Susan E. M. Clarke

Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer

BACKGROUND It is not known whether low-dose radioiodine (1.1 GBq [30 mCi]) is as effective as high-dose radioiodine (3.7 GBq [100 mCi]) for treating patients with differentiated thyroid cancer or whether the effects of radioiodine (especially at a low dose) are influenced by using either recombinant human thyrotropin (thyrotropin alfa) or thyroid hormone withdrawal. METHODS At 29 centers in the United Kingdom, we conducted a randomized noninferiority trial comparing low-dose and high-dose radioiodine, each in combination with either thyrotropin alfa or thyroid hormone withdrawal before ablation. Patients (age range, 16 to 80 years) had tumor stage T1 to T3, with possible spread to nearby lymph nodes but without metastasis. End points were the rate of success of ablation at 6 to 9 months, adverse events, quality of life, and length of hospital stay. RESULTS A total of 438 patients underwent randomization; data could be analyzed for 421. Ablation success rates were 85.0% in the group receiving low-dose radioiodine versus 88.9% in the group receiving the high dose and 87.1% in the thyrotropin alfa group versus 86.7% in the group undergoing thyroid hormone withdrawal. All 95% confidence intervals for the differences were within ±10 percentage points, indicating noninferiority. Similar results were found for low-dose radioiodine plus thyrotropin alfa (84.3%) versus high-dose radioiodine plus thyroid hormone withdrawal (87.6%) or high-dose radioiodine plus thyrotropin alfa (90.2%). More patients in the high-dose group than in the low-dose group were hospitalized for at least 3 days (36.3% vs. 13.0%, P<0.001). The proportions of patients with adverse events were 21% in the low-dose group versus 33% in the high-dose group (P=0.007) and 23% in the thyrotropin alfa group versus 30% in the group undergoing thyroid hormone withdrawal (P=0.11). CONCLUSIONS Low-dose radioiodine plus thyrotropin alfa was as effective as high-dose radioiodine, with a lower rate of adverse events. (Funded by Cancer Research UK; ClinicalTrials.gov number, NCT00415233.).

Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24

Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p=6.35×10−34), rs1867277A (p=5.90×10−24), rs944289T (p=6.95×10−7), and rs6983267G (p=0.016). rs6983267 was most strongly associated under a recessive model (PGG vs GT + TT=0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p=0.008) after accounting for genotypes at the nearby rs965513 (p=2.3×10−13) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (∼11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).

RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B

Constitutive activation of the RET receptor tyrosine kinase underlies the genesis and progression of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer predisposition. Importantly, although kinase activation represents a common theme in neoplasias, not all activating mutations are functionally equivalent. Consistent with this, we ascertained a patient with classical features of MEN 2B, but lacking either of the classical mutations in RET (M918T or A883F). Instead, the patient harbors a novel pair of germ line missense mutations in cis at codons 804 and 805. We evaluated the potential physiochemical effects of these substitutions in silico, predicting both to be moderately deleterious in isolation, but severely deleterious in combination. Consistent with this postulate, we show that the identified tandem mutations (V804M/E805K) are biologically active, transforming cells in culture and that their transforming capacity in combination is distinctly synergistic. Furthermore, the V804M/E805K tandem lesion confers resistance to the small molecule receptor tyrosine kinase inhibitor, PP1, suggesting a mode of action distinct from that known for classical MEN 2B mutations. To address this question, we used homology molecular modeling in silico to model the active site of RET. We predict that RET804 constitutes a critical gatekeeper residue that, when mutated in combination with RET805, induces a conformational change in the hinge region that locks the active site in a position permissive for ATP hydrolysis. Our findings have implications both in the clinic and in the successful development of novel kinase-targeted anticancer drugs.

SPECT/CT Identification of Post-Radioactive Iodine Treatment False-Positive Uptake in a Simple Renal Cyst

Post–iodine 131 (I) therapy planar imaging for papillary cell thyroid carcinoma (EThy-Ca) is the standard modality utilized for post-surgical assessment of functioning remnant thyroid tissue and metastases (1). If I uptake outside the thyroid bed is discovered, the challenge is to localize it more precisely and to distinguish aberrant uptake due to EThy-Ca metastases from uptake due to other causes. We describe a patient for whom fusion of functional with anatomical imaging provided conclusive results without the need for supplementary imaging. The patient was an 85-year-old woman who presented for follow-up of recurrent papillary thyroid carcinoma (initial staging T4 N1 M0). Eight years previously she had a twostage completion thyroidectomy with neck dissection. She relapsed 2 years later and then underwent debulking of the recurrent tumor. This was followed by radioactive iodine treatment and external radiation therapy. In the following years her serum thyroglobulin (Tg) concentrations were minimally elevated without clinical evidence of progressive disease. Subsequently, her Tg level rose to 3.7 mg=L (76 mg=L off l-thyroxine replacement) and she was admitted for therapeutic administration of 5.8 GBq I. Three days after I administration she had a I whole body scan. The planar whole body images demonstrate asymmetric uptake in the salivary glands with no uptake visualized in the region of the left parotid and submandibular glands consistent with her previous surgery and radioiodine therapy. An additional area of increased tracer uptake was noted in the right upper quadrant. This uptake was initially thought to be related to bowel (Fig. 1). This was further evaluated with single photon emission computed tomography=(multi-slice) computed tomography (SPECT=CT) (Philips Precedence 16, Royal Philips Electronics, Amsterdam, The Netherlands). The focal uptake localized to uptake in a 5.5 4.2 cm simple cyst at the upper pole of the right kidney (Figs. 2 and 3). The rise of Tg was attributed to multiple pulmonary metastases, which were identified on the CT component of the study. Physiological I uptake occurs in the salivary glands, nasopharynx, and gastrointestinal tract most commonly. Less common sites of uptake are liver, on delayed imaging, and the breasts (2–6). Metastases of EThy-Ca to the kidney are very rare (7–9), and uptake of I into renal cysts is quite uncommon (5,7,8,10). Two possible mechanisms for this have been postulated. One is that there is a communication between the renal cyst and the pelvic collection system (2,5,8). The other is that it is due to human sodium iodine symporter FIG. 1. Post I whole body planar images, anterior and posterior projections, demonstrate focal uptake projected over the right upper abdomen. The asymmetric salivary gland uptake is related to previous surgery and radioiodine therapy. The activity projected over the right upper arm was skin contamination.

Crystal structure and isomerism of a tumour targeting radiopharmaceutical: [ReO(dmsa)2]–(H2dmsa =meso-2,3-dimercaptosuccinic acid)

A crystal structure determination shows that one isomer of the complex anion [ReO(dmsa)2]–(H2dmsa =meso-2,3-dimercaptosuccinic acid), a compound which in radiopharmaceutical form has been shown to localise in certain human tumours, has a square-pyramidal structure with all carboxylic acid groups uncoordinated and oriented endo relative to the oxo ligand.

Recognition of the femoroacetabular impingement syndrome on MDP SPECT CT

The femoroacetabular impingement syndrome (FAI) is becoming increasingly recognized as a cause of intermittent hip or groin pain in physically active young adults (ie, 4th to 5th decades), which leads to early osteoarthritis. Repeated microtrauma from impingement of the femoral neck against the acetabulum occurs in those with predisposing hip geometries. Early diagnosis of this condition allows appropriate management, aimed at reducing the need for total hip replacement. This case demonstrates that FAI may be appreciated on SPECT CT MDP bone scanning.

Pharmacokinetics, biodistribution and dosimetry of 99tcm(v)dmsa in humans with squamous cell carcinoma

Technetum-99m (99Tcm)(V) dimercaptosuccinic acid (DMSA) is a new tumour imaging agent which has been used to evaluate squamous carcinoma (SCC) of the head and neck. This study evaluated the pharmacokinetics and biodistribution of 99Tcm(V)DMSA in patients with SCC and calculated the bone mass of a New Zealand White (NZW) rabbit. This data was then used to calculate the effective dose equivalent in man.A total of 16 patients were studied (5 with no tumour, 11 with tumour). 99Tcm(V)DMSA had a fast bi-exponential blood clearance in patients with no tumour (30 and 401 min) and patients with tumour (30 and 387 min) with no significant difference (p > 0.05) between the two groups. 99Tcm(V)DMSA had a fast cumulative urine excretion with mean half-times in non-tumour and tumour patients of 183 min and 244 min respectively. There was no significant difference (p > 0.05) between these two latter groups.The effective dose equivalent of 99Tcm(V)DMSA in man is 5.1 μSv/MBq.

99Tcm (v) DMSA: the pituitary sign

SummaryTechnetium-99m (99Tcm) (v) dimercaptosuccinic acid (DMSA) is a new tumour imaging agent which has been used to evaluate head and neck tumours. It has a normal head and neck biodistribution to include the lacrimal glands, nasal mucosa and the blood-pool. Seventy-seven patients were studied of whom 63 had a head and neck malignancy. Of these patients, 19 (25%) exhibited positive accumulation of radioactivity in the region of the pituitary gland and this was a constant finding in those followed-up after treatment. Biodistribution studies in forty New Zealand white rabbits confirmed pituitary accumulation of 99Tcm (v) DMSA. The pituitary gland region should be included in the normal biodistribution of 99Tcm (v) DMSA.

Synergistic impact of attenuation correction and gating in routine myocardial SPECT reporting: 2 year follow-up study

AimTo look at the combined impact of non-uniform attenuation correction (AC) and gated SPECT in the visual interpretation of myocardial SPECT imaging. This was compared to the individual benefit obtained by adding AC information and gated SPECT information to non-AC image information. MaterialsWe retrospectively studied a group of 141 patients with a 22–26 month follow-up who underwent myocardial perfusion scintigraphy imaging. All the studies were corrected for attenuation with 153Gd line source transmission data and were ECG gated. In patients who had abnormal studies, follow-up coronary angiography information was also obtained in addition to medical follow-up information. MethodsTwo experienced nuclear medicine physicians interpreted the images independently and were blinded to the other persons report. Non-attenuation corrected data was first evaluated followed by attenuation corrected data and gated SPECT data. Four approaches to interpretation of images were undertaken: (1) non-AC images only, (2) non-AC+AC images, (3) non-AC+gated images, and (4) non-AC+AC+gated images. Study results were divided into four categories based on how confident the observers were of the diagnosis: (1) normal, (2) borderline normal, (3) borderline abnormal, and (4) abnormal. ResultsWhen results for sensitivity and specificity using the four different interpretation techniques were compared there was a statistically significant improvement in the specificity compared to non-AC image (48%) with the addition of AC (77%) and gating (82%) information (P<0.001). The best improvement in the specificity was noted when both AC and gated information (91%) was used along with non-AC information. The normalcy rates almost doubled following the addition of AC and gated data. There was also a decrease in the number of borderline results, showing an improvement in the reporter confidence in interpreting myocardial SPECT studies. Sensitivity, however, did not show a significant change between the four different approaches to interpretation of the study. ConclusionAttenuation correction and gating when combined have a synergistic impact upon improving the specificity of myocardial SPECT reporting when compared to the use of individual techniques alone to improve the specificity.

Radionuclide therapy in the United Kingdom in 1995.

A postal survey was conducted in the UK in 1996 to determine the facilities available and the level of activity at centres where radionuclide therapy was practised in 1995. A response rate of 79% indicated that 102 centres were providing radionuclide therapy, with 339 clinicians holding ARSAC certificates, 57% of whom were clinical oncologists. There were 84 beds available for therapy and the total number of patients treated was 11,435. Patient numbers treated by disease or procedure were: haematological, 569 (5%); benign thyroid disease, 9059 (79.2%); malignant thyroid disease, 911 (8%); bone pain palliation, 425 (3.5%); radiosynovectomy, 321 (2.8%); neuroendocrine tumour therapy, 76 (0.7%); and intra-cavitary, 56 (0.5%). The total amounts of activity of individual radiopharmaceuticals administered in GBq were: 131I, 16,695; 90Y-colloid, 88; 32P, 94.6; 131I-MIBG, 646; 89Sr, 57.6; and 186Rh-HEDP, 16. Average waiting times varied from 1 to 5 weeks, with a range of 0 to 52 weeks for some therapies. Most centres had the services of a physicist available. Compared with teaching hospitals, the 61 district hospitals had fewer allocated beds, but treated almost half of all patients. The numbers of therapies undertaken were increasing at many centres and this has implications for long-term planning.