Thyroid nodules - publication overview

Version 7 – Apr 2019 Thyroid nodules – Overview of study and research results Study & research publication Study details Study results P.S. Prajwala et al.: The Efficacy Study design Safety and Safety of High-Intensity Retrospective analysis No patients experienced local skin burns or hematomas. Mean pain scores were 1.5 (±1.2) Focused Ultrasound (HIFU) immediate post-procedure, 0.8 (±1.5) at 1 week, and 0.6 (±1.2) at 1 month post-procedure, Therapy for Benign Thyroid Number of subjects respectively, with no reports of pain beyond 1 month. Only two (20.0%) patients had early, Nodules—A Single Center included temporary posttreatment voice hoarseness. Experience from Singapore; 10 patients with 13 World Journal of Surgery; Mar thyroid nodules Efficacy 2019 Mean maximum diameter reduced from 2.6 cm (±0.8) pretreatment to 1.4 cm (±0.7, P < 0.05) 6 months posttreatment. Mean nodule volume reduced from 5.2 cm3 (±4.2) pretreatment to B. Lang et al.; Two sequential Study design 1.5 cm3 (±1.3, P = 0.01) 6 months posttreatment. Mean volume reduction ratio (VRR) at applications of high-intensity Retrospective analysis 6 months posttreatment was 63.2% (±22.5, P < 0.05), with volume reduction of ≥50% in 10 of focused ultrasound (HIFU) 13 (76.9%) nodules. ablation for large benign thyroid Number of subjects Safety nodules; European Radiology, included Fifty patients underwent ablation of a large-sized nodule (baseline volume ≥ 20 mL and Jan 2019 50 patients diameter ≤ 50 mm). Thirty-one (62.0%) patients underwent single application (group I) while 19 (38.0%) underwent two sequential applications (group II). Patients undergoing sequential application are not at greater risks of treatment-related side effects afterwards. Pain severity and rates of vocal cord palsy (VCP), skin burn, and nausea/vomiting were comparable between the two groups (p > 0.05). B. Lang et al.; High-intensity Study design Efficacy focused ultrasound (HIFU) Retrospective analysis Sequential application led to better 6-month treatment efficacy than single application in ablation of benign thyroid large-sized nodules. Total energy delivered and treatment time were significantly more in nodule is safe and efficacious in Number of subjects group II (p < 0.001 and p = 0.001, respectively). Total energy per nodule volume (kJ/mL) was patients who continue taking an included also significantly greater in group II (1.01 kJ/mL vs. 0.57 kJ/mL, p < 0.001). The 6-month VRR anti-coagulation or anti-platelet 303 patients was significantly greater in group II (56.74 ± 11.47% vs. 43.49 ± 12.03%, p = 0.004). Sequential agent in the treatment period; application was an independent determinant of 6-month VRR (OR = 13.936, 95% CI = 1.738– 197.399, p = 0.036). Safety & Efficacy Twelve patients continued taking an anti-coagulation or anti-platelet agent while the other 291 patients did not during treatment. No patients in either group suffered active thyroid bleeding, intralesional/pericapsular hematoma or subcutaneous neck bruising in the first 4 days of treatment. Complication rate and the 6-month VRR were comparable between the two groups (0.0% vs. 1.7%, p =1.000 and 55.96% vs. 61.29%, respectively, p= 0.073)

Version 7 – Apr 2019 Study design Results Retrospective analysis Although treatment-related morbidity was comparable between the two groups (P = 0.368), International Journal of treatment time (P <0.001), duration of hospitalization (P <0.001), and medical cost (P <0.001) Hyperthermia; Dec 2018 Number of subjects were less in the high-intensity focused ultrasound group. After high-intensity focused included ultrasound ablation, the 6-month nodule shrinkage (mean ± SD) was 64% ± 26% and the 6- B. Lang et al.; A propensity- 154 patients (77 treated month symptom improvement score was comparable with lobectomy (P = 0.283). At 6 matched analysis of clinical with HIFU, 77 treated months, none of the acoustic parameters were changed from the baseline in both groups (P outcomes between open with lobectomy) >0.05), and the Voice Handicap Index questionnaire did not differ between the two groups (P thyroid lobectomy and high- >0.05). intensity focused ultrasound (HIFU) ablation of benign thyroid nodules; Surgery, Nov 2018 N. Kotewall et al; High-intensity Study design Safety and efficacy were not the preliminary objective of the study. focused ultrasound ablation as a Review Results treatment for benign thyroid HIFU is a novel ablation technique that can cause effective shrinkage of thyroid nodules and disease: the present and future; Number of subjects alleviate pressure symptoms. Its main treatment indication remains benign thyroid nodules. Ultrasonography; Nov 2018 included Although the published results are promising, prospective studies with a longer follow-up N.A. period are required. Future possibilities include evaluating its role in Graves’ disease and low- risk malignant conditions, as well as exploring its synergistic effect with systemic immunotherapy. B. Lang et al.; Changes in serum Study design Safety and efficacy were not the preliminary objective of the study. thyroglobulin and Retrospective analysis Results antithyroglobulin shortly Among the 276 eligible patients, 85 (30.8%) patients were positive for anti-Tg (Group I) while following high-intensity focused Number of subjects the others (n = 191, 69.2%) were negative (Group II). Relative to group II, Group I had a less ablation of benign thyroid included significant Tg rise on Day 4 (4121.78 ± 9321.90% vs. 5711.53 ± 23487.20%, p =.013). There nodules in patients with positive 276 patients was a fall in anti-Tg on day 4 for group I (11.56 ± 139.69%). This percentage anti-Tg drop antithyroglobulin status; significantly correlated with the 6- month VRR (p = -0.602, p = 0.030) but was not a significant International Journal of factor of treatment success. Given the fact that the percentage anti-Tg drop correlated Hyperthermia; Aug 2018 significantly with 6-month nodule shrinkage in group I, monitoring early anti-Tg change may help to predict the 6-month nodule shrinkage in patients with positive anti-Tg. B. Lang et al.; Role of second Study design Safety and efficacy were not the preliminary objective of the study. high-intensity focused Retrospective analysis Safety ultrasound (HIFU) treatment for Twenty-eight patients who did not achieve 50% volume reduction at 6 months after the first unsatisfactory benign thyroid Number of subjects HIFU treatment underwent a second HIFU treatment. No complications occurred after the nodules after first treatment; included second treatment. European Radiology; July 2018 28 patients Efficacy

Version 7 – Apr 2019 Study design The mean 6-month VRR was 21.78 ± 16.87% with a median (range) of 16.16 (1.63–54.07)%. Retrospective analysis At 6 months, only two (7.1%) patients achieved treatment success, while nine (32.1%) B. Lang et al.; Two-year efficacy patients had VRR < 10%. However, relative to baseline (3.96 ± 1.04), the mean VAS of single-session high-intensity Number of subjects significantly improved at 3 and 6 months (2.96 ± 1.43, p<0.001 and 2.58 ± 1.39, p<0.001, focused ultrasound (HIFU) included respectively). There was a significant correlation between VRR and improvement in VAS score ablation of benign thyroid 108 patients with benign at 6 months (ρ=0.438, p=0.025). Greater nodule volume before the second treatment nodules; European Society of thyroid nodules, treated (OR=1.169, 95% CI=1.004–1.361, p=0.045) was a significant factor for greater VRR after the Radiology, May 2018 with single-session HIFU second treatment. Safety P. Trimboli et al.; High- Study design Three (2.8%) patients developed unilateral vocal cord paralysis (VCP) afterwards but they all intensity focused ultrasound Retrospective analysis recovered (i.e. regained normal movement) within the first 3 months. One other patient (HIFU) therapy for benign (0.9%) suffered Horner’s syndrome on the side of the treatment. Her mild ptosis improved thyroid nodules without Number of subjects gradually over a period of 6 months anesthesia or sedation; included Endocrine; Feb 2018 26 patients with benign Efficacy thyroid nodules After treatment, the mean (± SD) Volume Reduction Ratio (VRR) at 3, 6, 12 ,18 and 24 months B. Lang et al.; Sequential high were 51.32 ± 20.71%, 62.99 ± 22.05%, 68.66 ± 18.48%, 69.76 ± 17.88% and 70.41 ± 17.39%, intensity focused ultrasound Study design respectively, while the median (IQR) Visual Analogue Scale (VAS) at baseline, 6, 12 and 24 (HIFU) ablation in the Observational months was gradually lowered from 4.0 (2.0), 2.0 (1.0), 2.0 (1.0) to 1.0 (2.0), respectively. treatment of benign retrospective study Sixty-three (58.3%) nodules had a further volume reduction (i.e. >4.5%) from 12 to 24 multinodular goitre: an months, while 22 (20.4%) nodules had a volume increase of > 4.5% from 12 to 24 months. observational retrospective Number of subjects Safety included 73% of patients described good comfort during treatment, 100% experienced good comfort 123 patients just after therapy, and tolerability was high. No complications were recorded. HIFU therapy can be performed without anesthesia. Efficacy Estimated nodule volume was 2.81 ± 2.04 mL. Nodules volume was significantly (p < 0.0001) reduced at 6 months of follow-up (1.83 ± 1.63 mL), and further at 1 year (1.57 ± 1.47 mL). Mean percentage of reduction over time of nodules was 48%. At one 1 year of follow-up, 85% of subjects reported a reduction of local symptoms. HIFU therapy is effective in reducing size of thyroid nodules with major diameter below 4 cm. Safety 104 (84.6%) patients underwent single ablation of a single nodule (group I), while 19 (15.4%) underwent sequential ablation of two relatively-dominant nodules in a multinodular goitre (group II). There was comparable safety in both groups. There was no significant difference in the occurrence of VCP and skin burn in group I and II. Pain score was significantly higher in group II in the morning after ablation (2.29 vs. 1.15, p = 0.047, on a 0-10 visual analogue

Version 7 – Apr 2019 scale) and nausea/vomiting occurred significantly more frequently in group II (15.8 % vs. 0%, p = 0.012). study; European Radiology; Mar 2018 B. Lang et al.; High intensity Study design Efficacy focused ultrasound (HIFU) Review Efficacy was comparable in both groups. All 19 (100%) sequential ablations were completed ablation of benign thyroid successfully. The 3- and 6-month volume reduction ratio between the first and second nodules - a systematic review; J Number of subjects nodules were comparable (p = 0.710 and p = 0.548, respectively). Ther Ultrasound; May 2017 included Safety NA No major complications including recurrent laryngeal nerve injury, skin burn or haematoma B. Lang et al.; Evaluation of were reported in all of the studies. pain during high-intensity Study design focused ultrasound ablation of Retrospective analysis Efficacy benign thyroid nodules; The overall nodule volume reduction after single session of HIFU ablation ranged between 45 European Society of Radiology; Number of subjects and 68%, depending on nodule size and length of follow-up. Nov 2017 included Results 128 patients with benign Median (range) pain score was 65.0 (0.00–100.00). Only 16 (12.5 %) patients had a pain score B. Lang et al.; Significance of thyroid nodules of zero. In multivariate analysis, only lower BMI (OR 1.265, 95 % CI 1.102–1.452, p=0.001) hyperechoic marks observed Study design and longer nodule diameter (OR 1.462, 95% CI 1.071–1.996, p=0.017) were independent during high-intensity focused Retrospective analysis factors for pain score ≤ 65.0. ultrasound (HIFU) ablation of benign thyroid nodules; Number of subjects Safety and efficacy were not the preliminary objective of the study. European Society of Radiology; included Results Nov 2017 136 patients with benign Patients with hyperechoic marks (HEMs) (n=91) had significantly greater 6-month volume thyroid nodules reduction ratio (VRR) than those without HEMs (n=45) (65.76%vs. 36.76%, p<0.001). By B. Lang et al.; The percentage regression analysis, smaller nodule volume at baseline (OR 1.143,95 % CI 1.038–1.256, of serum thyroglobulin rise in Study design p=0.006) and appearance of HEMs (OR 275.44, 95 % CI 26.63–2848.98, p<0.001) were the first-week did not predict Retrospective analysis independent predictors for treatment success. the eventual success of high- intensity focused ablation Number of subjects Safety and efficacy were not the preliminary objective of the study. (HIFU) for benign thyroid included Results nodules; International Journal 105 patients with The mean % of Tg rise in the first week was not different between those with and without 6- Of Hyperthermia; Dec 2017 symptomatic benign month treatment success (368.2% vs. 1068.7%, p = 0.381). No clinical factors significantly B. Lang et al.; Vocal cord thyroid nodules correlated with treatment success. paresis following single-session Study design Retrospective analysis Safety and efficacy were not the preliminary objective of the study. Safety

Version 7 – Apr 2019 Number of subjects Four (3.9%) patients suffered from a unilateral vocal cord paralysis (VCP) afterwards but they included all recovered fully within 6 weeks. The distance from tracheoesophageal groove (TEG) was high intensity focused ablation 103 patients with the only significant factor for VCP. None of the other variables including thermal power were (HIFU) treatment of benign symptomatic benign significant. The safe distance between focus point and TEG should be ≥1.1 cm. thyroid nodules: incidence thyroid nodules and risk factors; International Efficacy Journal Of Hyperthermia; 2017 Not part of the analysis Safety B. Lang et al.; The efficacy and Study design Complications were uncommon, but temporary vocal cord palsy occurred in 3-4% of patients. safety of high-intensity focused Review All complications resolved fully within the first 6 weeks after treatment. ultrasound ablation of benign thyroid nodules, Number of subjects Efficacy Ultrasonography, Oct 2017 included The extent of nodule shrinkage following treatment ranged from 48.8-68.8%. The shrinkage NA was greatest in the first 3-6 months. Safety Korkusuz Y et al; Thermal Study design None of the examined ablation techniques caused serious or permanent complications. With ablation of thyroid nodules: are Monocentric, HIFU treatment, no haematomas occurred and no surrounding structures were injured. radiofrequency ablation, comparative study microwave ablation and high Efficacy intensity focused ultrasound Number of subject RFA showed a significant volume reduction of nodules of 50 % (p<0.05), MWA of 44 % equally safe and effective included (p<0.05) and HIFU of 48 % (p<0.05) three months after ablation. For HIFU, With a median methods?; Eur Radiol (2017) 94 subjects with 118 post-ablative volume after three months being 1.6 ml (range 0.1 ml to 3.5 ml), the median benign, symptomatic volume reduction amounted to 49 % (range 12 % to 77 %). B. Lang et al; Single-session thyroid nodules Safety High Intensity Focused Study design Serum TSH at 6-month did not significantly change from baseline in either group I (p=0.246), Ultrasound (HIFU) Treatment in Retrospective analysis II (p=0.138) or III (p=0.556). Large-sized Benign Thyroid Nodules; Thyroid, March 2017 Number of subject Efficacy included Seventy-three nodules were treated successfully and followed for ≥6 months. The overall 75 subjects median six-month volume reduction was 68.3% (range 22.77-96.50%). Pre-ablation nodule volume >30 mL (odds ratio = 7.813 [confidence interval 1.908-32.258]; p = 0.004) and lower B. Lang et al.; Single-session Study design total energy per nodule volume (odds ratio = 3.313 [confidence interval 1.113-9.688]; high intensity focused ablation Retrospective analysis p = 0.029) were significant factors for less ablation success. (HIFU) versus open cervical Safety hemithyroidectomy for benign Number of subject No patients suffered skin burn. Redness and swelling were noted in 13 (30.0%) patients but thyroid nodule: analysis on included they all resolved in the first week. The incidence of subclinical hypothyroidism was early efficacy, safety and voice 146 subjects included significantly higher in the surgical group than the HIFU group (20.4% vs. 2.3%, p = 0.008), but hypothyroidism (low serum FT4) was not detected within the first 6 months in both groups.

Version 7 – Apr 2019 Study design Efficacy Prospective study Altogether, 43 patients had HIFU and 103 patients had a hemithyroidectomy. In the HIFU quality; International Journal of group, the extent of nodule shrinkage at 6-month was 51.71 ± 16.04%. The HIFU group had a Hyperthermia; 2017 Number of subject significantly shorter length of hospital stay (0.3 vs. 1.0 day, p < 0.001), lower incidence of included subclinical hypothyroidism (1/43 vs. 21/103, p = 0.008), higher symptom improvement score RD. Kovatcheva et al. ; Benign 20 euthyroid patients (p = 0.009) and was less costly (USD 1923.1 vs. USD 5384.6). Relative to HIFU, pitch quality Solid Thyroid Nodules: US- with a benign solitary or also worsen after surgery (p < 0.05). guided High-Intensity dominant thyroid nodule Safety Focused Ultrasound Ablation: Study design Minor transient complications (e.g., subcutaneous edema, mild skin redness) were observed Initial Clinical Outcomes; Open label study in two patients. Radiology. Aug 2015 Number of subject Efficacy H. Korkusuz et al.; Volume included Nodule volume had decreased to 3.05 mL ± 1.96 at the 3-month follow-up examination (n = reduction of benign thyroid 10 subjects with at least 20, P < .001), and reached 2.91 mL ± 2.43 by the 6-month follow-up examination (n = 16, P < nodules 3 months after a single 1 symptomatic benign .001). By then, the mean volume reduction was 48.7% ± 24.3 (P < .001). treatment with high-intensity thyroid nodule Safety focused ultrasound No major complications such as vocal cord palsy; tracheal, vagal or oesophageal injuries; (HIFU); Journal of Therapeutic Study design infections; or nodule rupture were observed. All minor complications resolved within days Ultrasound (2015) 3:4 Retrospective analysis of without needing any treatment. During the next 3 months, no further complications were data generated in a observed. Informal reports indicate that acceptance of treatment amongst patients was very Sennert M et al.; Further single-arm, open-label, good. Investigation on High intensity baseline-controlled focused ultrasound (HIFU) study Efficacy treatment of thyroid nodules: Median nodular volume reduction was 0.7 ml absolute and 48.8% relative to pre- Effectiveness Related to Number of subject interventional size (p < 0.05). Absolute shrinkage was negatively correlated with the average Baseline Volumes; Acad Radiol included treatment depth (τ = −0.61, p < 0.05). Absolute nodular volume was positively correlated with (2017) 15 subjects with 19 the scintigraphic nodular uptake reduction (τ = 0.66, p < 0.05). thyroid nodules Safety Not part of the analysis Efficacy The median percentage volume reduction of all 19 nodules after 3 months was 58%. An inverse correlation between preablative nodular volume and percentage volume shrinking was found (tau = -0.46, P < .05). Therapeutic success was achieved in 10 out of 19 patients (53%).

Version 7 – Apr 2019 Study design Safety Prospective study Pain was most severe during ablation (median, 3.5; IQR, 4.0) but improved immediately after B. Lang et al.; High-Intensity ablation (median, 1.0; IQR, 1.0). At discharge, the pain score fell to almost zero (median, 0; Focused Ultrasound for Number of subject IQR, 1.0). Only three (13.6%) patients had mild residual discomfort at the week 1 visit. No Treatment of Symptomatic included patients had skin burns or hoarseness. Skin redness and minor swelling were noted in 10 Benign Thyroid Nodules; 44 subjects with (45.5%) patients, but they all improved in the first week. On transcutaneous laryngeal US Radiology; 2017 symptomatic benign images, all had mobile bilateral vocal cords after ablation. thyroid nodules B. Lang et al.; High-intensity Efficacy focused ablation (HIFU) of Study design The 12-month mean volume reduction ± standard deviation in the HIFU group was significant single benign thyroid nodule Retrospective analysis (68.87% ± 15.27 [range, 47.35%-94.89%], P < .001) but not in the surveillance group (-2.11% ± rarely alters underlying thyroid 6.29 [range, -15.64% to 12.70%], P > .05). Preablation nodule volume was the only function; International Journal Number of subject determinant of ablation success (odds ratio, 1.877; 95% confidence interval [CI]: 1.085, 3.249; of Hyperthermia; 2017 included P = .024). At 12 months, patients in the HIFU group had less swelling (P < .001), lower 83 subjects with pressure symptom scores (P < .001), and higher physical composite scores (P = .006). Physical H. Korkusuz et al.; Localized symptomatic benign composite scores significantly correlated with 6-month reduction in nodule size (r = 0.768; thyroid tissue ablation by high thyroid nodules 95% CI: 0.660, 0.930; P < .001) and 12-month reduction in nodule size (r = 0.704; 95% CI: intensity focused ultrasound: 0.680, 940; P < .001) Volume reduction, effects on Study design Safety thyroid function and immune Single-arm, open-label, No patients developed hyperthyroidism while one (1.4%) developed hypothyroidism response; Rofo. (2015) baseline control study (FT4 = 11 pmol/L) at 3 months and 6 months. Interestingly, this patient had a previous Nov;187(11):1011-1015 lobectomy and an ablation volume ratio of 64.00%. Number of subject included Efficacy 12 subjects with a single Relative to baseline, 1-week serum TSH significantly dropped (from 1.16 to 0.76 benign thyroid nodule mIU/L, p < 0.001) while 1-week serum FT4 significantly rose (from 16.0 to 17.8 pmol/L, p < 0.001). However, 3- and 6-months TSH and FT4 did not changed significantly from baseline (p > 0.05). Safety HIFU treatment sessions were completed successfully for all twelve patients. All patients tolerated the treatment and interruption was not necessary. Efficacy All measured hormone levels were within normal ranges and remained stable (p > 0.05). No clinically meaningful immune reaction was induced (p > 0.05). Thyroglobulin serum levels increased significantly at 24 hours after ablation (p < 0.05) and decreased significantly at the 3-month follow-up (p < 0.05), returning to pre-ablative levels. The median reduction in nodular outline volume (NOV) was 55 % (p < 0.05).

Version 7 – Apr 2019 Study design Safety Open label study No major complications were observed. Subjective pain levels during pulse emission were H. Korkusuz et al.; Early moderate, but almost neglectable directly after treatment in most cases. One day assessment of high-intensity Number of subject postintervention, some patients developed slight erythrodermia and swelling in the treated focused ultrasound treatment included region, presumably due to the consistent cooling during the ablation as well as a localized of benign thyroid nodules by 10 subject with one immunological reaction to the ablated tissue. scintigraphic means; Journal of target benign thyroid Therapeutic Ultrasound 2014, nodule Efficacy 2:18, 2014 Relative nodular uptake in relation to total thyroidal uptake decreased after one session of HIFU in all cases. Median 99mTc-MIBI uptake reduction was 35.5% (ranging from 11% to 57%; H. Korkusuz et al.; Local Study design p < 0.1), while 99mTc-pertechnetate scintigraphy showed a median uptake reduction of 27% thyroid tissue ablation by high- Not communicated (range 10% to 44%; p < 0.1). No major complications were observed. intensity focused ultrasound: Safety Effects on thyroid function and Number of subject There were no serious adverse events such as infection, nodule rupture, secondary first human feasibility study included haemorrhage, hypoparathyroidism, voice change or injuries of the vagal or recurrent with hot and cold thyroid 10 subjects with one laryngeal nerve. In the post therapeutic observation period no other complications were nodules; International Journal thyroid nodule each observed. of Hyperthermia, Early Online: 1–6, 2014 Efficacy The HIFU treatment did not affect thyroid function, since hormone levels stayed stable RD. Kovatcheva et al.; High- Study design (p < 0.05). No serious immune reaction was induced. Thyroglobulin serum levels increased intensity focused ultrasound Review of existing significantly (p < 0.05) and were correlated to the total energy emitted by HIFU (p < 0.1). The for thyroid nodule ablation: the literature results of complex thyroid nodules did not differ from solid thyroid nodules. Similarly, the evidence to date; Reports in results of hot thyroid nodules did not differ from cold thyroid nodules. Medical Imaging. 2017:10 9–16 Number of subject Safety included The reported side effects of HIFU ablation have not been serious and major complications are NA uncommon. Burning pain is the most common complaint during the procedure, but it appears in the last 2–3 seconds of HIFU pulse and is usually tolerated by the patients. Most Esnault O et al.; High-Intensity Study design of the authors reported mild skin redness and subcutaneous edema that spontaneously Focused Ultrasound Ablation of disappeared few days after the treatment. Compared with surgery or other nonsurgical methods, fewer side effects are observed in HIFU-treated patients. Efficacy Despite different approach and study design, US-guided HIFU technique has demonstrated 48.7% efficacy in nodule volume reduction at 6 months, which is comparable with the other ablative therapies. Safety

Version 7 – Apr 2019 Open, single-centre, The most frequent adverse events were local pain, mild skin burns, and cough; during feasibility study treatment, local pain occurred in nine patients, mild skin burns appeared in seven patients, Thyroid Nodules: First Human and cough appeared in two patients. Out of the 25 treated patients, 3 were discontinued for Feasibility Study; Thyroid, Number of subject pain or skin micro-blister. Thus, these were excluded from the efficacy analysis. Volume 21, Number 9, 2011 included 25 subjects Efficacy O. Esnault et al.; Minimally Among the remaining 22 patients, 16 showed significant changes by ultrasound. At Invasive Ablation of a Toxic Study design pathological analysis, the extent of nodule destruction ranged from 2% to 80%. Five out of 22 Thyroid Nodule by High- Case report patients had over 20% pathological lesions unmistakably attributed to HIFU. Seventeen cases Intensity Focused had putative lesions including nonspecific necrosis, hemorrhage, nodule detachment, Ultrasound; AJNR Am J Number of subject cavitations, and cysts. Among these 17 cases, 12 had both ultrasound changes and cavitation Neuroradiol (2010) included at histology that may be expected for an HIFU effect. In the last three patients ablated at the 1 subject with a AFTN highest energy level, significant ultrasound changes and complete coagulative necrosis were Esnault O et al.; High-Intensity (autonomously observed in 80%, 78%, and 58% of the targeted area, respectively. Focused Ultrasound (Hifu) functioning thyroid Safety Treatment For Thyroid nodule) Treatment was well tolerated. The patient subjectively assessed his pain as 25 on a visual Nodules: Experimental And analog scale of 0–100. Neither blistering nor vocal cord palsy was observed. There was no First Clinical Study design clinical or biologic exacerbation of hyperthyroidism. Studies ;proceedings ISTU 2006 Feasibility study Efficacy Esnault O et al.; Localized Number of subject Two weeks after treatment, the nodule had become cystic. Biologic euthyroidism was ablation of thyroid tissue by included achieved at 3 months (TSH, 1.91 mIU/L) and was maintained at 6, 12, and 18 months. At 12 high-intensity focused 25 subjects with and 18 months, the treated nodule was barely seen as a nonvascularized hypoechoic scar of ultrasound: improvement of indication to thyroid 1.4 1.6 mm. Thyroid scintigraphy showed a recovery of the thyroid iodine uptake. noninvasive tissue necrosis surgery for multinodular Safety and feasibility methods; Thyroid, 2009 goiter There was no significant side effect caused by the HIFU treatment, particularly no Study design affect to the recurrent nerves or to the trachea. The histological lesions were clearly visible in Preclinical feasibility most of the fully treated patients, particularly those who received higher energy. Superficial study and reversible skin blisters were observed in 7 patients. The design of the treatment head was subsequently modified to eliminate such risk. Number of subject included Safety and feasibility Three series of experiments were conducted: thyroid lesion experiments (10 ewes), safety experiments (4 ewes), and reproducibility experiments (13 ewes). The results obtained in the ewe model show that thyroid lesions with a defined volume can be induced safely and suggest that the HIFU device is now ready for evaluation in humans.

Version 7 – Apr 2019 NA Safety and feasibility Study design No damage to the nerves, trachea, esophagus or muscle was observed. Only 3 ewes suffered Esnault O et al.; Localized Preclinical feasibility superficial skin burns. The desired thyroid lesions were obtained in 25/26 treated lobes, as Ablation of Thyroid Tissue by study demonstrated by fibrotic tissues, which replaced necrotic areas. These results obtained in the High-Intensity Focused ewe model show that thyroid lesions of defined volume can be induced safely and suggest Ultrasound: an Alternative to Number of subject that the HIFU device is now ready for human trials. Surgery? ;proceedings ISTU included 2005 NA

Version 7 – Apr 2019 Graves’ Disease – Overview of study and research results Study & research publication Study details Study results Lang et al.; Single-Session High- Study design Safety Intensity Focused Ultrasound Prospective study One patient (3.3%; 95% CI: 0.59%, 16.67%) experienced vocal cord palsy, while two patients Treatment for Persistent (6.7%; 95% CI: 1.85%, 21.33%) experienced Horner syndrome, but none of these conditions or Relapsed Graves’ Disease: Number of subject were permanent. No changes in gland volume, antithyroid autoantibody levels, and Preliminary Experience in a included ophthalmic parameters were found at 12-month follow-up. Prospective Study; Radiology, 30 female patients with July 2017 persistent or relapsed Efficacy Graves’ Disease The technical success rate was 96.7%. After 12 months, eight patients (26.7%; 95% confidence interval [CI]: 14.19%, 44.95%) experienced relapse. Baseline TSHR was found to have decreased significantly at 6- and 12-month follow-up (P < .001 for both). TSHR antibody (odds ratio [OR] = 1.414; 95% CI: 1.018, 1.965; P = .039) and gland volume (OR = 0.557; 95% CI: 0.353, 0.880; P = .012) were associated with 12-month relapse, with higher antibody levels conferring a higher likelihood and smaller gland volumes conferring a lower likelihood.