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Purpose: To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation. Patients and Methods: A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq–150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months. Results: Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3–4 AEs in 7 patients. Conclusions: Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

Context Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that are frequently associated with succinate dehydrogenase (SDH) germline mutations. When mutated, SDH losses its function, thus leading to succinate accumulation. Objective In this study, we evaluated serum succinate levels as a new metabolic biomarker in SDHx-related carriers. Methods Retrospective monocentric study of 88 PPGL patients (43 sporadic, 35 SDHB, 10 SDHA/C/D), 17 tumor-free familial asymptomatic carriers (13 SDHB, 4 SDHC/D), and 60 healthy controls. Clinical, biological, and imaging data were reviewed. Serum succinate levels (n = 280) were quantified by an ultra-performance liquid chromatography coupled to a tandem mass spectrometry method and correlated to SDHx mutational status, disease extension, and other biological biomarkers. Results Serum succinate levels > 7 μM allowed identification of tumor-free asymptomatic SDHB-mutated cases compared to a healthy control group (100% specificity; 85% sensitivity). At PPGL diagnosis, SDHB-mutated patients had a significantly increased median succinate level (14 μM) compared to sporadic patients (8 μM) (P Conclusions In this pilot study, we showed that serum succinate level is an oncometabolic biomarker that should be useful to identify SDHB-related carriers. Succinate levels are also a marker of metabolic tumor burden in patients with a metastatic PPGL and a potential marker of treatment response and follow-up.

Adrenocortical carcinoma (ACC) is a very rare and aggressive malignant disease. Therefore, overall survival (OS) has long been considered as the best endpoint. Yet, a unique endpoint is not optimal to take into account the heterogeneity in tumor profile and the diversification of therapeutic option. The purpose of this mini review was to describe endpoints used in the past, present and future in the field of ACC.Pubmed and Clinicaltrial.gov were used to identify relevant studies.Before year 2000 only three endpoints were regularly used: OS, recurrence-free survival (RFS) and response rate. These endpoints were used because ACC was seen as a homogeneous diseases with a high recurrence rate and low rate of long-term survival. Since 2000; along with the apparition of new class of drug, progression-free survival (PFS) has been more and more used. Other endpoints as "time to chemotherapy" or "Progression-free survival 2" were used to evaluate multimodal therapies or treatment with a delayed action. Finally, there is a hope that in the near future, quality of life along with other patient-reported outcomes may be used more frequently.While OS and PFS are currently the most used endpoints in ACC, new endpoints are needed to better take into account the challenges offered by different situations and treatment strategies.

The most frequent radioactive (RAI) refractory thyroid cancers are papillary thyroid carcinoma, followed by poorly differentiated thyroid carcinoma. They are rare and lethal. In recent years, significant therapeutic progress has been achieved.This paper offers insights on refractoriness to RAI treatment and the optimization of treatment initiation and treatment choice. Clinical trials performed with anti-angiogenic kinase inhibitors and with targeted inhibitors in patients with BRAF, RAS mutation or RET, TRK or ALK fusion are discussed.These treatments provide high response rates. Anti-angiogenic kinase inhibitors improve median progression-free-survival; however, their benefit in terms of overall survival has been shown in only few subsets of patients. Treatment sequencing is challenging; in the absence of targetable abnormality, lenvatinib should be used as first-line treatment. Options for second-line treatment include lenvatinib (if not given at first line), cabozantinib or the addition of an anti-checkpoint antibody. In patients with a targetable abnormality, specific inhibitors, might be used as first-line treatment and lenvatinib as second line or vice-versa. Further studies are needed, based on documented genomic and immunologic characteristics of the tumor to assess the potential role of combination and redifferentiation therapy.

Waterfall plot of the RECIST response

Swimmer plot of central RECIST response

Quality of Life scores

Purpose:To evaluate the efficacy and safety of dabrafenib-trametinib-131I for the treatment of radioactive iodine refractory metastatic differentiated thyroid cancer (DTC) with a BRAF p.V600E mutation.Patients and Methods:A prospective phase II trial including patients with RECIST progression within 18 months and no lesion > 3 cm. Following a baseline recombinant human (rh)TSH-stimulated diagnostic whole-body scan (dc1-WBS), dabrafenib and trametinib were given for 42 days. A second rhTSH-stimulated dc WBS (dc2-WBS) was done at day 28 and 131I (5.5 GBq–150 mCi after rhTSH) was administered at day 35. Primary endpoint was the 6-month RECIST objective response rate. In case of partial response (PR) at 6 or 12 months, a second treatment course could be given. Among 24 enrolled patients, 21 were evaluable at 6 months.Results:Abnormal 131I uptake was present on 5%, 65%, and 95% of the dc1-WBS, dc2-WBS, and post-therapy scans, respectively. At 6 months, PR was achieved in 38%, stable disease in 52%, and progressive disease (PD) in 10%. Ten patients received a second treatment course: one complete response and 6 PRs were observed at 6 months. The median progression-free survival (PFS) was not reached. The 12- and 24-month PFS were 82% and 68%, respectively. One death due to PD occurred at 24 months. Adverse events (AE) occurred in 96% of the patients, with 10 grade 3–4 AEs in 7 patients.Conclusions:Dabrafenib-trametinib is effective in BRAF p.V600E-mutated DTC patients for restoring 131I uptake with PR observed 6 months after 131I administration in 38% of the patients.

Tissue genotyping

Details of samples available for molecular analysis

Protocol inclusion and exclusion criteria

Radiological assessment

Background Prophylactic central neck dissection in clinically low-risk cT1bT2N0 papillary thyroid carcinoma is controversial, due to a large number of conflicting retrospective studies, some showing an advantage in terms of locoregional recurrence, others showing no advantage. These previous studies all show high rates of excellent response. We aim to demonstrate the non-inferiority of thyroidectomy alone as compared to total thyroidectomy with prophylactic central neck dissection in conjunction with adjuvant RAI 30 mCi with rTSH stimulation in terms of excellent response at 1 year. Trial design and methods Prospective randomized open multicenter phase III trial including patients with 11–40-mm papillary thyroid carcinoma (Bethesda VI) or suspicious cytology (Bethesda V) confirmed malignant on intra-operative frozen section analysis, with no suspicious lymph nodes on a specialized preoperative ultrasound examination. Patients will be randomized 1:1 into two groups: the reference group total thyroidectomy with bilateral prophylactic central neck dissection, and the comparator group total thyroidectomy alone. All patients will receive an ablative dose of 30mCi of radioactive iodine (RAI) within 4 months of surgery. The primary outcome is to compare the rate of excellent response at 1 year after surgery between the groups, as defined by an unstimulated serum thyroglobulin (Tg) level ≤ 0.2 ng/mL with no anti-Tg antibodies, an normal neck ultrasound and no ectopic uptake on the post-RAI scintiscan. Non-inferiority will be demonstrated if the rate of patients with excellent response at 1 year after randomization does not differ by more than 5%. Setting the significance level at 0.025 (one-sided) and a power of 80% requires a sample size of 598 patients (299 per group). Secondary outcomes are to compare Tg levels at 8 +/− 2 postoperative weeks, before RAI ablation, the rate of excellent response at 3 and 5 years, the rate of other responses at 1, 3, and 5 years (biochemical incomplete, indeterminate, and structurally incomplete responses), complications, quality of life, and cost-utility. Discussion (potential implications) If non-inferiority is demonstrated with this high-level evidence, prophylactic neck dissection will have been shown to not be necessary in clinically low-risk papillary thyroid carcinoma. Trial registration NCT 03570021. June 26,2018

Purpose Bone metastases (BM) from differentiated thyroid carcinoma (DTC) impact negatively the quality of life and the life expectancy of patients. The aim of the study was (a) to evaluate the overall survival (OS) and prognostic factors of OS and (b) to assess predictive factors of complete BM response (C-BM-R) using radioiodine treatment (RAI) either alone or in association with focal treatment modalities. Methods A total of 178 consecutive DTC patients harbouring BM, treated between 1989 and 2015, were enrolled in this retrospective study conducted in two tertiary referral centers. OS analysis was performed for the whole cohort, and only the 145 considered non-RAI refractory patients at BM diagnosis were evaluated for C-BM-R following RAI. Results The median OS from BM diagnosis was 57 months (IQR: 24–93). In multivariate analysis, OS was significantly reduced in the case of T4 stage, 18FDG uptake by the BM and RAI refractory status. Among the 145 DTC considered non-RAI refractory patients at BM diagnosis, 46 patients (31.7%) achieved a C-BM-R following RAI treatment, either alone in 32 (18%) patients or in association with focal BM treatment modalities in 14. The absence of extra-skeletal distant metastasis and of 18FDG uptake in BM were predictive for C-BM-R. Conclusions In nearly one-third of DTC patients with RAI avid BM, RAI alone or in combination with BM focal treatment can induce C-BM-R. The presence of 18FDG uptake in BM is associated with an absence of C-BM-R and with a poor OS. 18FDG PET-CT should be performed when BM is suspected.

BACKGROUND: Intraoperative neuromonitoring (IONM) in thyroid surgery requires electric stimulation of the vagus nerve to verify correct electrode placement. Classically the nerve is found deep to or in-between the common carotid artery and internal jugular vein, but previous studies have shown that the nerve can sometimes be found superficial to the vessels. Our aim was to determine the incidence of a superficial vagus nerve using ultrasound (US) and study possible clinical factors associated with an anteriorly-located vagus nerve. METHODS: Retrospective study of patients undergoing thyroid surgery (lobectomy or total thyroidectomy) with intermittent IONM. Substernal goiters, locally invasive tumors or bulky lymph nodes were excluded. The vagus nerve was identified at the level of the mid-thyroid lobe on each side on preoperative US performed by two specialized radiologists, and its location according to 6 possible positions in relationship to the common carotid artery was recorded. The anatomic variability of the vagus nerve was analyzed in relationship to patient demographics and thyroid pathology. RESULTS: Five-hundred twenty-seven patients were included. The right vagus nerve (n=522) was in-between, superficial or deep to the vessels in 92.3%, 6.1% and 1.5% and of cases, respectively, and the left vagus (n=517) in 80.2%, 18.6% and 1.2% of cases, respectively, with a statistically significant difference between right and left vagus nerves (P

Background Prophylactic central neck dissection in clinically low-risk cT1bT2N0 papillary thyroid carcinoma is controversial, due to a large number of conflicting retrospective studies, some showing an advantage in terms of locoregional recurrence, others showing no advantage. These previous studies all show high rates of excellent response. We aim to demonstrate the non inferiority of thyroidectomy alone as compared to total thyroidectomy with prophylactic central neck dissection in conjunction with adjuvant RAI 30 mCi with rTSH stimulation in terms of excellent response at 1 year. Trial Design and Methods Prospective randomized open multicenter phase III trial including patients with 11-40 mm papillary thyroid carcinoma (Bethesda VI) or suspicous cytology (Bethesda V) confirmed malginant on intraoperative frozen section analysis, with no suspicious lymph nodes on a specialized preoperative ultrasound examination. Patients will be randomized 1:1 into two groups : the reference group total thyroidectomy with bilateral prophylactic central neck dissetion, and the comparator group total thyroidectomy alone. All patients will receive an ablative dose of 30mCi of radioactive iodine (RAI) within 4 months of surgery. The primary outcome is to compare the rate of excellent response at 1 year after surgery between the groups, as defined by an unstimulated serum thyroglobulin (Tg) level ≤ 0.2 ng/mL with no anti-Tg antibodies, an normal neck ultrasound and no ectopic uptake on the post-RAI scintiscan. Non-inferiority will be demonstrated if the rate of patients with excellent response at 1 year after randomization does not differ by more than 5%. Setting the significance level at 0.025 (one-sided) and a power of 80% requires a sample size of 598 patients (299 per group). Secondary outcomes are to compare Tg levels at 8 +/- 2 postoperative weeks, before RAI ablation, the rate of excellent response at 3 and 5 years, the rate of other responses at 1, 3 and 5 years (biochemical incomplete, indeterminate and structurally incomplete responses), complications, quality of life and cost-utility. Discussion (potential implications) If non-inferiority is demonstrated with this high-level evidence, prophylactic neck dissection will have been shown to not be necessary in clinically low risk papillary thyroid carcinoma. Trial Registration : NCT 03570021

Thyroid cancer runs the gamut from indolent micropapillary carcinoma to highly aggressive metastatic disease. Today, using prognostic algorithms, treatment and follow-up can be tailored to each patient in order to decrease overtreatment and over-medicalization of indolent disease. Active surveillance of papillary thyroid carcinoma less than 1cm avoids surgery and thyroid hormone replacement in a large proportion of patient whose tumors remain stable for years. Total thyroidectomy, once a dogma in the treatment of all thyroid cancer, is being supplanted by thyroid lobectomy for low-risk cancers, thereby decreasing the surgical risks involved and improving patients' quality of life. Indications for prophylactic central neck dissection, once mandatory, are now being adapted to the risk of cancer recurrence. Radioactive iodine therapy, also previously mandatory for all, is now only employed according to risk factors and expected outcomes. Follow-up is also being tailored to risk factors for recurrence, with less frequent visits and less use of ultrasound and scintigraphy. For more advanced disease, molecular therapies tailored to somatic mutations are opening opportunities for redifferentiation of aggressive tumors which become amenable to radioactive iodine therapy which carries fewer side effects than other systemic therapies. These advances in the management of thyroid cancer with a personalized approach and de-escalation of treatment and follow-up are improving the way we treat thyroid cancer, avoiding overtreatment and improving patients' quality of life.

Introduction Multikinase inhibitor (MKI) treatments have shown efficacy in progressive radioiodine refractory thyroid cancers (RAIR-TC), but most patients experienced substantial adverse effects. This randomised multicentric study investigated intermittent versus continuous pazopanib administration. Patients and methods The PAZOTHYR study included RAIR-TC patients with progressive disease in the last 12 months, who may have received one prior MKI. RAIR-TC patients received pazopanib for 6 months, and patients with stable disease or tumour response were randomly assigned (1:1) to receive continuous (CP) or intermittent (IP) pazopanib until progression. The primary end-point was time to treatment failure (TTF) defined as the time from randomisation to permanent discontinuation of pazopanib, due to any cause. One hundred randomised patients were needed to demonstrate an increase from 50% (CP) to 70% (IP) (hazard ratio (HR) 0.515, 80% power) in the rate of patients still under treatment 6 months (6m-SuT) post-randomisation. Secondary end-points included the overall response rate (ORR), progression-free survival (PFS) under pazopanib and safety. Results RAIR-TC patients (168) enrolled from June 18, 2013 to January 16, 2018, received 6-month pazopanib treatment and showed 35.6% (95% CI 28.2–43.6) best response rate and 89.4% (83.5–93.7) disease control rate. One hundred patients were randomised (IP:50; CP:50). With a median follow-up of 31.3 months, median TTF was not statistically different between arms (IP:14.7, 95% confidence interval (CI) 9.3–17.4; CP:11.9, 95% CI 7.5–15.6) months (HR 0.79, 0.49–1.27). 6m-SuT rates were similar (IP:80% 66.0–88.7%; CP:78% 63.8–87.2%). Median PFS under pazopanib were not statistically different (IP:5.7 4.8–7.8; CP: 9.2 7.3–11.1) months (HR 1.36, 0.88–2.12). Pazopanib-related adverse events grade 3–4 occurred in 36 (IP: 19, 38%; CP: 17, 34%) randomised patients. Seven pazopanib-related deaths occurred. Conclusions Intermittent administration of pazopanib did not demonstrate significant superiority in efficacy or tolerance compared with continuous treatment. An intermittent administration scheme cannot be recommended outside clinical trials. This study was registered with ClinicalTrial.gov , number NCT01813136 .

Objective The presence of extrathyroidal extension (ETE) is generally considered as an indication for total thyroidectomy for differentiated thyroid cancer. The accuracy of neck ultrasound for the diagnosis of ETE is controversial. The aim of this study was to assess the diagnostic accuracy of preoperative ultrasound evaluation of ETE. Methods The retrospective and observational study of consecutive patients operated between 2016 and 2019 for cytologically suspicious or indeterminate thyroid nodules were analyzed. US images obtained preoperatively were retrospectively reviewed to identify signs of minimal or gross ETE. Histology was considered as the golden standard for diagnosis of ETE. The sensitivity, specificity, positive (PPV) and negative predictive values (NPV), and accuracy of US were evaluated. Results A cohort of 305 patients (75% females, median age 48 years) with 378 nodules (median size 18 mm) was studied. Seventy-five percent of the nodules (n = 228) were malignant on histology and ETE was present in 106 cases (28%): 83 minimal ETE and 23 gross ETE. Suspicion of minimal ETE on preoperative ultrasound was found in 50 (13%) with a sensitivity of 30%, a specificity of 93%, a PPV of 62% and an NPV of 78%, with an accuracy of 76%. Gross ETE on ultrasound was found in 19 (5%) nodules with a sensitivity of 78%, a specificity of 99.7% a PPV of 94.7% an NPV of 98.6% and an accuracy of 98%. Conclusions Preoperative US is very specific and accurate in diagnosing gross ETE which impacts the extent of initial surgery for thyroid cancers.

Current guidelines favor thyroid lobectomy for intrathyroidal cT1bT2cN0 papillary thyroid carcinoma. Prophylactic neck dissection (PND) is not recommended for these low-risk tumors due to the lack of high-level evidence on improvement in outcomes, but the information from PND may be used for staging. The aim of this study was to evaluate the rate of upstaging with ipsilateral PND.Retrospective study of patients with intrathyroidal unifocal cT1bT2cN0 papillary thyroid carcinoma from 2008 to 2021. All patients underwent total thyroidectomy and PND. Tumors were classified as low or intermediate risk based on the information from pathological analysis of the primary tumor and then from adding the analysis of the lymph nodes. The difference between the tumor-only and the PND-added risk staging was evaluated.Three hundred three patients (241 women, median age 45, median tumor size 17 mm) were included. Microscopic extrathyroidal extension was found in 23.4%, aggressive histology in 6.6%, vascular invasion in 29.3%, and lymph node metastases in 37.3%. One hundred ten patients (36.3%) were intermediate-risk based on the primary tumor. An additional 26 (8.6%) were upstaged to intermediate-risk based on the ipsilateral PND and 2% based on the contralateral PND. Kaplan-Meier 10-year event-free survival in tumors upstaged with ipsilateral PND was not statistically different from intermediate-risk tumors based on the primary tumor characteristics (92% versus 90.9%, Log Rank p = 0.943).Ipsilateral PND upstaged low-risk cT1bT2cN0 patients to intermediate risk in only 8.6% of cases, and contralateral PND in an additional 2%. Routinely performing PND may not be warranted.

Objective: Thyroid cancer encasing the recurrent nerve is rare, and the decision to resect or preserve the nerve is multifactorial. The objective of this study was to histopathologically analyze resected encased nerves to assess the rate of nerve invasion and risk factors. Materials and Methods: A retrospective study was carried out on consecutive patients with resection of the recurrent nerve for primary or recurrent follicular cell-derived or medullary thyroid carcinoma from 2005 to 2020. Demographics, pathology, locoregional invasion, metastases, recurrences and survival were analyzed. Slides were reviewed blindly by two specialized pathologists (AAG, RC) for diagnosis of invasion deep to the epineurium. Results: Fifty-two patients were included: 25 females; average age, 55 (range 8–87). In total, 87% percent (45/52) were follicular cell-derived with 17/45 (37.8%) aggressive variants; 13% (7/52) were medullary carcinoma. Preoperative vocal fold (VF) paralysis was present in 16/52 (30.7%). Pathologically, the nerve was invaded in 44/52 cases (85%): 82% of follicular cell-derived tumors (37/45), 88% of pediatric cases, and 100% of medullary carcinomas (7/7). Nerve invasion was observed in 11/16 (69%) with preoperative VF paralysis and 33/36 (92%) with normal VF function. Only aggressive histology was correlated with nerve invasion in follicular cell-derived tumors (p = 0.019). Conclusions: The encased nerves were pathologically invaded in 82% of follicular cell-derived tumors and in 100% of medullary carcinomas. Nerve invasion was statistically correlated with aggressive histopathological subtypes and was observed in the absence of VF paralysis in 92% of cases.

Introduction Serum calcitonin (CT) and carcinoembryonic antigen (CEA) are valuable tumour markers in patients with medullary thyroid carcinoma (MTC). Both markers most often evolve in parallel after treatment. Selpercatinib (LOXO-292) is a highly selective RET kinase inhibitor indicated in advanced RET-mutant MTC patients. Cases presentation In this study, we report two observations of RET-mutant progressive metastatic and symptomatic MTC patients who were treated with selpercatinib. Patient 1, a 61-year-old man, presented dyspnoea and diarrhoea at selpercatinib initiation with large neck lymph nodes and lung metastases. Patient 2, a 76-year-old man, had acute discomfort with flush and diarrhoea, with small but diffuse bone and liver disease. Both patients had an objective tumour response with rapid clinical improvement and RECIST 1.1 response (−90%) in patient 1. A rapid dramatic decrease in CT level was observed in both patients (−99% in both patients), while CEA levels gradually and sustainably increased after selpercatinib initiation (+207% at cycle 15 in patient 1 and + 835% at cycle 14 in patient 2). In both patients, 18FDG PET/CT did not show any abnormal uptake that could explain the CEA increase. Colonoscopy and oesogastric fibroscopy showed colonic polyposis with mild oesophagitis and gastritis in patient 1 and were normal in patient 2. Conclusion These observations show an unusual and lasting increase in serum CEA in two MTC patients who exhibited an objective tumour response to selpercatinib. The mechanism behind this unexpected rise in CEA level remains unknown. The frequency of this evolving profile will be determined in further phase III studies.

Kinase inhibitors (KI) for advanced and aggressive forms of differentiated, medullary and anaplastic thyroid carcinoma have been shown to provide significant tumor response, locally and in distant metastases. Their use, however, may also increase the risk for local complications such as fistula formation and bleeding, and head and neck surgeons may be solicited to palliatively remove potentially dangerous lesions before initiating these systemic treatments. During KI therapy for progressive metastatic and/or locally invasive disease, surgery may be urgently necessary to secure the airway or for symptomatic neck lesions. Finally, there are more and more reports of surgery following KI therapy that suggest a new neoadjuvant paradigm for extensive lesions. In this review, we aim to discuss the literature regarding surgery before, during and after KI therapy in the context of progressive metastatic and/or locally invasive thyroid cancer.

Simple Summary Neuroendocrine tumors (NET) are rare tumors, with long-term survival even for patients with liver metastases. Transarterial chemoembolization (TACE) is one of the most widely used treatments in this setting. The aim of the study was to assess the long-term efficacy of TACE in a large cohort of patients with NET liver metastases and to correlate imaging findings with survival. In our study including 202 patients with NET liver metastases and a mean follow-up of 8.2 years, TACE was effective to provide disease control for 26 months and a 5.3-year median overall survival (OS). Imaging responses using RECIST and mRECIST criteria were significantly correlated to OS: the median-OS was twice as long among mRECIST responders versus non-responders, with 80.5 months and 39.6 months respectively. These findings are of major importance for everyday practice as they confirm TACE’s effectiveness and usefulness of imaging evaluation to better tailor patient treatment and repeat TACE sessions whenever necessary. Abstract Background: transarterial chemoembolization (TACE) is an established treatment for neuroendocrine tumor (NET) liver metastases. The aim was to evaluate the long-term treatment efficacy of TACE for NET liver metastases, and correlate imaging response with survival. Methods: this IRB-approved, single-center, retrospective study evaluated all TACE procedures performed for NET liver metastases from 2003–2017 for imaging tumor response (RECIST and mRECIST), time to liver progression (TTLP), time to untreatable progression with TACE (TTUP), and overall survival (OS). Patient, tumor, and treatment characteristics were analyzed as prognostic factors. Survival curves according to the Kaplan–Meier method were compared by Log-rank test. Tumor responses according to RECIST and mRECIST were correlated with OS. Results: 555 TACE procedures were performed in 202 NET patients (38% grade 1, 60% grade 2) with primary tumors originating from pancreas, small bowel, and lung (39, 26, and 22% respectively). Median follow-up was 8.2 years (90–139 months). Median TTLP and TTUP were 19.3 months (95%CI 16.3–22.3) and 26.2 months (95%CI 22.3–33.1), respectively. Median OS was 5.3 years (95%CI 4.2–6.7), and was higher among mRECIST responders (80.5 months; 95%CI 64.6–89.8) than in non-responders (39.6 months; 95%CI = 32.8–60.2; p < 0.001). In multivariable analysis, age, tumor grade and liver involvement predicted worse OS, whereas administration of somatostatin analogs correlated with improved OS. Conclusion: TACE for NET liver metastases provides objective response and sustained local disease control rates. RECIST and mRECIST responses correlate with OS.

Functional imaging plays a central role in the management of thyroid cancer patients. In patients with a differentiated thyroid cancer (DTC), radioactive iodine (RAI) is used mostly with a therapeutic intent, either post-operatively or as the first line systemic treatment in patients with known structural disease. A whole body scan is performed a few days after the RAI administration, and this procedure is very sensitive to detect all tumor foci with RAI uptake. PET/CT with

Context Patients with adrenocortical carcinoma (ACC) are frequently on mitotane therapy for a long time period. The drug exerts adrenolytic activity requiring glucocorticoid supplementation, which can be potentially detrimental for bone. Objective To explore whether mitotane with/without chemotherapy is associated with an increased proportion of morphometric vertebral fractures (VFs) in ACC patients. Secondary objectives were proportion of patients with VF progression, or worsening of the spinal deformity index (SDI) during mitotane therapy; and to explore predictive factors of VF progression and a prognostic role of VF progression. Methods Multicenter, retrospective cohort study of patients with ACC who received mitotane alone or in association to chemotherapy, recruited from January 2010 to January 2020 in 2 reference centers in Italy and France. Results A significant increase in the frequency of VFs before and after mitotane therapy was seen both in Italian (28.3% vs 47.8%, P = .04) and French (17.8% vs 35.6%, P = .04) series. VF progression was observed in 39.1%, and 28.9% of patients, respectively. Baseline VFs and increased patient body mass index, but not the dose of cortisol supplementation, showed an independent association with VF progression at multivariate analysis. Among the 72 advanced ACC patients, progression of VFs was associated with a poorer survival. Conclusion The administration of mitotane with/without chemotherapy in ACC patients impairs bone health independently from cortisol supplementation. Appropriate preventive measures to decrease the fracture risk should be implemented in these patients.

Introduction: A taller-than-wide (TTW) shape is a suspicious feature of thyroid nodules commonly defined as an anteroposterior/transverse diameter (AP/T) ratio >1. An intraobserver variability of up to 18% in AP diameter evaluations has been described, which may lead to overreporting of this feature. To potentially improve the reliability of the TTW definition, we propose an arbitrary ratio of ≥1.2. Objective: The aim of this study was to estimate the impact of this definition on diagnostic performance. Methods: We prospectively analyzed 553 thyroid nodules referred for cytology evaluation at an academic center. Before fine-needle aspiration, two examiners jointly defined all sonographic features considered in risk stratification systems developed by the American Thyroid Association (ATA), the American Association of Clinical Endocrinologists (AACE), the American College of Radiology (ACR TIRADS), the European Thyroid Association (EU-TIRADS), and the Korean Society of Thyroid Radiology (K-TIRADS). TTW was defined according to the current definition (AP/T diameter ratio >1) and an arbitrary alternative definition (AP/T ratio >1.2). Results: The alternative definition classified fewer nodules as TTW (28, 5.1% vs. 94, 17%). The current and proposed definitions have a sensitivity of 26.2 and 11.9% (p = 0.03) and a specificity of 83.8 and 95.5% (p < 0.001). Thus, as a single feature, the arbitrary definition has a lower sensitivity and a higher specificity. When applied to sonographic risk stratification systems, however, the proposed definition would increase the number of avoided biopsies (up to 58.2% for ACR TIRADS) and the specificity of all systems, without negative impact on sensitivity or diagnostic odds ratio. Conclusions: Re-defining TTW nodules as those with an AP/T ratio ≥1.2 improves this marker’s specificity for malignancy. Using this definition in risk stratification systems will increase their specificity, reducing the number of suggested biopsies without significantly diminishing their overall diagnostic performance.

Low-risk papillary cancers, which represent the vast majority of thyroid cancers diagnosed today, do not require aggressive treatment or follow-up. Initial treatment consists of a total thyroidectomy without prophylactic lymph node dissection. A hemithyroidectomy is an alternative in some patients with an intrathyroidal tumor and with a normal contralateral lobe at pre-operative neck ultrasonography. The use of post-operative radioiodine should be restricted to selected patients. Follow-up at 6–18 months is based on serum thyroglobulin (Tg), Tg-antibody determination and neck ultrasonography. In the absence of any abnormality (excellent response to treatment), the risk of recurrence is extremely low and follow-up may consist of serum TSH monitoring that is maintained in the normal range, and a Tg and Tg-antibody titer determination every year. There is no need for referral to a specialized center. In patients with detectable serum Tg or detectable Tg antibodies, the trend over time of these markers on levothyroxine treatment will dictate subsequent follow-up: a decreasing trend is reassuring, but an increasing trend should lead to imaging, starting with neck ultrasonography.

Context Ultrasonography (US) is considered the most sensitive tool for imaging persistent or recurrent papillary thyroid cancer (PTC) in the neck. Objective To clarify the usefulness of routine neck US in low- and intermediate-risk patients with PTC with no evidence of disease 1 year after thyroidectomy. Design Retrospective analysis of prospectively recorded data. Setting Academic center. Patients Two hundred twenty-six patients with PTC with sonographically normal neck lymph nodes and unstimulated serum thyroglobulin (Tg) levels that were either undetectable ( Interventions Yearly assessment: unstimulated serum Tg level, anti-Tg-antibody (TgAb) titer, TSH levels, and ultrasound examination of neck lymph nodes. Main Outcome Measures Rates of ultrasonographic lymph node abnormalities at the 3-year and last follow-up visits. Results In patients with an undetectable Tg level at the 1-year evaluation, sonographically suspicious neck lymph nodes were found in 1.2% of patients at 3 years and in 1.8% at the last visit [negative predictive values (NPVs) of 1-year Tg < 0.2 ng/mL: 98.8% (95% CI 95.8% to 99.9%) and 98.2% (95% to 99.6%), respectively]. Similar NPVs emerged for low detectable 1-year Tg levels [98.2% (90.3% to 99.9%) and 94.5% (84.9% to 98.9%) at the 3-year and last visits, respectively]. Seventy-five percent of the nodal lesions were likely false positive; none required treatment. Conclusions Low- and intermediate-risk patients with PTC with negative ultrasound findings and unstimulated Tg levels

Radioiodine treatment (RAI) represents the most widespread and effective therapy for differentiated thyroid cancer (DTC). RAI goals encompass ablative (destruction of thyroid remnants, to enhance thyroglobulin predictive value), adjuvant (destruction of microscopic disease to reduce recurrences), and therapeutic (in case of macroscopic iodine avid lesions) purposes, but its use has evolved over time. Randomized trial results have enabled the refinement of RAI indications, moving from a standardized practice to a tailored approach. In most cases, low-risk patients may safely avoid RAI, but where necessary, a simplified protocol, based on lower iodine activities and human recombinant TSH preparation, proved to be just as effective, reducing overtreatment or useless impairment of quality of life. In pediatric DTC, RAI treatments may allow tumor healing even at the advanced stages. Finally, new challenges have arisen with the advancement in redifferentiation protocols, through which RAI still represents a leading therapy, even in former iodine refractory cases. RAI therapy is usually well-tolerated at low activities rates, but some concerns exist concerning higher cumulative doses and long-term outcomes. Despite these achievements, several issues still need to be addressed in terms of RAI indications and protocols, heading toward the RAI strategy of the future.

Context European and French guidelines for ENSAT stage IV low tumor burden or indolent adrenocortical carcinoma (ACC) recommend a combination of mitotane and locoregional treatments (LRT) as first-line treatment. Nevertheless, the benefit of LRT in combination with mitotane has never been evaluated in this selected group of patients. Objective This work aimed to evaluate the therapeutic strategy of LRT combined with mitotane in patients with low tumor burden stage IVA ACC. Methods A retrospective chart review was performed from 2003 to 2018 of patients with stage IV ACC with 2 or fewer tumoral organs who received mitotane in our center. The primary end point was the delay between mitotane initiation and first systemic chemotherapy. Secondary end points were progression-free survival (PFS) and overall survival (OS) from mitotane initiation. Adjusted analyses were performed on the main prognostic factors. Results Out of 79 included patients, 48 (61%) patients were female and the median age at stage IVA diagnosis was 49.8 years (interquartile range [IQR], 38.8-60.0 years). Metastatic sites were mainly lungs (76%) and liver (48%). Fifty-eight (73%) patients received LRT including adrenal bed radiotherapy (14 patients, 18%), surgery (37 patients, 47%), and/or interventional radiology (35 patients, 44%). Median time between mitotane initiation and first chemotherapy administration was 9 months (IQR, 4-18 months). Median PFS1 (first tumor-progression) was 6.0 months (95% CI, 4.5-8.6). Median OS was 46 months (95% CI, 41-68). PFS1, PFS2, and OS were statistically longer in the mitotane plus LRT group compared to the mitotane-only group (hazard ratio [HR] = 0.39; 95% CI, 0.22-0.68; HR = 0.35; 95% CI, 0.20-0.63; and HR = 0.27; 95% CI, 0.14-0.50, respectively). Ten (13%) patients achieved complete response (CR), all from the mitotane plus LRT group. Conclusion Our results endorse European and French guidelines for stage IV ACC with 2 or fewer tumor organs and favor the combination of mitotane and LRT as first-line treatment. For the first time, a significant number of CRs were observed. Prospective studies are expected to confirm these findings.

4596 Background: In advanced ACC, no significant progress has been made since introduction of mitotane and cisplatin-based therapy. EO2401 (EO) was designed to activate existing commensal memory T cells cross-reacting with tumor associated antigens (TAAs). EO includes microbial-derived, synthetically produced peptides corresponding to HLA-A2 restricted epitopes with molecular mimicry to three TAAs upregulated in ACC, IL13Rα2, BIRC5 and FOXM1, with the CD4 helper peptide UCP2 and the adjuvant Montanide. Pre-clinically EO generates strong immune responses and cross-reactive CD8 cells recognizing the TAAs. Methods: This Phase 1/2 trial (NCT04187404) investigated EO + nivolumab (N) (EO + N = EN) in pts with ACC. Cohort 1 lead-in established safety of EN. Cohort 2 includes pts with metastatic ACC, with (C2a), or without (C2b) prior systemic therapy. EN was given 4 times q2 w, followed by boosters q4 w until PD (iRECIST). Results: 33 pts with ACC started study treatment: C2a 26 pts (58% 1; 42% 2 prior lines), C2b 7 pts. Median age 47; 24% men; ECOG 0/52%, 1/42%, 2/6%; 61% ≥2 organs involved by metastases (61% liver, 76% lung). EN was well tolerated. The combination safety profile was consistent with the profile of N monotherapy except for higher local administration site reactions (any erythema/pain/induration in 35% of pts). Overall (n = 33), best RECIST response was PR 12%, SD 24%, PD 45%, NE 18%; median PFS was 1.9 mo (range 0.4-7.6+); median survival not reached, and survival rate at 6-mo 63% (median FU 4.9 mo, range 0.9-12.0). Strong CD8 T cell ELISPOT responses against the vaccine peptides (9/9 pts) and cross-reactivity against targeted TAAs (8/8 evaluable pts) was observed. Tetramer staining of specific CD8 cells for all 3 peptides was detected in 7/8 tested. When investigated, positive staining against BIRC5 was detected as early as 4 w after the first vaccination. In C2a, a group of pts (n = 10) with SD at the first CT (incl. 4 pts with PR) seemed to fare well; all investigated tumor samples in this group showed a low level of TMB, low MSI, and low PDL1 expression. In contrast, 10 pts had PD < 2mo and died < 6mo. There was no correlation between clinical benefit and a large panel of cytokines/chemokines. However, post-hoc analysis identified several clinical factors (prior mitotane, ECOG ≤ 1, ACC 1st diagnosis > 9 mo, max lesion ≤125 mm, ≤3 organs involved, lymphocytes ≤ grade 1) that excluded 90% of pts without benefit to EN. In the post-hoc selected group (n = 14) with median FU 6.9 mo (12 pts censored) the DCR was 64% (4 PR, 5 SD), 6-mo PFS was 42% and 6-mo survival rate 93%. Conclusions: EO2401 in combination with nivolumab was well tolerated and induced a specific immune response in all tested pts. In addition, efficacy was seen in a subpopulation of pts with ACC defined by clinical parameters in a post-hoc analysis. A randomized phase 2 study based on the findings of Cohort 2a is being planned. Clinical trial information: NCT04187404.

Advanced adrenocortical carcinoma (ACC) has poor but heterogeneous prognosis. Apart from Ki67 index, no prognostic or predictive biomarker has been validated in advanced ACC, so far. We aimed at analyzing expression of a large panel of proteins involved in known altered pathways in ACC (cell cycle, Wnt/ß-catenin, methylation) to identify and prioritize potential prognostic or predictive parameters metastatic ACC population. We conducted a retrospective multicentric study. Overall survival (OS) and partial response according to RECIST 1.1 were primary endpoints. TMA was set up and 16 markers were analyzed. Modified ENSAT and GRAS parameters were characterized for prognostic adjustment. Results: We included 66 patients with a mean age at metastatic diagnosis of 48.7 ± 15.5 years. Median survival was 27.8 months. After adjustment to mENSAT-GRAS parameters, p53 and PDxK were prognostic of OS. No potential biomarker has been identified as predictive factor of response. We identified for the first time P53 as an independent prognostic marker of metastatic adrenocortical carcinoma after mENSAT-GRAS parameter adjustment. Prognostic impact of Wnt/ß-catenin alterations was not confirmed in this cohort of metastatic ACC.

Ultrasonography (US) is the most accurate tool for exploring cervical lymph nodes for persistent/recurrent lesions in patients with papillary thyroid cancers (PTCs). Certain features are highly informative (the sole presence of punctuate hyperechogenicity or a cystic appearance, which predicts PTC involvement with an accuracy of 100 %; visualization of the lymph node “fatty” hilum, which virtually excludes malignancy). Other findings, such as nonvisualization of the hilum or a round rather than oval shape, are considered diagnostically indeterminate because of their limited specificity. The suspicious node’s location, the patient’s estimated risk of recurrence, and serum Tg levels are important considerations as well. Confirmation of metastatic involvement is usually based on cytological assessment of a fine-needle aspirate, but even in experienced hands, cytology can yield false-negative results (6–8 % of cases), and up to 10 % of aspirates are inadequate for diagnosis. The diagnostic yield can be enhanced by immunometric assay of Tg levels and/or PCR-based assay of transcript levels for thyroid-specific genes (Tg, TSHR) in washout fluid from the needle used to collect the cytology aspirate. The former can accurately identify PTC lymph node metastases (sensitivity, 88–100 %; specificity, 69–100 %), even in the presence of circulating Tg antibodies. Thanks to the use of PCR amplification, the genetic approach can correctly identify metastases from PTCs, even when the washout fluid contains only a few cells, and its accuracy vs. histology is 100 %.

Context Current guidelines recommend a selective use of radioiodine treatment (RAI) for papillary thyroid cancer (PTC). Objective This work aimed to determine how policy changes affect the use of RAI and the short-term outcomes of patients. Methods A retrospective analysis of longitudinal data was conducted in an academic referral center of patients with nonaggressive PTC variants; no extrathyroidal invasion or limited to soft tissues, no distant metastases, and 5 or fewer central-compartment cervical lymph node metastases. In cohort 1, standard treatments were total thyroidectomy and RAI (May 2005-June 2011); in cohort 2 decisions on RAI were deferred for approximately 12 months after surgery (July 2011-December 2018). Propensity score matching was used to adjust for sex, age, tumor size, lymph node status, and extrathyroidal extension. Intervention included immediate RAI or deferred choice. Main outcome measures were responses to initial treatment during 3 or more years of follow-up. Results In cohort 1, RAI was performed in 50 of 116 patients (51.7%), whereas in cohort 2, it was far less frequent: immediately in 10 of 156 (6.4%), and in 3 more patients after the first follow-up data. The frequencies of structural incomplete response were low (1%-3%), and there were no differences between the 2 cohorts at any follow-up visit. Cohort 2 patients had higher rates of “gray-zone responses” (biochemical incomplete or indeterminate response). Conclusion Selective use of RAI increases the rate of patients with “uncertain” status during early follow-up. The rate of structural incomplete responses remains low regardless of whether RAI is used immediately. Patients should be made aware of the advantages and drawbacks of omitting RAI.

Anaplastic thyroid cancer (ATC) is a rare lethal disease. Lenvatinib is an off-label therapeutic option for ATC in most countries, except in Japan. The aim of this multicenter retrospective survey was to analyze the efficacy and the toxicity profile of off-label lenvatinib treatment in all adults advanced ATC patients, in France. Of the 23 patients analysed (14 males; mean age 64 years), 15 were pure ATC and 8 were mixed tumors (i.e. with a differentiated or poorly differentiated component). Prior treatments included neck external beam irradiation in 74%, at least one line of chemotherapy in 22 cases, two lines of chemotherapy in 11 patients, other TKI in 4 cases. A central RECIST assessment was performed. Since lenvatinib initiation, median PFS was 2.7 months (95% CI; 1.9–3.5) and median OS was 3.1 months (95% CI; 0.6–5.5). OS was significantly longer in case of mixed tumors compared with pure ATC (6.3 vs 2.7 months, P = 0.026). Best tumor response was partial response in two cases and stable disease in seven. Clinical improvement was achieved in seven patients. Lethal adverse events occurred in three patients, consisting in haemoptysis in two cases and pneumothorax in one case. Among long-surviving ATC patients (>6 months), four underwent biopsy of distant metastasis, revealing poorly differentiated histology; three of them had initial mixed ATC histology. Efficacy of lenvatinib appears limited, although pure vs mixed ATC disclose differences in disease aggressiveness and treatment response. Long-surviving ATC patients might benefit from biopsy of persistent disease, searching for histological transition or molecular target.

Context The behavior of locally advanced pheochromocytoma (LAP) remains unknown. Objective We characterized the population with LAP and recurrence-free survival (RFS). Methods This retrospective multicentric study was run within the ENDOCAN-COMETE network and French Group of Endocrine Tumors (GTE) from 2003 to 2018, including patients from 11 French referral centers with LAP as defined by capsular invasion, vascular invasion, adipose tissue invasion, and/or positive locoregional lymph nodes at diagnosis without evidence of distant metastasis. The main outcome measure was recurrence, defined as tumor reappearance, including local site and/or distant metastasis. The primary endpoint was RFS analysis; secondary endpoints were characterization, overall survival (OS), and prognostic factors of recurrence. Results Among 950 patients, 90 (9%) exhibited LAP criteria and 55 met inclusion criteria (median age, 53 years; 61% males; 14% with germline mutation; 84% with catecholamine excess). LAP was defined by 31 (56%) capsular invasions, 27 (49%) fat invasions, 6 (11%) positive lymph nodes, and 22 (40%) vascular invasions. After median follow-up of 54 months (range, 6-180), 12 patients (22%) had recurrences and 3 (5%) died of metastatic disease. Median RFS was 115 months (range, 6-168). Recurrences were local in 2 patients, distant in 2, and both local and distant in 8 patients. Median OS of patients was not reached. Size above 6.5 cm (P = 0.019) and Ki-67 > 2% (P = 0.028) were identified as independent significant prognostic factors in multivariate analysis. Conclusion LAP represents 9% of pheochromocytoma’s population and has a metastatic behavior. This study paves the way for future pathological TNM classification.

Localization of the vagus nerve is required during intraoperative neuromonitoring (IONM) for thyroid surgery in order to electromyographically verify the functional integrity of inferior laryngeal nerve and aim to reduce the risk of postoperative vocal fold paralysis. Classically, the vagus nerve courses within the carotid sheath between the common carotid artery and internal jugular vein, but anatomic variations have been described. Our aim was to compare preoperative ultrasound (US) and intraoperative localization of vagus nerve and to document anatomic variations. Retrospective study of patients undergoing thyroidectomy. The vagus nerve was identified 2 cm below the inferior border of the cricoid cartilage, on US performed 6 weeks prior to surgery; then, vagus nerve was identified surgically. For 82 patients, on preoperative US, the right vagus nerve was in between, superficial, or deep to the vessels in 94%, 2.4%, and 3.6%, and on the left in 72%, 24.4%, and 3.6%. Intraoperatively, the right vagus was in between, superficial, or deep in 90%, 4%, and 6%, and on the left in 67%, 27%, and 6%. US correlated with surgery on the right in 79/82 (96%) and on the left in 78/82 (95%). To our knowledge, this is the first study directly comparing US and intraoperative findings. The US and surgical findings were identical in 95% on the left and 96% on the right The vagus nerve was superficial in 27% of cases on the left and 4% on the right. Identifying this anatomic variation preoperatively may facilitate IONM. • Localization of the vagus nerve is necessary during thyroid surgery when using neuromonitoring for electromyographic testing of the inferior laryngeal nerve to reduce the risk of postoperative vocal fold paralysis. • The vagus nerve in the neck can be routinely visualized using ultrasound, and is generally in between the common carotid artery and the internal jugular vein. Its location on ultrasound corresponds very closely to that observed in vivo during surgery (95%). • At the level of the thyroid lobe, there is an anatomic variant with the vagus nerve superficial to the common carotid artery which is seen more often on the left than on the right.

Anaplastic thyroid carcinoma (ATC) is a rare and undifferentiated form of thyroid cancer. Its prognosis is poor: the median overall survival (OS) of patients varies from 4 to 10 months after diagnosis. However, a doubling of the OS time may be possible owing to a more systematic use of molecular tests for targeted therapies and integration of fast-track dedicated care pathways for these patients in tertiary centers. The diagnostic confirmation, if needed, requires an urgent biopsy reread by an expert pathologist with additional immunohistochemical and molecular analyses. Therapeutic management, defined in multidisciplinary meetings, respecting the patient’s choice, must start within days following diagnosis. For localized disease diagnosed after primary surgical treatment, adjuvant chemo-radiotherapy is recommended. In the event of locally advanced or metastatic disease, the prognosis is very poor. Treatment should then involve chemotherapy or targeted therapy and decompressive cervical radiotherapy. Here we will review current knowledge on ATC and provide perspectives to improve the management of this deadly disease.

Over 50% of newly diagnosed thyroid nodules are either cytologically benign or presumed to be benign on the basis of low-suspicion sonographic findings. The strategies used for their long-term surveillance are based mainly on the estimated residual risk of malignancy calculated with various ultrasonographic classification systems (e.g., Thyroid Image Reporting and Data Systems [TIRADS]). We conducted a longitudinal study to evaluate the temporal stability of the initial risk estimates computed with five widely used systems and to determine whether risk class increases during follow-up are indeed predictive of malignancy.We re-analyzed data prospectively collected at a single academic referral center on 232 patients (age: 54.1 ± 13.7 years) with 432 asymptomatic, sonographically or cytologically benign thyroid nodules at baseline (T0) and 122 new nodules that were present five years later (T5). At both time points, the sonographically estimated risk of malignancy was calculated as recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi, the American College of Radiologists' TIRADS, the American Thyroid Association's 2015 practice guidelines, the European Thyroid Association's TIRADS (EU-TIRADS), and the TIRADS of the Korean Society of Thyroid Radiology (K-TIRADS).For 57 to 127 (13.2-29.4%) of the original nodules, depending on the system used, the estimated malignancy risk increased over the 5-year interval. Of the nodules whose baseline risk had not warranted cytological assessment, very few (6.3-8.3%) met the criteria for cytology at the 5-year evaluation. Biopsy was indicated for only 4 to 8 (3.3-6.6%) of the new nodules based on T5 risk estimates. Despite these changes, none of the 232 patients was ever diagnosed with a cancer.Ultrasound-based risk classes of presumably benign thyroid nodules remain fairly stable over time, and changes warranting biopsy are rare indeed. The appearance of new nodules is a frequent event, but very few (5%) are classified as high risk, and only the 3-7% meet the criteria for cytological assessment. Collectively, these findings support the view that patients with presumably benign thyroid nodules can be safely followed with less intensive protocols.

Aim of this study was to evaluate the association between body mass index (BMI) and aggressive features of differentiated thyroid cancer (DTC) in a prospective cohort. Patients with DTC were prospectively enrolled at a tertiary referral center and grouped according to their BMI. Aggressive clinic-pathological features were analyzed following the American Thyroid Association Initial Risk Stratification System score. The cohort was composed of 432 patients: 5 (1.2%) were underweight, 187 (43.3%) normal weight, 154 (35.6%) overweight, 68 (15.7%) grade 1 obese, 11 (2.5%) grade 2 obese and 7 (1.6%) grade 3 obese. No single feature of advanced thyroid cancer was more frequent in obese patients than in others. No significant correlation was found between BMI, primary tumor size (Spearman’s ρ − 0.02; p = 0.71) and ATA Initial Risk Stratification System score (ρ 0.03; p = 0.49), after adjustment for age. According to the multivariate logistic regression analysis, male gender and pre-surgical diagnosis of cancer were significant predictors of cancer with high or intermediate–high recurrence risk according to the ATA system (OR 2.06 and 2.51, respectively), while older age at diagnosis was a protective factor (OR 0.98), and BMI was not a predictor. BMI was a predictor of microscopic extrathyroidal extension only (OR 1.06). Obesity was not associated with aggressive features in this prospective, European cohort of patients with DTC.