[Local ablative procedures for treatment of thyroid nodules]. / Lokalablative Verfahren zur Behandlung von Schilddrüsenknoten.

Thyroid nodules are very frequent in the iodine deficiency regions of central Europe and some of the affected patients are referred for definitive treatment, such as surgery and radioiodine treatment. In recent years nonsurgical and non-radioiodine techniques have been introduced to treat thyroid gland pathologies. These techniques include the probe-based techniques of radiofrequency, microwave and laser application. The only noninvasive technique is high-intensity focused ultrasound. All mentioned techniques have the goal to reduce the volume of the thyroid nodule by application of energy/heat. The knowledge of all techniques and their advantages and risks is necessary to help physicians and patients in making decisions for the appropriate method of treatment of thyroid nodules.

Thyroid surgery in children and adolescents: results from a multi-institutional German and Austrian database.

BACKGROUND: Outcomes of paediatric thyroid surgery have only been reported in smaller series or over long intervals. The aim of this multicentre study was to describe the recent outcomes of paediatric thyroid surgery in Germany and Austria. METHODS: Patients aged less than or equal to 18 years who underwent thyroid surgery and were prospectively documented in the StuDoQ|Thyroid registry between March 2017 and August 2022 were studied. RESULTS: In total, 604 patients from 90 institutions were included. The mean age was 15.4 years and 75 per cent of patients were female. The most frequent benign pathologies were nodular goitre (35.6 per cent), follicular adenoma (30.1 per cent), and Graves' disease (28.5 per cent). Among 126 thyroid malignancies, papillary thyroid carcinoma was diagnosed in 77.8 per cent of patients, follicular thyroid carcinoma was diagnosed in 10.3 per cent of patients, and medullary thyroid carcinoma was diagnosed in 8.7 per cent of patients. Lymph node metastases were found in 45.9 per cent of patients with papillary thyroid carcinoma and in 36.4 per cent of patients with medullary thyroid carcinoma. Vascular invasion was found in 62.9 per cent of patients with follicular thyroid carcinoma. The mean tumour diameters were 18, 42, and 13 mm in patients with papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary thyroid carcinoma respectively. Early postoperative recurrent laryngeal nerve injury was seen in 27 of 556 patients (4.9 per cent) (22 of 617 (3.6 per cent) nerves at risk with intermittent intraoperative nerve monitoring and 5 of 237 (2.1 per cent) nerves at risk with continuous intraoperative nerve monitoring). Persistent recurrent laryngeal nerve injury was documented in 4 of 556 patients (0.7 per cent). Early postoperative hypoparathyroidism correlated with Graves' disease, thyroid carcinoma, and lymph node dissection. CONCLUSION: Papillary thyroid carcinoma and follicular thyroid carcinoma in children were often advanced at presentation. Persistent or recurrent lymph node metastases were mainly seen in papillary thyroid carcinoma. Overall survival was excellent, but longer follow-up is needed.

Proof-of-concept and Randomized, Placebo-controlled Trials of an FcRn Inhibitor, Batoclimab, for Thyroid Eye Disease.

CONTEXT: Inhibition of the neonatal fragment crystallizable receptor (FcRn) reduces pathogenic thyrotropin receptor antibodies (TSH-R-Ab) that drive pathology in thyroid eye disease (TED). OBJECTIVE: We report the first clinical studies of an FcRn inhibitor, batoclimab, in TED. DESIGN: Proof-of-concept (POC) and randomized, double-blind placebo-controlled trials. SETTING: Multicenter. PARTICIPANTS: Patients with moderate-to-severe, active TED. INTERVENTION: In the POC trial, patients received weekly subcutaneous injections of batoclimab 680 mg for 2 weeks, followed by 340 mg for 4 weeks. In the double-blind trial, patients were randomized 2:2:1:2 to weekly batoclimab (680 mg, 340 mg, 255 mg) or placebo for 12 weeks. MAIN OUTCOME: Change from baseline in serum anti-TSH-R-Ab and total IgG (POC); 12-week proptosis response (randomized trial). RESULTS: The randomized trial was terminated because of an unanticipated increase in serum cholesterol; therefore, data from 65 of the planned 77 patients were analyzed. Both trials showed marked decreases in pathogenic anti-TSH-R-Ab and total IgG serum levels (P < .001) with batoclimab. In the randomized trial, there was no statistically significant difference with batoclimab vs placebo in proptosis response at 12 weeks, although significant differences were observed at several earlier timepoints. In addition, orbital muscle volume decreased (P < .03) at 12 weeks, whereas quality of life (appearance subscale) improved (P < .03) at 19 weeks in the 680-mg group. Batoclimab was generally well tolerated, with albumin reductions and increases in lipids that reversed upon discontinuation. CONCLUSIONS: These results provide insight into the efficacy and safety of batoclimab and support its further investigation as a potential therapy for TED.

High intensity focused ultrasound in the therapy of benign thyroid nodules-first German bicentric study with long-term follow-up.

PURPOSE: The study evaluated high-intensity-focused ultrasound (HIFU) for benign thyroid nodules in terms of efficiency, complication rate, influence of preablative nodule size, parameters influencing the therapeutic success and hormonal-thyroid-function. METHODS: Seventy-two patients with 75 nodules were treated with HIFU at 2 centers from 2014-2019. Median nodule volume was 4.4 ml (range 0.33-53). The therapeutic ultrasound probe (EchoPulse THC900888-H) generated 80-90 °C in the target tissue with 87.6-320.3 J per sonication. Nodal volume was measured at baseline and over 12 months after therapy in a retrospective bicentric-study with long-term follow-up. Hormonal-thyroid function (TSH, T3, T4) was measured before and after ablation. Complications were assessed. RESULTS: Significant volume reduction (p < 0.05 Wilcoxon-signed-rank test) of thyroid nodules was 38.98% at 3 months, 37.32% at 6 months, 61.54% at 9 months and 60.66% at 12 months. Volume reduction of nodules <3 ml did not differ significantly from nodules >3 ml (p > 0.05 Mann-Whitney test). At 3 months solid nodules had a significant volume reduction of 52.08%, complex nodules of 32.57%, nodules treated under regional anesthesia of 33.07% and under general anesthesia of 49.47%. Hormonal-thyroid function was not influenced significantly by HIFU therapy (p > 0.05 Wilcoxon-signed-rank test). Complication rate was 3.8%. No long-term complications occurred. CONCLUSION: Significant volume reduction of thyroid nodules up to 12 months after HIFU was shown. All complications were reversible. Therapy was more efficient in solid than complex nodules and in nodules treated under general anesthesia than with regional anesthesia. Hormonal-thyroid-function was not affected. TRIAL REGISTRAFTION NUMBER: 2020-1728-evBO. Date of registration: 16.06.2020. Agency: Ethik-Kommission bei der Landesäztekammer Hessen.

Heavier Weight of Resected Thyroid Specimen Is Associated With Higher Postoperative Morbidity in Benign Goiter.

OBJECTIVE: The impact of heavier weight of resected thyroid specimen on postoperative morbidity after total thyroidectomy for multinodular benign goiter remains unclear. METHODS: Data from the prospective StuDoQ|Thyroid registry of the German Society of General and Visceral Surgery were analyzed regarding the weight of the resected thyroid specimen and perioperative morbidity (vocal cord palsy, hemorrhage, surgical site infection, and hypocalcemia). To achieve a homogeneous patient population, only patients with total thyroidectomy for multinodular benign goiter were included. RESULTS: A total of 7911 patients from 105 departments underwent total thyroidectomy for benign conditions (January 2017-July 2020). The median resected weight of the thyroid specimen in all patients was 53 g (interquartile range 32-92). In 1732 patients, the specimen weight exceeded 100 g. Intraoperative neuromonitoring was used in 99.5% of patients. Postoperative laryngoscopy revealed vocal cord dysfunction in 480 of 15 822 (3.03%) nerves at risk, with unilateral dysfunction in 454 (2.87%) of patients and bilateral dysfunction in 13 patients (0.08%). In multivariable analysis, a thyroid weight >100 g was an independent predictor of early postoperative vocal cord dysfunction [odds ratio (OR) 1.462, 95% CI 1.108-1.930, P = 0.007). Heavier (>100 g) thyroid weight was an independent predictor of surgical site infection (OR 1.861, 95% CI 1.203-2.880, P = 0.005) and also predicted postoperative hemorrhage in the univariate analysis (OR 1.723, 95% CI 1.027-2.889, P = 0.039). On the contrary, postoperative parathyroid function was not affected. CONCLUSIONS: Heavier (>100 g) resected thyroid weight independently predicts higher postoperative morbidity, including early vocal cord palsy and surgical site infection after total thyroidectomy for benign multinodular goiter.

Effectiveness of High-intensity Focused Ultrasound (HIFU) Therapy of Solid and Complex Benign Thyroid Nodules - A Long-term Follow up Two-center Study.

PURPOSE: To investigate the effectiveness of high-intensity focused ultrasound (HIFU) of solid and complex benign thyroid nodules. METHODS: Fifty-eight patients with benign thyroid nodules were treated with HIFU at two centers from 2014-2019. The device, EchoPulse (Teraclion, Malakoff, France), heats the nodes to 80-90 °C. Nodal volumes were measured by ultrasound at regular intervals before and up to 12 months after therapy. In a retrospective long-term two-center study, average volume reductions in relation to baseline volume were statistically analyzed by the Wilcoxon signed-rank test. Side effects were documented. RESULTS: In solid nodules, the average percent volume reductions at the 3, 6, 9, and 12-months follow-up were 49.98%, 46.40%, 65.77%, and 63.88%, respectively. The results were significant with p<0.05 in the Wilcoxon signed-rank test at the 3, 6, and 9-months follow-up. In complex nodules, the average percent volume reduction was 35.2% at 3 months, 36.89% at 6 months, and 63.64% at twelve months follow up. The results were significant with p<0.05 in the Wilcoxon signed-rank test at the 3- and 6-months follow-up. The complication rate was 5.2%. All complications occurred in patients with solid nodules. CONCLUSION: The study showed that HIFU is an effective treatment method for both solid and complex nodules. The complication rate is relatively high at 5.2%. No long-term complications occurred. The solid nodules responded better to HIFU than complex nodules.

Effects of Regional and General Anesthesia on the Therapeutic Outcome of Benign Thyroid Nodules Treated with High Intensity Focused Ultrasound (HIFU).

BACKGROUND: The study investigated whether anesthesia performed during high-intensity-focused-ultrasound treatment (HIFU) of benign thyroid nodules influenced the therapy outcome, based on volume reduction and the amount of energy delivered. METHODS: Thirty patients with benign thyroid nodules were treated with HIFU under general or regional anesthesia at two centers from 2014 to 2019. During HIFU, a therapeutic ultrasound probe, EchoPulse (Teraclion, Malakoff, France), heats the focus to 80-90 degrees Celsius. Nodal volumes were measured by ultrasound before and 3 months after therapy. For statistical analysis, the total population was divided into two groups according to the anesthesia performed. In a retrospective long-term multicenter study, volume reduction and the energy delivered were analyzed using the Wilcoxon signed-rank test and the Mann-Whitney test. RESULTS: At three months follow-up, the total study population had an average volume reduction of 39.26% (range 4.03-91.16%, p < 0.001, n = 30), the general anesthesia group of 47.46% (range 13.64-91.16%, p = 0.001, n = 15) and the regional anesthesia group of 31.06% (range 4.03-68.63%, p = 0.001, n = 15). Under regional anesthesia a median energy of 3.16 kJ/cm3 (range: 0.96 - 8.2 kJ/cm3) and under general anesthesia a median energy of 0.88 kJ/cm3 (range: 0.18 - 1.63 kJ/cm3) were delivered. All results were significant with p < 0.05. The complication rate was 6.67%. CONCLUSION: HIFU is an effective method to treat benign thyroid nodules. Comparing anesthesia methods, volume reduction is higher in patients treated under general anesthesia and less energy has to be delivered under general anesthesia. TRIAL REGISTRATION NUMBER: 2020-1728-evBO. AGENCY: Ethik-Kommission bei der Landesäztekammer Hessen.

Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study.

OBJECTIVE: In this retrospective cohort study, we describe the clinical presentation and workup of parathyroid carcinoma (PC) and determine its clinical prognostic parameters. Primary outcome was recurrence free survival. SUMMARY BACKGROUND DATA: PC is an orphan malignancy for which diagnostic workup and treatment is not established. METHODS: Eighty-three patients were diagnosed with PC between 1986 and 2018. Disease-specific and recurrence-free survivals were estimated with the Kaplan-Meier method. Risk factors for recurrence were identified by binary logistic regression with adjustment for age and sex. Thirty-nine tumors underwent central histopathological review. RESULTS: Renal (39.8%), gastrointestinal (24.1%), bone (22.9%), and psychiatric (19.3%) symptoms were the most common symptoms. Surgical treatment was heterogeneous [parathyroidectomy [PTx)] alone: 22.9%; PTx and hemithyroidectomy: 24.1%; en bloc resection 15.7%; others 37.3%] and complications of surgery were frequent (recurrent laryngeal nerve palsy 25.3%; hypoparathyroidism 6%). Recurrence of PC was observed in 32 of 83 cases. In univariate analysis, rate of recurrence was reduced when extended initial surgery had been performed (P = 0.04). In multivariate analysis low T status [odds ratio (OR) = 2.65, 95% confidence interval (CI) 1.02-6.88, P = 0.045], N0 stage at initial diagnosis (OR = 6.32, 95% CI 1.33-30.01, P = 0.02), Ki-67 <10% (OR = 14.07, 95% CI 2.09-94.9, P = 0.007), and postoperative biochemical remission (OR = 0.023, 95% CI 0.001-0.52, P = 0.018) were beneficial prognostic parameters for recurrence-free survival. CONCLUSION: Despite a favorable overall prognosis, PC shows high rates of recurrence leading to repeated surgery and postoperative recurrent laryngeal nerve palsy and hypoparathyroidism. In view of the reduced recurrence rate in cases of extended surgery, ipsilateral completion surgery may be considered when PC is confirmed.

Preoperative calcitonin testing improves the diagnosis of medullary thyroid carcinoma in female and male patients.

AIM: Calcitonin (Ctn) measurement in patients with thyroid disease could potentially increase the detection rates of medullary thyroid carcinoma (MTC) but remains a controversial issue. The aim of this study was to evaluate routine preoperative Ctn measurements. METHODS: All patients with thyroid surgery documented in the prospective StuDoQ|Thyroid registry between March 2017 and September 2020 were included. Cutoff levels for Ctn were determined with receiver-operating characteristic analyses to assess the preoperative diagnosis of MTC in subgroups for females and males. FINDINGS: In 29 590 of 39 679 patients (75%) participating in the registry, routine preoperative Ctn testing was performed. In 357 patients (227 females and 130 males), histopathology confirmed MTC with a mean tumor size of 14.7 mm (±12.43). Biochemical cure was achieved in 71.4% of the patients. Ctn levels between 11 and 20 pg/mL were seen in 2.6% of the patients, and only 0.7% of the patients had Ctn levels above 21 pg/mL. Cutoff levels for the diagnosis of MTC were 7.9 pg/mL for females and 15 pg/mL for males (P < 0.001). The sensitivity and specificity for females were 95 and 98%, and 96 and 97% for males, respectively. CONCLUSION: Routine Ctn testing is a reliable predictor for MTC and provides the opportunity for earlier thyroidectomy before lymph node metastases occur, resulting in a better prognosis. Females with Ctn levels >7.9 pg/mL and males >15 pg/mL without any other extrathyroidal sources for an elevated Ctn should be monitored. Thyroid surgery should be considered if Ctn levels are increasing or ultrasound detects suspicious thyroid lesions.

Short-Term Hypocalcemia Prophylaxis With Calcitriol Before Thyroidectomy.

BACKGROUND: Total thyroidectomy is the most common surgical treatment of thyroid diseases, and postoperative hypocalcemia is its most common complication. Hypocalcemia prolongs the patient's hospital stay and impairs his or her quality of life. Although a low vitamin D level is a recognized risk factor, the utility of preoperative vitamin D administration to prevent postoperative hypocalcemia is unclear. In this trial, therefore, we studied the effect of giving vitamin D before total thyroidectomy. METHODS: In a multicenter, randomized, minimally interventional trial (registration number: DRKS 00005615), patients about to undergo total thyroidectomy were randomized either to an intervention group that received 0.5 µg of calcitriol per os twice daily for three days up to the day immediately before surgery, or to a control group that did not (no placebo was given). The primary endpoint was the absence of hypocalcemia (serum calcium <2.1 mmol/L) in the postoperative course. RESULTS: Of the 287 patients recruited in six hospitals over the period 23 July 2014 to 20 March 2017, 246 were included in the final analysis. The intervention and control groups did not differ significantly with respect to the rate of postoperative hypocalcemia (29.2% and 33.6%, respectively; p = 0.546, power 8.8%). The duration of postoperative hypocalcemia was, however, shorter in the intervention group (3.5 vs. 7 days; p = 0.016, power 68%). The rates of hypocalcemia in the individual trial locations varied widely, ranging from 13.9% to 71.4%. CONCLUSION: Short-term administration of calcitriol did not affect the rate of occurrence of hypocalcemia after thyroidectomy, but did shorten its duration. The rate of postoperative hypocalcemia varied widely across hospitals, probably because of differences in surgical technique.

Short-Term Outcomes of Surgery for Graves' Disease in Germany.

BACKGROUND: Surgical treatment of Graves' disease (GD) has a potentially increased incidence of postoperative hypoparathyroidism, recurrent laryngeal nerve palsy (RLNP) and bleeding. The aim of this study was to evaluate the current extent of surgery for the treatment of GD and its safety as a short-term outcome. METHODS: Patients who underwent thyroid resection for GD were identified from the prospective StuDoQ/Thyroid registry. Patient data were retrospectively analyzed regarding demographics, surgical procedures and perioperative outcomes. Statistics were performed with Student's t-test or Fisher's exact test and multivariate Cox regression analysis. The level of statistical significance was set at p < 0.05. RESULTS: A total of 1808 patients with GD with a median age of 44 (range 14-85) years were enrolled in a 25-month period by 78 departments, of which 35.7% (n = 645) had an endocrine orbitopathy and 0.1% (n = 6) had thyrotoxic crisis. Conventional open surgery was used in 98.6% of cases and minimally invasive or remote-access approaches were used in 1.4%. Total thyroidectomy was performed in 93.4% of cases (n = 1688). Intraoperative neuromonitoring (IONM) was used in 98.9% (n = 1789) of procedures. In 98.3% (n = 1777) at least one parathyroid gland was visualized and in 20.7% (n = 375) parathyroids were autografted. The rates of unilateral and bilateral transient RLNP were 3.9% (n = 134/3429 nerves at risk) and 0.1% (n = 4/3429 NAR). The rates of transient RLNP tended to be higher when intermittent IONM was used compared to continuous IONM (4.1% vs. 3.4%, p < 0.059). The rate of transient postoperative hypoparathyroidism was overall 29% (n = 525/1808). Multivariate analysis revealed fewer than 300 thyroid resections and fewer than 15 thyroid resections for GD per year, male sex, BMI > 30, autotransplantation of parathyroid glands and previous bilateral thyroid surgery as independent risk factors for postoperative temporary hypoparathyroidism. Reoperations for bleeding (1.3%) were rare. CONCLUSION: Total thyroidectomy with IONM is safe and currently the most common surgical therapy for GD in Germany. Postoperative hypoparathyroidism is the major complication which should be focused on.

Non-Surgical and Non-Radioiodine Techniques for Ablation of Benign Thyroid Nodules: Consensus Statement and Recommendation.

Thyroid nodules and cysts are frequently diagnosed in Germany with a prevalence of about 20% in young adults reaching up to 70% in older adults. Surgery is the standard treatment of symptomatic nodules, nodules with suspicion of malignancy and thyroid cancer. Radioiodine treatment is applied for autonomously functioning nodules. During the last years new non-surgical and non-radioiodine techniques have been introduced to treat thyroid nodules. These techniques include ethanol/polidocanol treatment, radiofrequency, microwave, and laser ablation, and high frequency ultrasound ablation. A significant reduction in nodule size could be documented for these techniques in several studies, but long-term outcome data are missing. Until now, there is no general consensus regarding the appropriate indications for these methods. For this reason, the Thyroid Section (German Society for Endocrinology), the Thyroid Working Committee (German Society for Nuclear Medicine), and the German Association of Endocrine Surgeons (CAEK) for the German Society of General and Visceral Surgery (DGAV) reviewed the respective literature, discussed the pro and cons and developed a consensus statement and recommendation to help physicians and patients in their decision making.

Current Practice of Surgery for Benign Goitre-An Analysis of the Prospective DGAV StuDoQ|Thyroid Registry.

BACKGROUND: To evaluate the current indications, resection strategies and short-term outcomes of surgery for benign goitre in a country with endemic goitre. METHODS: Data of patients who underwent surgery for benign goitre were retrieved from the prospective StuDoQ/Thyroid registry and retrospectively analysed regarding the patient's demographics, indications for surgery, surgical procedures, histology, and perioperative outcomes. RESULTS: In a 15-month period, 12,888 patients from 83 departments underwent thyroid resections for benign conditions. Main indications for surgery were exclusion of malignancy (68%), compression symptoms (20.7%) and hyperthyroidism (9.7%). Preoperative fine needle aspiration cytology was performed in only 12.2% of patients with the indication "exclusion of malignancy". Thyroidectomy (49.8%) or hemithyroidectomy (36.9%) were performed in 86.7% of patients. Minimally invasive or alternative surgical techniques were applied in only 2.2%. Intraoperative neuromonitoring was used in 98.4% of procedures, in 97.5% of patients at least one parathyroid gland was visualized, and in 15.3% of patients parathyroid tissue was autografted, respectively. The rates of unilateral and bilateral transient recurrent nerve palsy were 3.6% and 0.07% of nerves at risk, the rate of transitory hypoparathyroidism was 15.3%. The rates of postoperative bleeding and wound infections requiring reoperation were 1.4% and 0.07%, respectively. CONCLUSIONS: The indication "exclusion of malignancy" is made too liberally, and there is a strong attitude to perform complete thyroid resections. Postoperative hypoparathyroidism is the major complication after surgery for benign thyroid disease, thus requiring more awareness.

Comparison between microwave ablation and bipolar radiofrequency ablation in benign thyroid nodules: differences in energy transmission, duration of application and applied shots.

PURPOSE: Comparison between different thermal ablation systems for thyroid nodules regarding their different procedural characteristics such as treatment-time, number of shots and energy transmission in the context of their clinical performance such as complication rate and volume reduction after three months. METHODS: A total of 60 patients with 65 nodules underwent thermal ablation of thyroid nodules with either microwave ablation (MWA) (9 male, 15 female and mean age 57 ± 13 years) or radiofrequency ablation (RFA) (12 male, 24 female and mean age 54 ± 12 years). RESULTS: Mean initial volume (MWA: 23.90 ± 17.35 ml; RFA: 29.44 ± 30.09 ml), energy transmission (MWA: 13.56 ± 10.17 kJ; RFA: 15.12 ± 13.45 kJ), energy transmission per ml (MWA: 0.85 ± 1.01 kJ/ml; RFA: 0.65 ± 0.32 kJ/ml), power (MWA: 22.69 ± 12.32 J/s; RFA: 20.97 ± 7.86 J/s) and duration of ablation (MWA: 618 ± 304 s; RFA: 695 ± 463 s) were not statistically different (p > .05). MWA required significantly less shots (MWA: 3 ± 1; RFA: 6 ± 3) than RFA (p < .05). At three-months follow-up a significant mean nodular volume reduction of 53.54 ± 15.40% after MWA and 51.21 ± 16.58% after RFA (p < .05) was measured. However, mean nodular volume reduction was not significantly different between both systems (p > .05). One patient treated by MWA reported a transient Horner's syndrome, which recovered without any further treatment. Major complications such as nodule rupture, infection or persisting nerve injuries did not occur. CONCLUSION: Both systems are suitable to treat thyroid nodules and show no significant difference in the duration of application, energy transmission and volume reduction. However, MWA requires less shots to treat the whole nodule.

Local recurrence in the neck and survival after thyroidectomy for metastatic renal cell carcinoma.

BACKGROUND: Most investigations of thyroidectomy for metastatic renal cell carcinoma (RCC) are case studies or small series. This study was conducted to determine the contribution of clinical and histopathologic variables to local recurrence in the neck and overall survival after thyroidectomy for RCC metastases. METHODS: The medical records of 140 patients with thyroidectomy for metastatic RCC performed between 1979 and 2012 at 25 institutions in Germany and Austria were analyzed. RESULTS: The median interval between nephrectomy and thyroidectomy was 120 months. Concurrence of thyroid and pancreatic metastases was present in 23 % of the patients and concurrence of thyroid and adrenal metastases in 13 % of the patients. Clinical outcome data were available for 130 patients with a median follow-up period of 34 months. The 5-year overall survival rate was 46 %, and 28 % of patients developed a local neck recurrence at a median of 12 months after thyroidectomy. Multivariate analysis showed that invasion of adjacent cervical structures (hazard ratio [HR] 3.2; p = 0.001), patient age exceeding 70 years (HR 2.5; p = 0.004), and current or past evidence of metastases to nonendocrine organs (HR 2.4; p = 0.003) were independent determinants of inferior overall survival. Conversely, invasion of adjacent cervical structures (HR 12.1; p < 0.0001) and year of thyroidectomy (HR 5.7 before 2000; p < 0.0001) were shown to be independently associated with local recurrence in the neck by multivariate analysis. CONCLUSIONS: Although significant improvement of local disease control in patients with thyroid metastases of RCC has been achieved during the last decade, overall outcome continues to be poor for patients with locally invasive thyroid metastases.

FOXE1 association with differentiated thyroid cancer and its progression.

BACKGROUND: Single nucleotide polymorphisms (SNPs) near thyroid transcription factor genes (FOXE1 rs965513/NKX2-1 rs944289) have been shown to be associated with differentiated thyroid cancer (DTC) in Caucasoid populations. We investigated the role of those SNPs in German patients with DTC and also extended our analysis to tumor stages and lymphocytic infiltration of the tumors (ITL). METHODS: Patients with DTC (n=243; papillary, PTC; follicular, FTC) and healthy controls (HC; n=270) were analyzed for the rs965513 and rs944289 SNPs. RESULTS: The case-control analysis for rs965513 SNP showed that the genotypes "AA," "AG," and minor allele "A" were more frequent in patients with DTC than in HC (pronounced in PTC p(genotype)=0.000084, p(allele)=0.006 than FTC p(genotype)=0.29 and p(allele)=0.06). Furthermore, subgroup analysis of the DTC patients stratified for primary tumor stage (T1-T2, T3-T4), the absence or presence of regional lymph node metastases (N0, N1), for distant metastases (M0, M1), as well as for ITL, showed an association of rs965513 with stages T1-T2, T1-T3, N1, and absence of ITL. The NKX2-1 SNP rs944289, however, was not associated with DTC. CONCLUSION: Our results confirm that the FOXE1 rs965513 SNP confers an increased risk for DTC in the German population, particularly allele "A" and the genotypes "AA" and "AG" for PTC. This increased risk was also observed in advanced tumor stages and absence of ITL, which may reflect the course of a more aggressive disease. The NKX2-1 rs944289 SNP, however, appears to play a secondary role in the development of DTC in the German population.

Impaired vitamin D activation and association with CYP24A1 haplotypes in differentiated thyroid carcinoma.

BACKGROUND: Common polymorphisms of the vitamin D receptor gene have been reported to affect the risk of breast, colon, prostate, and differentiated thyroid cancer (DTC), but polymorphisms within the genes of vitamin D metabolizing enzymes have not been studied in DTC. The aim of the present study was to investigate the genes for vitamin D enzymes in patients with DTC and healthy controls (HC) as well as the vitamin D (25-hydroxyvitamin D(3), and 1,25-hydroxyvitamin) status. METHODS: German patients (n=253) with DTC (papillary thyroid carcinoma [PTC] and follicular thyroid carcinoma [FTC]) and HC (n=302) were genotyped for polymorphisms within the vitamin D metabolizing enzymes such as 25-hydroxylase (CYP2R1[rs12794714, rs10741657]), 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1[rs10877012, rs4646536]), and 25-hydroxyvitamin D 24-hydrolase (CYP24A1[rs927650, rs2248137, rs2296241]). Furthermore, the 25-hydroxyvitamin D(3) [25(OH)D(3)] and 1,25-hydroxyvitamin [1,25(OH)(2)D(3)] plasma levels were measured by a radioimmunoassay. RESULTS: There was no difference in the genotypes; however, the CYP24A1 haplotype analysis showed that rs2248137C/rs2296241A (13.1% vs. 19.1%; corrected p [pc]=0.04) was less frequent in the PTC, whereas the haplotypes rs2248137C/rs2296241G (56.0% vs. 41.9%; pc=0.03), rs927650C/rs2296241G (22.5% vs. 8.4%; pc=1.6×10(-3)), and rs927650C/rs2248137C/rs2296241G (21.1% vs. 7.3%; pc=1.5×10(-3)) were more frequent in the FTC compared with HC. Furthermore, if patients and controls were grouped according to four 25(OH)D(3) categories (severely deficient, deficient, insufficient, and sufficient), then the patients with both DTC subtypes had significantly lower levels of circulating 1,25(OH)(2)D(3), especially in the group with a deficient 25(OH)D(3) status compared with the controls. Although the polymorphisms showed no differences stratified for the four 25(OH)D(3) categories, the activation status by 1,25(OH)(2)D(3) differed significantly depending on the genotypes of the investigated CYP24A1 polymorphisms. CONCLUSIONS: A higher risk for DTC is conferred by haplotypes within the CYP24A1 gene, low circulating 25(OH)D(3) levels (deficiency), and a reduced conversion to 1,25(OH)(2)D(3). These results confirm and extend previous observations and also support a role of the vitamin D system in the pathogenesis of DTC. How deficient 25(OH)D(3) levels in combination with certain CYP24A1 haplotypes affect vitamin D activation is the subject of future studies.

Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10.

Multiple endocrine neoplasia type 2 is characterized by germline mutations in RET. For exon 10, comprehensive molecular and corresponding phenotypic data are scarce. The International RET Exon 10 Consortium, comprising 27 centers from 15 countries, analyzed patients with RET exon 10 mutations for clinical-risk profiles. Presentation, age-dependent penetrance, and stage at presentation of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism were studied. A total of 340 subjects from 103 families, age 4-86, were registered. There were 21 distinct single nucleotide germline mutations located in codons 609 (45 subjects), 611 (50), 618 (94), and 620 (151). MTC was present in 263 registrants, pheochromocytoma in 54, and hyperparathyroidism in 8 subjects. Of the patients with MTC, 53% were detected when asymptomatic, and among those with pheochromocytoma, 54%. Penetrance for MTC was 4% by age 10, 25% by 25, and 80% by 50. Codon-associated penetrance by age 50 ranged from 60% (codon 611) to 86% (620). More advanced stage and increasing risk of metastases correlated with mutation in codon position (609→620) near the juxtamembrane domain. Our data provide rigorous bases for timing of premorbid diagnosis and personalized treatment/prophylactic procedure decisions depending on specific RET exon 10 codons affected.

Real-time ultrasound elastography--a noninvasive diagnostic procedure for evaluating dominant thyroid nodules.

PURPOSE: Ultrasound elastography (USE) is a newly developed technique for the evaluation of tissue stiffness. It is known that malignancies often show a low-strain value. So far, only limited data for thyroid nodules is available. METHODS: This study included 309 prospective evaluated patients with dominant, nontoxic thyroid nodules. All patients were referred to surgery. USE was performed preoperatively. Three measuring groups were formed: hard (< 0.15), intermediate (0.16-0.3), and soft (> 0.31). The measurements were correlated to the final histological findings. RESULTS: The strain rated from 0.01 to 0.84 (mean 0.26 ± 0.13). A total of 50 thyroid malignancies (35 papillara carcinoma, 9 medullary carcinoma, and 6 follicular carcinoma) were observed. Patients (81) were within the hard group, 35 of them (43.2%) had thyroid cancer (TC) in final histology. Out of 132 patients in the intermediate group, 15 patients had TC (11.4%). All 96 patients from the soft group showed benign histological results (NPV 100%). Seventy percent of patients with TC were within the hard group (PPV 42%). These results were highly significant (p < 0.001). Coarse calcifications and cystic nodules were not connected with reliable measurements and therefore are not suitable for USE. CONCLUSION: USE is a useful adjunctive tool in the workup of thyroid nodules. A low strain value needs surgical intervention, whereas a high strain value predicts a benign histology. It might substitute fine-needle aspiration cytology in the future.