinjection. And the ratios of tumor to muscle were 0.74 +/- 0.04 in biodistribution study and 1.15 +/- 0.36 in antisense imaging study. Both results of %ID/g of tumor tissue and ratio of tumor to muscle in SON group were significantly lower than those in ASON group at every check-time (P < 0.01). Furthermore, the tumor imaging was diminished in nude mice pretreated with unlabeled survivin ASON, and the ratio of tumor to muscle was only 0.93 +/- 0.23 at 4 h postinjection and significantly lower than 2.48 +/- 0.44 in nude mice untreated (P < 0.01). CONCLUSION: The accumulation of (99m)Tc-survivin ASON in hepatocellular carcinoma tissue is specific. The antisense imaging with (99m)Tc-survivin ASON may be a promising method for diagnosis of hepatocellular carcinoma.