High-risk patients with differentiated thyroid cancer T4 primary tumors achieve remnant ablation equally well using rhTSH or thyroid hormone withdrawal.

BACKGROUND: Few data exist on using thyrotropin alfa (recombinant human thyroid-stimulating hormone [rhTSH]) with radioiodine for thyroid remnant ablation of patients who have T4 primary tumors (invasion beyond the thyroid capsule). METHODS: A retrospective chart review protocol at nine centers in Europe was set up with special waiver of need for informed consent, along with a careful procedure to avoid selection bias when enrolling patients into the database. Data on 144 eligible patients with T4 tumors were collected (T4, N0-1, M0-1; mean age 49.7 years; 65% female; 88% papillary cancer). All had received (131)I remnant ablation following TSH stimulation with rhTSH or thyroid hormone withdrawal (THW) since January 2000 (rhTSH n=74, THW n=70). The primary endpoint was based on evaluation of diagnostic radioiodine scan thyroid bed uptake more than six months after the ablation procedure, while stimulated serum Tg was a secondary endpoint. Safety was evaluated within 30 days after rhTSH or (131)I. RESULTS: Successful ablation judged by scan was achieved in 65/70 (92.9%) of rhTSH and in 61/67 (91.0%) of THW patients; the success rates were comparable, since noninferiority criteria were met. Although some patients in the initial cohort had tumor in cervical nodes and metastases, considering all evaluable patients regardless of various serum anti-Tg antibody assessments, the stimulated Tg was <2 ng/mL in 48/70 (68.6%) and 39/67 (58.2%) in rhTSH and THW groups respectively; if patients with anti-Tg antibody levels >30 IU/mL were excluded, the stimulated Tg was <2 ng/mL in 42/62 (67.7%) and 37/64 (57.8%) respectively. No serious adverse events occurred within the 30-day window after ablation. CONCLUSIONS: Use of rhTSH as preparation for thyroid remnant ablation in patients with T4 primary tumors achieved a rate of ablation success that was high and noninferior to the rate seen after THW, and rhTSH was well tolerated.

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

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

Oncofetal fibronectin mRNA is highly abundant in the blood of patients with papillary thyroid carcinoma and correlates with high-serum thyroid-stimulating hormone levels.

BACKGROUND: Papillary thyroid carcinoma (PTC) cells express oncofetal fibronectin (onfFN) mRNA, which may be useful to detect circulating tumor cells. The objective of this study was to determine the fraction of PTC patients having onfFN mRNA in their peripheral blood and to determine if onfFN mRNA levels are correlated with the status of the disease or with thyroid-stimulating hormone (TSH) serum concentrations. METHODS: This study included 95 PTC patients, who were previously treated by thyroidectomy and radioactive iodine administration. Patients were examined by cervical sonography, whole-body (131)I scintigraphy, thyroglobulin measurement, and onfFN mRNA quantification both when they were being treated with L-thyroxine (L-T4) and after L-T4 withdrawal. The mean value for onfFN mRNA in blood from 25 healthy subjects was used as control for the onfFN mRNA assay. RESULTS: After L-T4 withdrawal, serum TSH levels rose and onfFN mRNA was found in the peripheral blood of 33 of 64 (52%) disease-free patients, 15 of 23 (65%) patients with local residual disease, and 6 of 8 (75%) patients with known local or distant metastases. Continuous administration of L-T4 repressed serum TSH. In this state none of 17 (0%) disease-free patients and 1 of 4 (25%) patients with local residual disease had an elevated onfFN mRNA level, and 2 of 4 (50%) patients with metastasis had positive tests for serum onfFN mRNA. CONCLUSIONS: onfFN transcripts are highly abundant in the peripheral blood of patients with PTC. L-T4 withdrawal, which produced elevated serum TSH concentrations in these athyroidic patients, markedly increased the fraction with positive tests for serum onfFN mRNA at all stages of the disease. Analyzing onfFN mRNA in the absence of a TSH stimulus allows a much better discrimination of different states of PTC disease and, based on current concepts of the significance of circulating mRNA, may be a useful tool to detect circulating thyroid cancer cells.

In vitro experimental (211)At-anti-CD33 antibody therapy of leukaemia cells overcomes cellular resistance seen in vivo against gemtuzumab ozogamicin.

PURPOSE: Monoclonal anti-CD33 antibodies conjugated with toxic calicheamicin derivative (gemtuzumab ozogamicin, GO) are a novel therapy option for acute myeloid leukaemia (AML). Key prognostic factors for patients with AML are high CD33 expression on the leukaemic cells and the ability to overcome mechanisms of resistance to cytotoxic chemotherapies, including drug efflux or other mechanisms decreasing apoptosis. Alpha particle-emitting radionuclides overwhelm such anti-apoptotic mechanisms by producing numerous DNA double-stranded breaks (DSBs) accompanied by decreased DNA repair. METHODS: We labelled anti-CD33 antibodies with the alpha-emitter (211)At and compared survival of leukaemic HL-60 and K-562 cells treated with the (211)At-labelled antibodies, GO or unlabelled antibodies as controls. We also measured caspase-3/7 activity, DNA fragmentation and necrosis in HL-60 cells after treatment with the different antibodies or with free (211)At. RESULTS: The mean labelling ratio of (211)At-labelled antibodies was 1:1,090 +/- 364 (range: 1:738-1:1,722) in comparison to 2-3:1 for GO. Tumour cell binding of (211)At-anti-CD33 was high in the presence of abundant CD33 expression and could be specifically blocked by unlabelled anti-CD33. (211)At-anti-CD33 decreased survival significantly more than did GO at comparable dilution (1:1,000). No significant differences in induction of apoptosis or necrosis or DNA DSB or in decreased survival were observed after (211)At-anti-CD33 (1:1,090) versus GO (1:1) treatment. CONCLUSION: Our results suggest that (211)At is a promising, highly cytotoxic radioimmunotherapy in CD33-positive leukaemia and kills tumour cells more efficiently than does calicheamicin-conjugated antibody. Labelling techniques leading to higher chemical yield and specific activities must be developed to increase (211)At-anti-CD33 therapeutic effects.

Oncogenic osteomalacia: exact tumor localization by co-registration of positron emission and computed tomography.

UNLABELLED: In oncogenic osteomalacia, the causative tumor is almost always difficult to find. A novel diagnostic approach is presented that facilitates a precise and rapid localization of the associated lesion by PET-CT co-registration using the radiotracer (68)Ga-DOTANOC. INTRODUCTION: Oncogenic osteomalacia (OOM) is an uncommon disorder characterized by hyperphosphaturia, hypophosphatemia, decreased vitamin D(3) serum levels, and osteomalacia. The paraneoplastic syndrome is exclusively driven by a small somatostatin receptor (sst)-positive tumor that produces phosphatonins, proteins that cause renal phosphate loss. OOM can be cured completely on tumor removal. However, the exact tumor localization is the most challenging step, because the lesion is notoriously difficult to detect by common imaging techniques. MATERIALS AND METHODS: A 60-year-old woman complained of severe pain in her back and chest wall, muscle weakness, and reduced physical activity for >1 year. She suffered a metatarsal fracture and presented with hyperphosphaturia and hypophosphatemia. OOM was suspected, and a meticulous search for the tumor was initiated by conventional imaging techniques, sst-mediated imaging using (111)In-octreotide scintigraphy, and (68)Ga-DOTANOC-based positron emission tomography (PET)-CT co-registration. (68)Ga-DOTANOC is a novel radiopharmaceutical compound in which the somatostatin analog octreotide is modified at position 3, chelated with DOTA, and complexed with (68)Gallium. (68)Ga-DOTANOC has an improved affinity to sst2 and sst5 relative to other radiopeptides. RESULTS: Whereas common imaging techniques such as CT failed to localize the tumor, (111)In-octreotide scintigraphy was able to detect the lesion, but only PET-CT using (68)Ga-DOTANOC revealed the exact tumor localization in the right femoral head. On tumor resection, the well being of the patient improved significantly, and biochemical parameters returned to normal. CONCLUSIONS: (68)Ga-DOTANOC-based PET-CT is a novel and powerful approach to detect sst-positive tumors in a timely manner and to provide highly resolved images facilitating the development of a therapeutic strategy.

Effective cancer therapy with the alpha-particle emitter [211At]astatine in a mouse model of genetically modified sodium/iodide symporter-expressing tumors.

PURPOSE: The sodium/iodide symporter (NIS) gene is currently explored in several trials to eradicate experimental cancer with radiodine ((131)I) by its beta-emission. We recently characterized NIS-specific cellular uptake of an alternative halide, radioastatine ((211)At), which emits high-energy alpha-particles. The aim of this study was to investigate in vivo effects of the high linear energy transfer (LET) emitter (211)At on tumor growth and outcome in nude mice. EXPERIMENTAL DESIGN: We administered radioastatide in a fractionated therapy scheme to NMRI nude mice harboring rapidly growing solid tumors established from a papillary thyroid carcinoma cell line genetically modified to express NIS (K1-NIS). Animals were observed over 1 year. Tumor growth, body weight, blood counts, survival, and side effects were measured compared with control groups without therapy and/or lack of NIS expression. RESULTS: Within 3 months, radioastatide caused complete primary tumor eradication in all cases of K1-NIS tumor-bearing nude mice (n = 25) with no tumor recurrence during 1 year follow-up. Survival rates of the K1-NIS/(211)At group were 96% after 6 months and 60% after 1 year, in contrast to those of control groups (maximum survival 40 days). CONCLUSION: Our study indicates that (211)At represents a promising substrate for NIS-mediated therapy of various cancers either with endogenous or gene transfer-mediated NIS expression.