Preoperative imaging in primary hyperparathyroidism: Are 11 C-Choline PET/CT and 99m Tc-MIBI/123 Iodide subtraction SPECT/CT interchangeable or do they supplement each other?

OBJECTIVE: Preoperative location of hyperfunctioning parathyroid glands (HPGs) is vital when planning minimally invasive surgery in patients with primary hyperparathyroidism (PHPT). Dual-isotope subtraction scintigraphy with 99m Tc-MIBI/123 Iodide using SPECT/CT and planar pinhole imaging (Di-SPECT) has shown high sensitivity, but is challenged by high radiation dose, time consumption and cost. 11 C-Choline PET/CT (faster with a lower radiation dose) is non-inferior to Di-SPECT. We aim to clarify to what extent the two are interchangeable and how often there are discrepancies. DESIGN: This is a prospective, GCP-controlled cohort study. PATIENTS AND MEASUREMENTS: One hundred patients diagnosed with PHPT were included and underwent both imaging modalities before parathyroidectomy. Clinical implications of differences between imaging findings and negative imaging results were assessed. Surgical findings confirmed by biochemistry and pathology served as reference standard. RESULTS: Among the 90 patients cured by parathyroidectomy, sensitivity was 82% (95% confidence interval [CI]: 74%-88%) and 87% (95% CI: 79%-92%) for Choline PET and Di-SPECT, respectively, p = .88. In seven cases at least one imaging modality found no HPG. Of these, neither modality found any true HPGs and only two were cured by surgery. When a positive finding in one modality was incorrect, the alternative modality was correct in approximately half of the cases. CONCLUSION: Choline PET and Di-SPECT performed equally well and are both appropriate as first-line imaging modalities for preoperative imaging of PHPT. When the first-line modality fails to locate an HPG, additional preoperative imaging with the alternate modality offers no benefit. However, if parathyroidectomy is unsuccessful, additional imaging with the alternate modality has merit before repeat surgery.

Metabolic consequences of gonadotropin-releasing hormone agonists vs orchiectomy: a randomized clinical study.

OBJECTIVES: To compare the metabolic changes between men with advanced prostate cancer commenced on a gonadotropin-releasing hormone (GnRH) agonist and those treated with orchiectomy. PATIENTS AND METHODS: Fifty-eight hormone-naive men with advanced prostate cancer were randomly assigned (1:1) to either subcapsular orchiectomy or triptorelin 22.5 mg/24 week depot injections. The participants were followed for 48 weeks, with study visits at baseline, 12, 24 and 48 weeks. The primary endpoint was changes in fasting plasma glucose. Secondary endpoints included changes in body composition (i.e. weight, fat mass, visceral adipose tissue [VAT], subcutaneous adipose tissue [SAT], lean body mass [LBM] and android/gynoid fat [AG] ratio) assessed with dual X-ray absorptiometry, serum lipid profiles, and insulin resistance evaluated during an oral glucose tolerance test. Linear mixed models were used to analyse the between-group differences. RESULTS: No treatment differences in the changes in fasting plasma glucose (0.2 mmol/L, 95% confidence interval [CI] -0.1, 0.4; P = 0.32) were observed. The orchiectomy group experienced greater increases in total fat mass (+2.06 kg, 95% CI 0.55, 3.56), SAT (+133 cm3 , 95% CI 22, 243) and weight (+3.30 kg, 95% CI 0.74, 5.87) at 48 weeks than did the triptorelin group (all P < 0.05), with the increases in fat mass being moderately correlated with increases in insulin resistance (P < 0.001). No differences in changed VAT, LBM or AG ratio were observed between the groups. The pooled analyses, combining data from both groups, showed androgen deprivation therapy (ADT) to significantly increase fat mass, SAT, VAT, serum cholesterols (total, high-density lipoprotein and low-density lipoprotein) and all measures of insulin resistance over time, while LBM decreased as compared with baseline values (all P < 0.05). These changes were apparent after only 12-24 weeks of ADT. CONCLUSIONS: Androgen deprivation therapy leads to adverse changes in body composition and increased insulin resistance and serum cholesterols, with changes already observed after only 12-24 weeks of treatment. This study further demonstrates that orchiectomy causes greater increases in fat accumulation compared with GnRH agonists and that these increases are associated with an increase in insulin resistance.

Luteinizing Hormone-Releasing Hormone Agonists are Superior to Subcapsular Orchiectomy in Lowering Testosterone Levels of Men with Prostate Cancer: Results from a Randomized Clinical Trial.

PURPOSE: Recent evidence suggests that reaching the lowest achievable levels of testosterone with androgen deprivation therapy delays disease progression and increases overall survival in men with advanced prostate cancer. The aim of this analysis was to compare posttreatment serum testosterone levels between patients undergoing subcapsular orchiectomy and patients treated with the luteinizing hormone-releasing hormone agonist triptorelin. MATERIALS AND METHODS: In this randomized clinical trial we included 58 consecutive hormone naïve men diagnosed with advanced prostate cancer at Herlev and Gentofte University Hospital, Herlev, Denmark from September 2013 to March 2015. Followup was 48 weeks. Participants were randomly assigned 1:1 to subcapsular orchiectomy or triptorelin 22.5 mg given as 24-week depot injections. Androgen status was measured by liquid chromatography-tandem mass spectrometry prior to treatment and after 12, 24 and 48 weeks. Between group differences in achieved hormone levels were analyzed by longitudinal Tobit regression. RESULTS: Triptorelin injections resulted in 29% lower testosterone levels (95% CI 17.2-41.7) compared to subcapsular orchiectomy (p <0.001). A significantly higher proportion of men receiving triptorelin had testosterone levels less than 20 ng/dl at 12 and 48 weeks compared to men undergoing orchiectomy (97% vs 79% and 100% vs 87%, respectively, p <0.05). There was no detectable difference in the adrenal androgen reduction between the treatment groups. CONCLUSIONS: The use of 24-week depot triptorelin injections results in significantly lower testosterone levels compared to subcapsular orchiectomy. To our knowledge this is the first randomized study to demonstrate a difference in treatment effect between surgical and medical castration on testosterone levels.

(18)F-FET-PET in Primary Hyperparathyroidism: A Pilot Study.

Preoperative localisation of the diseased parathyroid gland(s) in primary hyperparathyroidism (PHP) is a prerequisite for subsequent minimally invasive surgery. Recently, as alternatives to conventional sestamibi parathyroid scintigraphy, the (11)C-based positron emission tomography (PET) tracers methionine and choline have shown promise for this purpose. We evaluated the feasibility of using the (18)F-based PET tracer fluoroethyl-l-tyrosine (FET), as the longer half-life of (18)F makes it logistically more favourable. As a proof-of-concept study, we included two patients with PHP in which dual-isotope parathyroid subtraction single photon emission computed tomography had determined the exact location of the parathyroid adenoma. A dynamic FET PET/CT scan was performed with subsequent visual evaluation and calculation of target-to-background (TBR; parathyroid vs. thyroid). The maximum TBR in the two patients under study was achieved approximately 30 min after the injection of the tracer and was 1.5 and 1.7, respectively. This ratio was too small to allow for confident visualisation of the adenomas. FET PET/CT seems not feasible as a preoperative imaging modality in PHP.

A Prospective Comparative Study of Parathyroid Dual-Phase Scintigraphy, Dual-Isotope Subtraction Scintigraphy, 4D-CT, and Ultrasonography in Primary Hyperparathyroidism.

PURPOSE: Preoperative localization of the diseased parathyroid gland(s) in primary hyperparathyroidism allows for minimally invasive surgery. This study was designed to establish the optimal first-line preoperative imaging modality. PATIENTS AND METHODS: Ninety-one patients were studied consecutively in a prospective head-to-head comparison of dual isotope (Tc-MIBI vs I) subtraction parathyroid scintigraphy (PS), dual-phase PS, 4-dimensional (4D) CT, and ultrasonography (US). Surgery, histological confirmation, and postoperative normalization of Ca and parathyroid hormone were the reference standard. RESULTS: Ninety-seven hyperfunctioning parathyroid glands (HPGs) were identified by the reference standard. Sensitivity and specificity for subtraction PS, dual-phase PS, 4D-CT, and US were 93%, 65%, 58%, and 57% as well as 99%, 99.6%, 86%, and 95%, respectively. Interrater agreement was excellent for subtraction PS (κ = 0.96) while only fair for 4D-CT (κ = 0.34). Pinhole imaging and subtraction of delayed images (the latter especially in case of a nodular thyroid gland) increased the sensitivity of subtraction PS. SPECT/low-dose CT did not increase sensitivity but aided in the exact localization of the HPGs. Of 7 negative subtraction PS studies, 4D-CT and US were able to locate 3 and 1 additional HPGs, respectively. CONCLUSIONS: Dual isotope pinhole subtraction PS has higher diagnostic accuracy compared with dual-phase PS, 4D-CT, and US as a first-line imaging study in primary hyperparathyroidism. In case of a negative scintigraphy or suspicion of multiglandular disease, 4D-CT and/or US is recommended as a second-line modality. However, diagnostic algorithms should be adapted in accordance with local availability and expertise.

A simple procedure for routine RNA extraction and miRNA array analyses from a single thyroid in vivo fine needle aspirate.

CONTEXT: microRNA (miRNA) expression profiling and classification of tissue obtained from fine-needle aspirates (FNA) could be a major improvement of the preoperative diagnosis of thyroid nodules. OBJECTIVE: Before this can be clinically implemented, a robust and non-toxic method for obtaining sufficient quantity and quality of RNA from single in vivo FNA has to be established. RNAlater is a non-toxic RNA-stabilizing agent. However, due to the high density of RNAlater, pelleting of the tissue samples is difficult, and results in low recovery of RNA that is insufficient for subsequent miRNA array expression analysis. We therefore developed a simple centrifugation method for capturing tissue stored in RNAlater on a 0.45-µm filter. DESIGN: FNA from 24 patients with a solitary cold thyroid nodule was stored in Trizol, liquid nitrogen, or RNAlater. The tissue stored in RNAlater was either pelleted by centrifugation or captured on the 0.45-µm filters. RNA was extracted using the Trizol method. To validate results, FNA from additional 30 patients were analyzed based on the modified RNAlater protocol. MAIN OUTCOME: Capturing FNA tissue samples on the filters increased the RNA yield 10 fold and maintained RNA purity, permitting miRNA array expression profiling and allowing comparable levels of known miRNA-clusters regardless of preservation technique. Results were confirmed in an additional 30 patients. CONCLUSION: The modified RNAlater protocol is well suited for isolating RNA from single thyroid in vivo FNA in a clinical setting. Furthermore this permits shipping of FNA samples at room temperature from peripheral centers to a centralized array core facility.

Differences between endocrinologists and endocrine surgeons in management of the solitary thyroid nodule.

BACKGROUND: It is not known whether management of the solitary thyroid nodule differs between endocrinologists and endocrine surgeons. METHODS: A questionnaire containing a hypothetical case (a 42-year-old euthyroid woman with a 2-x-3-cm solitary thyroid nodule) and 13 clinical variations was sent to endocrinologists and endocrine surgeons in Australia. RESULTS: The response rate was 51%, including 122 endocrinologists and 48 endocrine surgeons. For the index case, serum thyroid-stimulating hormone (TSH), fine needle aspiration biopsy (FNAB) and ultrasonography were widely used by both groups, but thyroid antibody tests and scintigraphy were ordered more commonly by endocrinologists. In the setting of benign cytology, treatment differed significantly between specialties for the index case (endocrinologists: no treatment 78%, surgery 11%, thyroxine 11%; surgeons: no treatment 73%, surgery 25%, thyroxine 2%; P = 0.032). Treatment recommendations also differed significantly for 12 of the 13 clinical variations. In particular, for a patient with a suppressed serum TSH concentration, a majority of endocrinologists recommended radioiodine treatment, whereas surgeons favoured surgery (endocrinologists: radioiodine 53%, surgery 22%, no treatment 25%; surgeons: surgery 60%, radioiodine 11%, no treatment 27%; P < 0.001). For most of the variations, a higher proportion of surgeons than endocrinologists recommended surgical treatment. Comparison with previous surveys of European Thyroid Association and American Thyroid Association members (predominantly endocrinologists) demonstrated considerable international differences in management. CONCLUSION: There are clinically significant differences between Australian endocrinologists and endocrine surgeons in management of the solitary thyroid nodule, and international differences in management of this disorder.

Resumption of methimazole after 131I therapy of hyperthyroid diseases: effect on thyroid function and volume evaluated by a randomized clinical trial.

OBJECTIVE: Retrospective studies have indicated that anti-thyroid drugs (ATD) might possess a radioprotective effect, leading to a higher rate of recurrence of hyperthyroidism after iodine-131 ((131)I) therapy. DESIGN: A randomized clinical trial was performed to clarify whether resumption of methimazole after (131)I influences the final outcome of this treatment. METHODS: We assigned 149 patients with Graves' disease or a toxic nodular goitre to groups either to resume (+ATD) or not to resume (-ATD) methimazole 7 days after (131)I. Before (131)I therapy, all patients were rendered euthyroid by methimazole, which was discontinued 4 days before the (131)I therapy. RESULTS: During the follow-up period of 12 Months, 13 patients developed hypothyroidism, 42 were euthyroid, and 18 had recurrence of hyperthyroidism in the +ATD group; the respective numbers in the -ATD group were 16, 42 and 18 (P=0.88). At 3 weeks after (131)I therapy, the serum free-thyroxine index was slightly decreased (by 5.7%; 95% confidence interval (CI) -15.5 to 5.4%) in the +ATD group, in contrast to an increase of 35.9% (95% CI 18.8 to 55.5%) in the -ATD group (P<0.001 between groups). In the subgroup that remained euthyroid during follow-up, thyroid Volume reduction, assessed by ultrasonography, was smaller in the +ATD group [38.7% (95% CI 33.3 to 44.1%)] than in the -ATD group [48.6% (95% CI: 41.5-55.6%)] (P<0.05). CONCLUSION: No radioprotective effect could be demonstrated, with regard to final thyroid function, for the resumpton of methimazole 7 days after (131)I therapy. Although resumption of methimazole slightly reduced the magnitude of shrinkage of the goitre obtained by (131)I, the prevention of a temporary thyrotoxicosis in the early period after radiation favours this regimen.

Management of simple nodular goiter: current status and future perspectives.

The simple nodular goiter, the etiology of which is multifactorial, encompasses the spectrum from the incidental asymptomatic small solitary nodule to the large intrathoracic goiter, causing pressure symptoms as well as cosmetic complaints. Its management is still the cause of considerable controversy. The mainstay in the diagnostic evaluation is related to functional and morphological characterization with serum TSH and (some kind of) imaging. Because malignancy is just as common in patients with a multinodular goiter as patients with a solitary nodule, we support the increasing use of fine-needle aspiration biopsy (cytology). Most patients need no treatment after malignancy is ruled out. In case of cosmetic or pressure symptoms, the choice in multinodular goiter stands between surgery, which is still the first choice, and radioiodine if uptake is adequate. In addition to surgery, the solitary nodule, whether hot or cold, can be treated with percutaneous ethanol injection therapy. If hot, radioiodine is the therapy of choice. Randomized studies are scarce, and the side effects of nonsurgical therapy are coming into focus. Therefore, the use of the optimum option in the individual patient cannot at present be based on evidence. However, we are of the view that levothyroxine, although widely used, should no longer be recommended routinely for this condition. Within a few years, the introduction of recombinant human TSH and laser therapy may profoundly alter the nonsurgical treatment of simple nodular goiter.

Management of the nontoxic multinodular goiter: a North American survey.

To assess approaches to the diagnosis and therapy of patients with nontoxic multinodular goiter, a questionnaire was circulated to all members of the American Thyroid Association (ATA). An index case report was presented (42-yr-old woman with an irregular, nontender, bilaterally enlarged thyroid of 50-80 g and no clinical suspicion of malignancy or thyroid dysfunction), and 11 variations were proposed to evaluate how each alteration would affect management. One hundred and forty responses were retained (approximately 50% of clinically active ATA members). For the index case, a TSH determination was the routine choice of 100%, and serum thyroid autoantibodies were measured by 74%. Simultaneous use of serum TSH, a thyroid hormone assay, and antithyroid peroxidase was employed by 49%. Only 4% included a calcitonin assay. The median number of blood tests ordered was 3 (range, 1-7). Ultrasound was used by 59%, thyroid scintigraphy by 24%, and both imaging modalities by 11%. Fine needle aspiration biopsy (FNAB) was performed by 74%. If scintigraphy showed inhomogeneous tracer distribution or a dominant hypofunctioning region, FNAB was performed by 15% and 97%, respectively. L-T4 treatment was preferred by 56%, radioiodine by 1%, surgery by 6%, and 36% would recommend no treatment. A large goiter, a history of external radiation, or rapid growth increased the preference for surgery. In case of a suppressed serum TSH level, radioiodine was used by 56%. In conclusion, in the work-up of patients with nontoxic multinodular goiter, ATA clinicians employ determinations of TSH often combined with a T4 and/or T3 assay and antithyroid peroxidase antibodies. Thyroid imaging, primarily ultrasound, is performed by more than two thirds, and FNAB by three fourths. This diagnostic evaluation is significantly less extensive than that of the European Thyroid Association members, but the distribution of treatment choices is quite similar. In accordance with their European colleagues, the majority of ATA members prefer the use of L-T4 therapy. There is, however, still a wide variation in the perceived optimal management of this condition among members of both organizations.