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Background and purposeThis study aimed to investigate the factors that influence physiotherapists’ decision in choosing restorative or compensatory rehabilitation during gait training in people with neurological disorders (PwNDs) and the different treatments used in the approaches.MethodsThis cross-sectional analysis used the baseline data from an observational cohort study. We analyzed data from 83 PwNDs (65 people after stroke, 5 with multiple sclerosis, and 13 with Parkinson’s disease) who underwent at least 10 sessions of physiotherapy (PT) focusing on gait function. Performance was quantified using the modified Dynamic Gait Index (MDGI), three impairment domains of Fugl–Meyer Assessment for lower extremity (mFM-LL), Activities-specific Balance Confidence (ABC), modified Barthel Index (mBI), Mini-Mental State Examination (MMSE), and Motivational Index (MI). Forty-three physiotherapists completed a treatment report form categorizing the rehabilitation approach and specifying treatments used (e.g., resistance training and proprioceptive exercises).ResultsFifty-six subjects underwent restorative rehabilitation approach. The univariate predictors of restorative approach were being in the subacute phase with a disease onset of less than 180 days, (odds ratio [95%CI]; 3.27[1.19–9.24]), mFM-LL (1.25[1.11–1.44]), MMSE (0.85[0.67–1.00]), and number of sessions (1.03[1–1.01]). The backward stepwise analysis revealed an association between restorative and subacute phase (36.32[4.11–545.50]), mFM-LL (3.11[1.55–9.73]), mBI (1.79[1.08–3.77]), MMSE (0.46[0.25–0.71]), and the interaction between mFM-LL and mBI (0.99[0.98–1.00]). No statistically significant association between treatments used and approach was found (p = 0.46).Discussion and conclusionThe restorative approach was more commonly used to improve gait. The main variables associated with this approach were: being in the subacute phase of the disease, a low level of impairment, and a high level of functional independence at baseline. However, few differences were found between the treatments used for the restorative or compensatory approaches, as similar PT treatments were used for both.

Background: When the histological examination indicates papillary thyroid carcinoma (PTC), there is no unanimity on the need to proceed with completion thyroidectomy (CT). This study aims to assess the histologic parameters that influenced the decision to perform CT., Materials and Methods: This study included PTC patients who underwent thyroid lobectomy between 2019 and 2022. Group A included patients who underwent thyroid lobectomy without further treatments, whereas Group B included those who underwent CT based on histological findings. Differences in terms of histologic parameters were analyzed., Results: Group A included 291 patients (68.3 ​%), whereas Group B 135 patients (31.7 ​%). Multivariate analysis identified associations between CT and tumor size (p ​< ​0.001), aggressive variant (p ​= ​0.009), and vascular invasion (p ​< ​0.001). ROC curve analysis established a tumor size cut-off of 21 ​mm for CT. At ROC curve analysis, the cut-off number of aggressive factors required for CT was 2., Conclusion: A thorough comprehensive assessment encompassing all pathological characteristics might be necessary in case of PTC with aggressive histologic features after thyroid lobectomy., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest related to the research presented in this article. They have not received funding or support from organizations that may benefit from or be influenced by the research findings. Additionally, they have no affiliations or financial interests with companies or entities that may have a direct interest in the discussed research. The authors confirm that this work was conducted independently and that the opinions and conclusions expressed are solely based on the presented data and analysis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The impact of obesity on outcomes after adrenalectomy for pheochromocytoma is unclear. This study aims to evaluate outcomes after minimally invasive and open adrenalectomy for pheochromocytoma in patients with obesity and to determine factors that may affect outcomes. Patients undergoing adrenalectomy for pheochromocytoma in 46 international centers between 2012 and 2022 were reviewed, analyzing baseline information, length of hospital stay (LOS), and postoperative complications., Patients and Methods: Obese (body mass index (BMI) ≥ 30 kg/m 2 ) and nonobese patients were compared. Multivariable analysis was utilized to evaluate outcomes and risk factors for complications, LOS, and increased comprehensive complication index (CCI)., Results: Of the 2016 patients, 639 (31.7%) had obesity. Operative time (110.0 versus 105.0 min; p = 0.467), conversion to open rate (3.1% versus 4.7%; p = 0.079), estimated blood loss (20.0 versus 20.0 ml, p = 0.088), rate of complications (19.3% versus 20.8%; p = 0.425), and CCI were similar. However, patients with obesity required a median of 1 day longer LOS (4.0 days versus 5.0 days; p < 0.001). On multivariable analysis, obesity was not significantly associated with complications or higher CCI. Analyzing solely obese patients, laparoscopic (OR 0.24; p < 0.001) and robotic (OR 0.22; p = 0.011) approaches were independently associated with less morbidity. Additionally, multivariable modeling demonstrated that a retroperitoneal approach in patients with BMI ≥ 30 kg/m 2 was independently associated with reduced CCI (- 3.74; p = 0.017). Similar results were demonstrated when analyzing severe obesity (BMI ≥ 35)., Conclusions: Obesity does not increase complications or CCI following pheochromocytoma resection, but it does increase LOS. A retroperitoneal approach may uniquely benefit patients with obesity. In view of rising obesity rates, these results warrant further research to validate findings., Competing Interests: Disclosure: The authors declare no conflicts of interest. Ethical approval: The study was approved with registration: CARMS-18769., (© 2024. Society of Surgical Oncology.)

A 3D thyroid model was developed to address the limitations of 2D cultures and study the effects of compounds like 3-MNT on dehalogenase 1 (IYD) and metabolic activity. Morphology was assessed by TEM, and the expression of tissue-specific genes (TPO, TSHR, PAX8, TTF-1, NIS, IYD, TG) and metabolic features were analyzed using qRT-PCR, immunofluorescence, western blotting, ELISA, and LC-MS/MS, with and without TSH stimulus and 3-MNT treatment. Confocal and TEM analyses confirmed a follicle-like 3D structure. Expression of TPO, NIS, TG, TSH, and PAX markers was significantly higher (p < 0.05) in 3D versus 2D cultures, and ELISA showed increased TG protein production. 3-MNT treatment inhibited IYD activity, indicated by increased MIT and DIT in the media, and significantly altered (p < 0.05) NIS, TG, IYD, TSHR, and TPO expression. These findings suggest 3D thyroid cultures closely replicate tissue traits and functionality, providing a valuable tool for thyroid research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Parathyroid gland (PG) surgery is often challenging due to the small size and indistinct nature of these glands. The introduction of intraoperative near-infrared autofluorescence (NIRAF) has shown promise in localizing parathyroid tissue. However, the NIRAF features of parathyroid adenomas remain unclear. The aim of this study is to assess the NIRAF pattern of parathyroid adenomas., Methods: Patients who underwent surgery for primary hyperparathyroidism at the University Hospital of Pisa, Endocrine Surgery Unit, between December 2021 and February 2022 were enrolled in this study. Intraoperative NIRAF patterns of suspected parathyroid adenomas were evaluated, with particular attention given to the presence of a bright cap., Results: A retrospective study was conducted on 11 patients with primary hyperparathyroidism who underwent parathyroidectomy at our institution. Histopathological examination of the 15 resected specimens confirmed 14 parathyroid adenomas (12 chief cell parathyroid adenomas, 1 oxyphil cell parathyroid adenoma, and 1 mixed cell parathyroid adenoma) and one schwannoma. All adenomas exhibited a heterogeneous NIRAF pattern, distinct from the homogeneous pattern observed in the schwannoma. A bright cap was identified in 9 out of 14 (64.3%) parathyroid adenomas (all chief cell adenomas). On the contrary, all 9 macroscopically normal PGs identified during surgery presented an homogeneous pattern., Conclusion: Our findings support the integration of NIRAF into parathyroid surgical procedures. The heterogeneous NIRAF pattern observed in parathyroid adenomas, often accompanied by a bright cap, offers a promising intraoperative diagnostic tool to differentiate hyperfunctioning from normal parathyroid tissue. Larger-scale randomized trials are warranted to further validate these findings., (© 2024. The Author(s).)

Background: Differentiated thyroid carcinoma (DTC), mainly papillary (PTC), at low risk of recurrence is currently managed with active surveillance strategies or less aggressive surgeries. However, total thyroidectomy with 131 I treatment is still performed both if these tumors are diagnosed before or occasionally after surgery. This real-life study aimed to evaluate the rate of biochemical, structural, and functional events in a large series of consecutive DTCs at low risk of recurrence treated by total thyroidectomy, but not with 131 I, in a medium-long-term follow-up., Patients and Methods: We evaluated clinical-pathologic data of 383 consecutive patients (2006-2012) with unifocal DTC [T1a/b(s)] at low risk of recurrence, treated with total thyroidectomy but without lymph node dissection and 131 I treatment after surgery. We evaluated if structural, biochemical, and functional events were detected during the follow-up., Results: Females accounted for 75.7% of our study group, and the median age was 50 years. The median tumor dimension was 0.4 cm (range 0.1-1.2). Most of the patients had a unifocal T1a tumor (98.9%), and 73.6% had a classic variant of PTC. We divided the patients according to the absence (group A-n = 276) or presence (group B-n = 107) of interfering TgAb at first control after surgery. After a median follow-up of 10 years, no structural events were detected. Sixteen out of three hundred and eighty-three (4.2%) patients developed biochemical events: 12/276 (4.3%) in group A and 4/107 (3.7%) in group B. The median time elapsed from surgery to detecting a biochemical event was 14.5 and 77.5 months in groups A and B, respectively. No patients performed additional treatments and were followed up with an active surveillance strategy., Conclusions: This study confirmed that patients with DTC at low risk of recurrence showed an excellent outcome in a medium long-term follow-up since no structural events were diagnosed. Significant variations in Tg/TgAb were detected in a few cases, all managed with an active surveillance strategy without the need for other treatments. Therefore, a relaxed follow-up with neck ultrasound and Tg/TgAb measurement is enough to early identify those very unusual cases of recurrence.

Background and Objective: Robotic adrenalectomy (RA) has attracted interest as an alternative to laparoscopic adrenalectomy (LA) for patients with pheochromocytoma, although its beneficial effects are uncertain. Our aim was to compare RA and LA outcomes for these patients., Methods: Data for patients who underwent RA or LA for pheochromocytoma in 46 international centers between 2012 and 2022 were reviewed. We analyzed baseline characteristics and postoperative complications at discharge, 90 d, and 1 yr. We conducted propensity score matching (PSM; 1:1 ratio) and multivariable analyses to evaluate outcomes and risk factors for the occurrence of complications and higher Comprehensive Complication Index (CCI)., Key Findings and Limitations: Of 1755 patients, 1613 (91.9%) underwent LA and 142 (8.1%) underwent RA. Estimated blood loss, conversion rate, complication rate, and CCI at discharge, 90 d, and 1 yr were similar between the groups. However, RA was associated with a longer operative time in comparison to LA (100 vs 123 min; p < 0.001), but not after PSM (p = 0.120). Multivariable analysis revealed that Charlson comorbidity index (odds ratio [OR] 1.17, 95% confidence interval [CI] 1.07-1.29; p = 0.001), and tumor size per 1-cm increment (OR 1.13, 95% CI 1.07-1.21; p < 0.001) were independently associated with the incidence of complications, but there was no significant difference in complication rates between the LA and RA groups (OR 1.09, 95% CI 0.63-1.87; p = 0.767). After PSM, RA was associated with a lower rate of severe (grade ≥3a) complications in comparison to LA (p = 0.023)., Conclusions and Clinical Implications: RA is a safe alternative to LA and yields similar outcomes for patients with pheochromocytoma. RA may be associated with a lower likelihood of severe complications. Further studies are warranted to determine the role of robotic surgery in pheochromocytoma., Patient Summary: Pheochromocytoma is a rare tumor in the adrenal gland and the gold-standard treatment is surgical removal. We assessed patient outcomes after robot-assisted surgery compared with laparoscopic surgery and found that outcomes are similar, but the rate of severe complications may be lower if a surgical robot is used., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Primary hyperparathyroidism (PHPT) is a common endocrine disorder in which surgery is the only curative therapy. Ectopic parathyroid adenoma in the pyriform sinus resulting from a pathological migration of parathyroid glands along the embryological development is a rare cause of PHPT. We describe a case of a persistent primary hyperparathyroidism after previous unsuccessful surgery due to an ectopic parathyroid adenoma within the pyriform sinus and we review the previous reports on this issue., Case Presentation: A 62-year-old woman was referred for persistent hypercalcemia following unsuccessful cervical exploratory surgery. Cervical ultrasound did not detect any parathyroid abnormalities. At variance, 99m Tc-sestamibi SPECT/CT and CT scan of the neck identified a parathyroid adenoma in the left pyriform sinus, which was confirmed by endoscopy. The patient was successfully treated by transoral robotic resection and the pathology confirmed a parathyroid adenoma., Conclusions: The ectopic parathyroid adenoma in the pyriform sinus is so uncommon that only fourteen cases have been reported. However, the pyriform sinus should be considered a possible location of ectopic parathyroid glands, especially in the setting of persistent or recurrent PHPT after parathyroid surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Sardella, Seccia, Giambalvo, Pierotti, Dinoi, Della Valentina, Pardi, Materazzi, Dallan, Berrettini and Cetani.)

Background: Thyroid diseases are one of the most common health problems worldwide. Although they represent a necessary step in order to perform thyroidectomy, hyperextension of the neck can potentially increase postoperative pain. The aim of this study is to determine a correlation between the degree of neck hyperextension on the operative table and the postoperative pain in patients undergoing open thyroidectomy., Methods: Patients were prospectively enrolled from the cohort of patients operated at the Endocrine Surgery Unit of the University Hospital of Pisa, between May and July 2021. Both of patients who underwent total thyroidectomy or hemi-thyroidectomy were recruited. The following data were analysed in order to find a correlation with postoperative pain at 24 h: age, gender, type of surgery, BMI, operative time, and degree of neck extension., Results: Overall, 195 patients were enrolled. A direct, statistically significant correlation emerged between the degree of neck hyperextension and the postoperative pain 24 h after surgery, regardless of the pain of the surgical wound (p < 0.001; beta 0.270)., Conclusions: A direct correlation emerges between neck tilt angle and postoperative neck pain. Moreover, total thyroidectomy (TT) predisposes more to postoperative neck pain, considering the type of surgery., (© 2024. The Author(s).)

Background: Tyrosine kinase inhibitors (TKIs) and immunotherapy have been proposed for advanced metastatic anaplastic thyroid cancer (ATC). We report a case of BRAF V600E-mutated ATC in which lenvatinib (L) plus pembrolizumab (P) enabled neoadjuvant treatment., Case Presentation: A male patient aged 65 years presented with a rapidly enlarging left latero-cervical mass. Fine needle aspiration was suggestive of ATC. Surgical consultation excluded radical surgery. While awaiting molecular profile analysis and considering the fast evolution of the disease, treatment with L and P was started. L was started at a dose of 14 mg daily, while P was started at the standard regimen (200 mg every 3 weeks). After 1 month, computerized tomography showed a reduction in the mass with almost complete colliquative degeneration, and the carotid artery wall was free from infiltration. Radical surgery was performed. Histology confirmed papillary thyroid cancer (PTC) in the left lobe and ATC with extensive necrosis in the left latero-cervical lymph node metastasis. The margins were free of tumors (R0). A BRAF V600E mutation was present in both PTC and ATC. At the 1-year follow-up, the patient was free of disease., Conclusion: L and P in combination also appeared to be effective as a neoadjuvant treatment for BRAF V600E-mutated ATC. This combination treatment could be used when there is an opportunity for complete resection of the cancer, and as soon as possible. The intermediate dose of 14 mg of L appeared to be well tolerated and effective., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Barbaro, Forleo, Profilo, Lapi, Giani, Torregrossa, Macerola and Materazzi.)

Purpose: Assessing vocal cord mobility is crucial for patients undergoing thyroid surgery. We aimed to evaluate the feasibility and efficacy of surgeon-performed transcutaneous laryngeal ultrasound (TLUS) compared to flexible nasolaryngoscopy., Method: From February 2022 to December 2022, we conducted a prospective observational study on patients scheduled for total thyroidectomy at our Institution. All patients underwent TLUS followed by flexible nasolaryngoscopy by a blinded otolaryngologist. Findings were classified as normal or vocal cord movement impairment and then compared. Patients evaluable on TLUS were included in Group A, while those not evaluable were included in Group B, and their features were compared., Results: Group A included 180 patients, while Group B included 21 patients. Male sex (p < 0.001), age (p = 0.034), BMI (p < 0.001), thyroid volume (p = 0.038), and neck circumference (p < 0.001) were associated with Group B. TLUS showed a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 100%, 99.4%, 94.4%, 100%, and 99.4%, respectively. Cohen's K value was 0.984., Conclusion: TLUS is a valid, easy-to-perform, non-invasive, and painless alternative for evaluating vocal cords in selected patients. It can be used either as a first level exam and as screening tool for selecting cases for flexible nasolaryngoscopy. TLUS should be integrated into routine thyroid ultrasound examination., (© 2024. The Author(s).)

Introduction: The COVID-19 pandemic has limited the availability of healthcare resources for non-COVID patients and decreased elective surgeries, including thyroidectomy. Despite the prioritization of surgical procedures, it has been reported that thyroidectomy for thyroid cancer (TCa) was adversely impacted. We assessed the impact of the pandemic on the surgical activities of two high-volume referral centers., Materials and Methods: Patients operated at two National Referral Centers for Thyroid Surgery between 03/01/2020 and 02/28/2021 (COVID-19 period) were included (P-Group). The cohort was compared with patients operated at the same Centers between 03/01/2019 and 02/29/2020 (pre-COVID-19 pandemic) (C-Group)., Results: Overall, 7017 patients were included: 2782 in the P-Group and 4235 in the C-Group. The absolute number of patients with TCa was not significantly different between the two groups, while the rate of malignant disease was significantly higher in the P-Group (1103/2782 vs 1190/4235) (P < 0.0001). Significantly more patients in the P-Group had central (237/1103 vs 232/1190) and lateral (167/1103 vs 140/1190) neck node metastases (P = 0.001). Overall, the complications rate was significantly lower (11.9% vs 15.1%) and hospital stay was significantly shorter (1.7 ± 1.5 vs 1.9 ± 2.2 days) in the P-Group (P < 0.05)., Conclusion: The COVID-19 pandemic significantly decreased the overall number of thyroidectomies but did not affect the number of operations for TCa. Optimization of management protocols, due to limited resource availability for non-COVID patients, positively impacted the complication rate and hospital stay., (© 2024. Italian Society of Surgery (SIC).)

A task force of the United Italian society of Endocrine Surgery (SIUEC) was commissioned to review the position statement on diagnostic, therapeutic and health‑care management protocol in parathyroid surgery published in 2014, at the light of new technologies, recent oncological concepts, and tailored approaches. The objective of this publication was to support surgeons with modern rational protocols of treatment that can be shared by health-care professionals, taking into account important clinical, healthcare and therapeutic aspects, as well as potential sequelae and complications. The task force consists of 12 members of the SIUEC highly trained and experienced in thyroid and parathyroid surgery. The main topics concern diagnostic test and localization studies, mode of admission and waiting time, therapeutic pathway (patient preparation for surgery, surgical treatment, postoperative management, management of major complications), hospital discharge and patient information, outpatient care and follow-up, outpatient initial management of patients with pHPT., (© 2024. The Author(s).)

Purpose: Surgery plays a key role in the treatment of thyroid cancer (TC) patients. Locally advanced cases, however, can require an extensive surgical approach with technical issues and a high risk of complications. In these cases, a multidisciplinary evaluation should be carried out to evaluate pros and cons. The aim of this study was to share our experience, as a multidisciplinary team, in the management of patients with locally advanced TC with a particularly extensive local disease, whose surgical approach could be challenging and part of a multimodal treatment., Methods: We retrospectively evaluated clinical, surgical, and oncologic features of all patients with locally advanced TC who had undergone multidisciplinary surgery from January 2019 to June 2020., Results: Six patients (two cases each of poorly differentiated, papillary, and medullary TC) were included. Four out of six were suffering from symptoms related to the advanced disease. At pre-surgical evaluation, a multidisciplinary team proposed extended surgery with radical intent via cervicotomy and sternotomy, considering other therapies not feasible or probably ineffective without it. No one passed away in intra- or perioperative time. At the end of follow-up (median 2.6 years), all patients presented a remission of symptoms due to the advanced disease, four patients were submitted to adjuvant therapies and only one patient died for a cause unrelated to the disease., Conclusion: This series of very advanced TCs shows the effectiveness of a surgery performed by a multidisciplinary team in controlling symptoms, allowing adjuvant therapies, and improving the survival of patients whose cases would otherwise be very difficult to manage., (© 2023. The Author(s).)

Obesity's role in thyroid cancer development is still debated, as well as its association with aggressive histopathological subtypes (AHSs). To clarify the link between Body Mass Index (BMI) and AHS of differentiated thyroid carcinoma (DTC), we evaluated patients who underwent thyroidectomy for DTC from 2020 to 2022 at four European referral centres for endocrine surgery. Based on BMI, patients were classified as normal-underweight, overweight, or obese. AHSs were defined according to 2022 WHO guidelines. Among 3868 patients included, 34.5% were overweight and 19.6% obese. Histological diagnoses were: 93.6% papillary (PTC), 4.8% follicular (FTC), and 1.6% Hürthle cell (HCC) thyroid carcinoma. Obese and overweight patients with PTC had a higher rate of AHSs ( p = 0.03), bilateral, multifocal tumours ( p = 0.014, 0.049), and larger nodal metastases ( p = 0.017). In a multivariate analysis, BMI was an independent predictor of AHS of PTC, irrespective of gender ( p = 0.028). In younger patients (<55 years old) with PTC > 1 cm, BMI predicted a higher ATA risk class ( p = 0.036). Overweight and obese patients with FTC had larger tumours ( p = 0.036). No difference was found in terms of AHS of FTC and HCC based on BMI category. Overweight and obese patients with PTC appear to be at an increased risk for AHS and aggressive clinico-pathological characteristics.

Introduction: Goiter is a common problem in clinical practice, representing a large part of clinical evaluations for thyroid disease. It tends to grow slowly and progressively over several years, eventually occupying the thoracic inlet with its lower portion, defining the situation known as retrosternal goiter. Total thyroidectomy is a standardized procedure that represents the treatment of choice for all retrosternal goiters, but when is performed for such disease, a higher risk of postoperative morbidity is variously reported in the literature. The aims of our study were to compare the perioperative and postoperative outcomes in patients with cervical goiters and retrosternal goiters undergoing total thyroidectomy., Methods: In our retrospective, multicentric evaluation we included 4,467 patients, divided into two groups based on the presence of retrosternal goiter (group A) or the presence of a classical cervical goiter (group B)., Results: We found statistically significant differences in terms of transient hypoparathyroidism (19.9% in group A vs. 9.4% in group B, p  < 0.001) and permanent hypoparathyroidism (3.3% in group A vs. 1.6% in group B, p  = 0.035). We found no differences in terms of transient RNLI between group A and group B, while the occurrence of permanent RLNI was higher in group A compared to group B (1.4% in group A vs. 0.4% in group B, p  = 0.037). Moreover, no differences in terms of unilateral RLNI were found, while bilateral RLNI rate was higher in group A compared to group B (1.1% in group A vs. 0.1% in group B, p  = 0.015)., Discussion: Wound infection rate was higher in group A compared to group B (1.4% in group A vs. 0.2% in group B, p  = 0.006). Based on our data, thyroid surgery for retrosternal goiter represents a challenging procedure even for highly experienced surgeons, with an increased rate of some classical thyroid surgery complications. Referral of these patients to a high-volume center is mandatory. Also, intraoperative nerve monitoring (IONM) usage in these patients is advisable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Cappellacci, Canu, Rossi, De Palma, Mavromati, Kuczma, Di Filippo, Morelli, Demarchi, Brazzarola, Materazzi, Calò, Medas and our Mediastinal Goiter Study Collaborative Group.)

Obesity is a well-known public health concern in Western World. Accordingly, an elevated number of obese patients undergo thyroidectomy every year. We aim to assess the impact of obesity on intraoperative and postoperative outcomes of patients who undergo thyroidectomy. 1228 patients underwent thyroidectomy at our department between January 2021 and September 2021. We divided patients into two groups according to body mass index (BMI): non-obese (BMI < 30 kg/m 2 ) and obese (BMI ≥ 30 kg/m 2 ). A propensity score approach was performed to create 1:1 matched pairs (matching according to age, gender, diagnosis, nodule size and type of operation). After matching, the final population included 522 patients, equally divided between each group: non-obese group (Group A; n = 261) and obese group (Group B; n = 261). The primary endpoint of the study was the overall rate of postoperative complications; secondary endpoints of the study were operative time, use of energy device and length of hospital stay. The duration of hospital stay resulted longer in Group B (p = 0.002). No statistically significant differences were documented in terms of operative time (p = 0.206), use of energy devices (p = 0.855) and surgical complications (p = 0.429). Moreover, no statistically significant differences were documented considering each specific complication: transient and permanent hypocalcemia (p = 0.336; p = 0.813, respectively), transient and permanent recurrent laryngeal nerve palsy (p = 0.483; p = 0.523, respectively), hematoma (p = 0.779), bleeding (p = 0.178), wound infection (p = 0.313) and cheloid formation (p = 0.412). Thyroidectomy can safely be performed in obese patients. Outcomes resulted comparable; nonetheless, obesity correlates to longer hospital stay., (© 2023. The Author(s).)

Background: Second 131I treatment is commonly performed in clinical practice in patients with differentiated thyroid cancer and biochemical incomplete or indeterminate response (BiR/InR) after initial treatment., Objective: The objective of the is study is to evaluate the clinical impact of the second 131I treatment in BiR/InR patients and analyze the predictive factors for structural incomplete response (SiR)., Patients and Methods: One hundred fifty-three BiR/InR patients after initial treatment who received a second 131I treatment were included in the study. The clinical response in a short- and medium- long-term follow-up was evaluated., Results: After the second 131I treatment (median 8 months), 11.8% patients showed excellent response (ER), 17% SiR, while BiR/InR persisted in 71.2%. Less than half (38.5%) of SiR patients had radioiodine-avid metastases. Patients who, following the second 131I treatment, experienced SiR had larger tumor size and more frequently aggressive histology and vascular invasion than those experienced BiR/InR and ER. Also, the median values of thyroglobulin on levothyroxine therapy (LT4-Tg), Tg peak after recombinant human TSH stimulation (rhTSH-Tg) and thyroglobulin antibodies (TgAb) were significantly higher in patients who developed SiR. At last evaluation (median: 9.9 years), BiR/InR persisted in 57.5%, while 26.2% and 16.3% of the patients showed ER and SiR, respectively. About half of BiR/InR patients (71/153 (46.4%)) received further treatments after the second 131I treatment., Conclusions: Radioiodine-avid metastatic disease detected by the second 131I is an infrequent finding in patients with BiR/InR after initial treatment. However, specific pathologic and biochemical features allow to better identify those cases with higher probability of developing SiR, thus improving the clinical effectiveness of performing a second 131I treatment.

Context: Prognosis is excellent for papillary thyroid carcinoma (PTC), noninvasive follicular thyroid neoplasia with papillary-like nuclear features (NIFT-P), and follicular thyroid carcinoma (FTC) but is poor for poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC). Among PTCs, the prognosis is more favorable for follicular (FV-PTC) and classic (CV-PTC) than for tall cell (TCV-PTC), and solid (SV-PTC) variants., Objective: To associate histotypes and variants of thyroid carcinoma with ultrasound and cytological features., Methods: Histology of 1018 benign tumors and 514 PTC (249 CV, 167 FV, 49 TC, 34 SV, and 15 other variants), 52 NIFT-P, 50 FTC, 11 PDTC, and 3 ATC was correlated with fine-needle aspiration biopsy categories (Italian classification: TIR1, TIR2, TIR3A, TIR3B, TIR4, and TIR5) and ultrasound features at the Endocrinology Unit, University Hospital of Pisa. In total, 1117 patients with thyroid nodule(s) who underwent thyroidectomy were included., Results: Of PTC, 36.3% had indeterminate cytology (TIR3A or TIR3B), 56.6% were suspicious for malignancy or malignant (TIR4 or TIR5); 84.0% FTC and 69.3% NIFT-P were TIR3A or TIR3B; 72.5% FV-PTC and 73.6% SV-PTC were TIR3A or TIR3B; 79.9% CV-PTC and 95.9% TCV-PTC were TIR4 or TIR5. The association of a hypoechoic pattern, irregular margins, and no microcalcifications was more frequent in TCV-PTC than in CV-PTC (P = .02, positive predictive value = 38.9%; negative predictive value = 85.5%)., Conclusion: At cytology, most FTC, NIFT-P, FV-PTC, and SV-PTC were indeterminate, most CV-PTC and TCV-PTC were suspicious for malignancy or malignant. Ultrasound can be helpful in ruling out TCV-PTC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Postoperative cervical haematoma represents an infrequent but potentially life-threatening complication of thyroidectomy. Since this complication is uncommon, the assessment of risk factors associated with its development is challenging. The main aim of this study was to identify the risk factors for its occurrence., Methods: Patients undergoing thyroidectomy in seven high-volume thyroid surgery centers in Europe, between January 2020 and December 2022, were retrospectively analysed. Based on the onset of cervical haematoma, two groups were identified: Cervical Haematoma (CH) Group and No Cervical Haematoma (NoCH) Group. Univariate analysis was performed to compare these two groups. Moreover, employing multivariate analysis, all potential independent risk factors for the development of this complication were assessed., Results: Eight thousand eight hundred and thirty-nine patients were enrolled: 8,561 were included in NoCH Group and 278 in CH Group. Surgical revision of haemostasis was performed in 70 (25.18%) patients. The overall incidence of postoperative cervical haematoma was 3.15% (0.79% for cervical haematomas requiring surgical revision of haemostasis, and 2.35% for those managed conservatively). The timing of onset of cervical haematomas requiring surgical revision of haemostasis was within six hours after the end of the operation in 52 (74.28%) patients. Readmission was necessary in 3 (1.08%) cases. At multivariate analysis, male sex ( P  < 0.001), older age ( P  < 0.001), higher BMI ( P  = 0.021), unilateral lateral neck dissection ( P  < 0.001), drain placement ( P  = 0.007), and shorter operative times ( P  < 0.001) were found to be independent risk factors for cervical haematoma., Conclusions: Based on our findings, we believe that patients with the identified risk factors should be closely monitored in the postoperative period, particularly during the first six hours after the operation, and excluded from outpatient surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2023 Canu, Medas, Cappellacci, Rossi, Gjeloshi, Sessa, Pennestrì, Djafarrian, Mavromati, Kotsovolis, Pliakos, Di Filippo, Lazzari, Vaccaro, Izzo, Boi, Brazzarola, Feroci, Demarchi, Papavramidis, Materazzi, Raffaelli, Calò and REDHOT Study Collaborative Group.)

Background: Parathyroid cancer (PC) is a rare sporadic or hereditary malignancy whose histologic features were redefined with the 2022 WHO classification. A total of 24 Italian institutions designed this multicenter study to specify PC incidence, describe its clinical, functional, and imaging characteristics and improve its differentiation from the atypical parathyroid tumour (APT)., Methods: All relevant information was collected about PC and APT patients treated between 2009 and 2021., Results: Among 8361 parathyroidectomies, 351 patients (mean age 59.0 ± 14.5; F = 210, 59.8%) were divided into the APT (n = 226, 2.8%) and PC group (n = 125, 1.5%). PC showed significantly higher rates ( p < 0.05) of bone involvement, abdominal, and neurological symptoms than APT (48.8% vs. 35.0%, 17.6% vs. 7.1%, 13.6% vs. 5.3%, respectively). Ultrasound (US) diameter >3 cm (30.9% vs. 19.3%, p = 0.049) was significantly more common in the PC. A significantly higher frequency of local recurrences was observed in the PC (8.0% vs. 2.7%, p = 0.022). Mortality due to consequences of cancer or uncontrolled hyperparathyroidism was 3.3%., Conclusions: Symptomatic hyperparathyroidism, high PTH and albumin-corrected serum calcium values, and a US diameter >3 cm may be considered features differentiating PC from APT. 2022 WHO criteria did not impact the diagnosis.

Robot-assisted transaxillary thyroidectomy is widely performed in Asian countries, although it is still under discussion in the Western World. However, there have been few studies reporting on the learning curve of robot-assisted transaxillary thyroidectomy. We used the cumulative sum (CUSUM) analysis to assess the learning curve of gasless robot-assisted transaxillary thyroidectomy at a third-level institution in Europe. We included all consecutive patients operated by a single surgeon without previous experience of robotic surgery from February 2012 to January 2023. The primary endpoint of the study was the learning curve extracted from the median operative time using the CUSUM method for the quantitative assessment. Overall, 583 patients were enrolled. The median operative time for thyroid lobectomy and total thyroidectomy was 70 and 90 min, respectively. The CUSUM analysis showed that the learning curve for thyroid lobectomy and total thyroidectomy is 66 and 56 cases, respectively. Moreover, the presence of thyroiditis resulted associated with shorter operative time for total thyroidectomy (p = 0.044), whereas no factors resulted associated with surgical complications. The learning curve for performing robotic transaxillary thyroid lobectomy for a surgeon without previous robotic experience is 66 cases. After that, 56 cases must be performed to acquire proficiency in robotic transaxillary total thyroidectomy. Training programs may reduce the slope of the learning curve., (© 2023. The Author(s).)

Background: The use of robot-assisted transaxillary thyroidectomy (RATT) has rapidly spread in the last 2 decades, although it is mostly limited to Asian countries., Method: We retrospectively enroled all patients with histologic diagnoses of thyroid cancer who underwent RATT at the University Hospital of Pisa from May 2012 to September 2020., Results: The study included 242 patients; 128 (47%) underwent total thyroidectomy and 114 (53%) underwent thyroid lobectomy, among which 28 patients (24.6%) required completion thyroidectomy. Radioactive iodine ablation therapy was required in 90 patients (37%). The complication rate was 5.3%. After a median follow-up of 38 months, an excellent response to therapy was achieved in 107 patients (74%), whereas the response was indeterminate in 12 (8%) and incomplete in 16 (11%). No local or distant relapses or increases in thyroglobulin or antibody levels were documented., Conclusions: In experienced hands, RATT represents a valid option for the treatment of thyroid cancer in selected cases., (© 2023 John Wiley & Sons Ltd.)

Objective: Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFT-P) is an encapsulated follicular variant of papillary thyroid carcinoma (PTC) with nonaggressive clinical behavior. However, since its diagnosis is exclusively possible after surgery, it represents a clinical challenge. Neck ultrasound (US) shows good sensitivity and specificity in suggesting malignancy in thyroid nodules. However, little information is available about its ability in identifying NIFT-P., Design: The aim of this study was to evaluate the US features of NIFT-P, comparing them with other follicular-patterned thyroid tumors, and to test the ability of the main US risk stratification system (RSS) in identifying NIFT-P., Methods: We retrospectively evaluated 403 consecutive patients submitted to thyroid surgery, with positive histology for at least 1 nodule being NIFT-P, follicular variant of PTC (FV-PTC), follicular thyroid carcinoma (FTC), or follicular adenoma (FA)., Results: The US features of NIFT-P (n = 116), FV-PTC (n = 170), FTC (n = 76), and FA (n = 90) were reported. Follicular variant of PTC and FTC more frequently showed irregular margins, presence of calcifications, "taller than wide" shape, and the absence of halo compared with NIFT-P. Furthermore, FTC and also FA were larger and more frequently hypoechoic than NIFT-P. Most cases (77%) showed an indeterminate cytology. Regardless of the US RSS considered, NIFT-P and FA were less frequently classified in the high-suspicious category compared with FV-PTC and FTC., Conclusions: Ultrasound features of NIFT-P are frequently superimposable to those of nodules with low suspicion of malignancy. The NIFT-P is almost never classified in the high-suspicious category according to the main US RSS. Therefore, although the preoperative identification of NIFT-P remains a challenge, neck US can be integrated in the algorithm of management of nodules with indeterminate cytology, suggesting a possible conservative approach in those with low-suspicious features., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In 2016, the American Thyroid Association published a statement on remote-access thyroid surgery claiming that it should be reserved to patients with thyroid nodule ≤ 3 cm, thyroid lobe < 6 cm and without thyroiditis. We retrospectively enrolled all patients who underwent robotic transaxillary thyroidectomy between February 2012 and March 2022. We compared surgical outcomes between patients who presented a thyroid gland with a nodule ≤ 3 cm, thyroid lobe < 6 cm and without thyroiditis (Group A) and patients without these features (Group B). The rate of overall complications resulted comparable (p = 0.399), as well as the operative time (p = 0.477) and the hospital stay (p = 0.305). Moreover, bleeding resulted associated to thyroid nodule > 3 cm (p = 0.015), although all bleedings but one occurred in the remote-access site from the axilla to the neck. In experienced hands, robotic transaxillary thyroidectomy is feasible and safe even in patients with large thyroid nodules or thyroiditis., (© 2023. The Author(s).)

Trans-axillary robot-assisted total thyroidectomy (RATT) is nowadays worldwide accepted but the completeness obtained by RATT is still debated. The Aim of this study was to compare the completeness and safety of RATT with conventional open thyroidectomy (OT). We enrolled patients with nontoxic multinodular goiter, cytologically indeterminate nodules and well differentiated thyroid cancer without local and/or distant metastasis. In all cases the biggest nodule should be < 6 cm. The surgical completeness was evaluated by means of serum thyroglobulin (hs-Tg) and neck ultrasound (nUS) performed three months postoperatively. 100 patients underwent either RATT or OT. The type of surgical procedure was chosen by patients. They were then divided in two subgroups based on benign or malignant histology. There were no significant differences in the postoperatively values of hs-Tg in patients operated with RATT or OT, both in benign and malignant subgroups. The post-operative thyroid remnant volume estimated by nUS was not significantly different between the two groups, both in benign and malignant subgroups. We also analyzed the difference of the volume of the thyroid remnant ipsilateral to the axillary access vs that of the remnant on the contralateral side and there was not significantly difference in both subgroups. RATT was demonstrated to determine a comparable surgical completeness as OT, both in benign and malignant thyroid diseases, with no differences in the prevalence of surgical complications. In our hands the surgical completeness of RATT by a single trans-axillary was satisfying., (© 2023. Italian Society of Surgery (SIC).)

Purpose: Laboratory, imaging, and pathological features of Graves' disease (GD), although well characterized, have been barely correlated each other. Aim of the study was to link laboratory and ultrasound characteristics of GD with its pathological features., Methods: We correlated laboratory and ultrasound data at the time of diagnosis in 28 consecutive GD patients who underwent thyroidectomy with their pathological features, i.e., lymphocytic infiltration and follicular hyperplasia (both classified as mild or severe)., Results: Thyroid volume correlated positively with the levels of FT4 (P = 0.002, r 2  = 0.42), FT3 (P = 0.011, r 2  = 0.22), autoantibodies to thyroglobulin (TgAbs) (P = 0.016, r 2  = 0.32), autoantibodies to thyroid peroxidase (TPOAbs) (P = 0.011, r 2  = 0.34) and the extent of lymphocytic infiltration (P = 0.006 comparing mild to severe lymphocytic infiltration) but not with the levels of autoantibodies to the thyrotropin receptor (TRAbs) and to follicular hyperplasia. Compared to subjects with mild lymphocytic infiltration, those with severe lymphocytic infiltration showed higher levels of TgAbs (316 vs 0.0 IU/mL, P < 0.0001) and TPOAbs (295 IU/mL vs 14 IU/mL, P < 0.0001) and similar levels of TRAbs (7.5 vs 13 IU/mL, P = 0.68). Compared to patients with mild, those with severe follicular hyperplasia had similar levels of TgAbs (76 vs 30 IU/mL, P = 0.31) and TPOAbs (251 IU/mL vs 45 IU/mL, P = 0.26) but higher levels of TRAbs (39 vs 7.2 IU/mL, P < 0.001)., Conclusion: In GD, TgAbs and TPOAbs levels correlate with the extent of lymphocytic infiltration, TRAbs levels with the degree of follicular hyperplasia. Thyroid volume, the main factor influencing the severity of hyperthyroidism, is related to lymphocytic infiltration and not to follicular hyperplasia., (© 2023. The Author(s).)

Context: The clinical response after surgery is a determinant in the management of patients with medullary thyroid carcinoma (MTC). In case of excellent or structural incomplete response, the follow-up strategies are well designed. Conversely, in case of biochemical incomplete response (BiR) the management is not clearly defined., Objective: This work aimed to evaluate the overall and per-site prevalence of structural disease detection in sporadic MTC patients with BiR and to assess the predictive value of various clinical, biochemical, and genetic features., Methods: We evaluated data of 599 consecutive patients surgically treated for sporadic MTC (2000-2018) and followed-up at the endocrine unit of the University Hospital of Pisa., Results: After a median of 5 months from surgery, 145 of 599 (24.2%) patients were classified as BiR. Structural disease was detected in 64 of 145 (44.1%), after a median time of 3.3 years. In 73.6%, structural disease was detected at a single site, prevalently cervical lymph nodes. Among several others, at the time of first evaluation after surgery, only basal calcitonin (bCTN) and stage IVa/b were independent predictive factors. Also, structural disease was more frequent in patients with shorter CTN doubling time and somatic RET mutation., Conclusion: In sporadic MTC patients with BiR, the risk of detection of structural disease was about 50% at 10 years. Higher bCTN levels and staging predicted the risk of detecting structural disease. According to these findings, stricter follow-up should be reserved for MTC with BiR and elevated values of bCTN and to those with an advanced stage. Long follow-up should be considered for all BiR patients since 50% of them develop structural disease within 10 years., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

In this paper we describe the current status of sentinel node mapping (SNM) in thyroid tumors and its potential perspectives. SNM in thyroid cancer has been tested since the end of the twentieth century, mainly in papillary thyroid cancer (PTC) and in medullary thyroid cancer (MTC). In PTC, it has been employed to find occult lymph node metastases in the central compartment of the neck as an alternative or indication for prophylactic dissection, by several methods. All of them have proven effective in spotting sentinel nodes, but the results have been somewhat diminished by uncertainty about the clinical significance of occult metastases in differentiated thyroid cancer. SNM in MTC has also been used to find occult lymph node metastases in the lateral compartments of the neck, also with excellent results hindered by a similar doubt about the real clinical significance of MTC micrometastases. Well designed, adequately sized randomized controlled trials are lacking, so SNM in thyroid tumors remains an interesting yet experimental methodology. New technology is emerging that could facilitate such studies, which could add solid information about the clinical significance of occult neck metastases in thyroid cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Puccini, Ambrosini, Rossi, De Napoli and Materazzi.)

Background: Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours., Methods: In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186., Findings: Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78·6%] female patients and 4922 [21·4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1·4 [IQR 0·6-3·4]) compared with the prepandemic phase (2·0 [0·9-3·7]; p<0·0001) and pandemic decrease phase (2·3 [1·0-5·0]; p<0·0001). Compared with the prepandemic phase, in the pandemic decrease phase we observed an increased occurrence of thyroid tumours larger than 10 mm (2554 [69·0%] of 3704 vs 1515 [71·5%] of 2119; OR 1·1 [95% CI 1·0-1·3]; p=0·042), lymph node metastases (343 [9·3%] vs 264 [12·5%]; OR 1·4 [1·2-1·7]; p=0·0001), and tumours at high risk of structural disease recurrence (203 [5·7%] of 3584 vs 155 [7·7%] of 2006; OR 1·4 [1·1-1·7]; p=0·0039)., Interpretation: Our study suggests that the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic period could have led to an increased occurrence of aggressive thyroid tumours. However, other compelling hypotheses, including increased selection of patients with aggressive malignancies during this period, should be considered. We suggest that surgery for indeterminate thyroid nodules should no longer be postponed even in future instances of pandemic escalation., Funding: None., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: 20% of sporadic MTC has no RET/RAS somatic alterations or other known gene alterations. Aim of this study was to investigate RET/RAS negative MTC for the presence of NF1 alterations., Methods: we studied 18 sporadic RET/RAS negative MTC cases: Next generation sequencing of tumoral and blood DNA was performed using a custom panel including the entire coding region of the NF1 gene. The effect of NF1 alterations on the transcripts were characterized by RT-PCR and the loss of heterozygosity of the other NF1 allele was investigated with Multiplex Ligation-dependent Probe Amplification., Results: Two cases showed bi-allelic inactivation of NF1 with a prevalence of about 11% of RET/RAS negative cases. In a patient affected by neurofibromatosis there was a somatic intronic point mutation determining the transcript alteration in one allele and a germline loss of heterozygosity (LOH) in the other. In the other case described both the point mutation and the LOH were somatic events; this latter finding shows, for the first time, a driver role of NF1 inactivation in MTC independent of RET/RAS alterations and the presence of neurofibromatosis., Conclusions: About 11% of our series of sporadic RET/RAS negative MTC harbor biallelic inactivation of NF1 suppressor gene also regardless neurofibromatosis status. According to our results, NF1 alterations should be searched in all RET/RAS negative MTC as possible driver. Moreover, this finding reduces the number of negative sporadic MTCs and may have important clinical implications in the management of these tumors., (Published by Oxford University Press on behalf of European Society of Endocrinology 2023.)

Clinical and biochemical presentation of adrenal tumors may rarely conflict with their histologic features. In the present report, we describe a rare case of adrenal neoplasm clinically and biochemically labeled as pheochromocytoma which at histologic examination resulted adrenal cortical tumor. The neoplasm was examined with the electron microscope which revealed the presence of electron-dense neuroendocrine-type granules next to intracytoplasmic lipid droplets. The patient underwent laparoscopic left adrenalectomy which leads to normalization of 24 h urinary metanephrine and normetanephrine. This exceptional entity should be taken into consideration when the clinical and laboratory features conflict with the histological examination. The pathologist can clarify the mixed nature of the tumor by means of the identification of neuroendocrine granules at the electron microscope examination.

The tall-cell variant of papillary thyroid carcinoma (TCPTC) is the most common aggressive variant of papillary thyroid carcinoma (PTC) and typically occurs in older patients. In this study, we analyzed retrospectively the largest mono-institutional series of PTCs with tall-cell features (989 patients) over a 17-year period, re-evaluating tumors based on age at presentation and outcomes in different age groups. We divided patients into three age groups following different criteria (the criterion from the American Joint Committee on Cancer Tumor Node Metastasis (AJCC TNM) guidelines, criterion for the statistical division into tertiles and adolescent/post-adolescent criterion) to analyze the clinicopathological characteristics in different age groups, especially in terms of recurrence-free survival (RFS) and distant recurrence-free survival (DRFS). We obtained three main results: 1. the population is distributed among the different age groups, and therefore, this type of cancer is not exclusively found among those of an older age; 2. in the RFS analysis, we can see a higher probability of local recurrence in the younger and older groups and, unexpectedly, a lower probability of local recurrence in the "median age" group; and 3. in the DRFS analysis, we can observe a higher probability of distant recurrence in older patients. From a molecular perspective, no significant differences in the mutational status of BRAF were detected according to different age groups, while mutations in the TERT promoter were exclusively present in older patients of all age groups, highlighting the potential prognostic implications of TERT promoter mutations in PTCs. In conclusion, the results of this series confirm that TC morphology alone in PTCs does not have the same negative prognostic significance in the younger population as in the older population. The reason for these different outcomes remains unclear and needs further studies.

The incidence of thyroid cancer (TC) in Italy is one of the highest in Europe, and the reason for this is unclear. The intra-country heterogeneity of TC incidence suggests the possibility of an overdiagnosis phenomenon, although environmental factors cannot be excluded. The aim of our study is to evaluate the TC incidence trend in southern Tuscany, Italy, an area with particular geological characteristics, where the pollution and subsequent deterioration of various environmental matrices with potentially toxic elements (heavy metals) introduced from either geological or anthropogenic (human activities) sources are documented. The Tuscany cancer registry (ISPRO) provided us with the number of cases and EU standardized incidence rates (IR) of TC patients for all three provinces of southeast Tuscany (Siena, Grosseto, Arezzo) during the period of 2013-2016. In addition, we examined the histological records of 226 TC patients. We observed that the TC incidence rates for both sexes observed in Grosseto Province were significantly higher than those observed in the other two provinces. The increase was mostly due to the papillary (PTC) histotype (92% of cases), which presented aggressive variants in 37% of PTCs and tumor diameters more than 1 cm in 71.3% of cases. We demonstrated a high incidence of TC in Grosseto province, especially among male patients, that could be influenced by the presence of environmental heavy metal pollution.

Background: Near-infrared autofluorescence and indocyanine green fluorescence are 2 recent tools introduced to improve postoperative parathyroid function during thyroid surgery., Methods: We conducted a randomized prospective study. Patients undergoing total thyroidectomy were randomly assigned either to the fluorescence group, in which near-infrared autofluorescence and indocyanine green fluorescence were used, or to the control group. The primary outcomes of the study were the rate of postoperative transient and symptomatic hypocalcemia., Results: A significantly higher number of parathyroid glands were identified in the fluorescence group (3.83 vs 3.64, P = .028). The rate of postoperative symptomatic hypocalcemia was significantly lower in the fluorescence group (6% vs 17%, P = .015), as was the dosage (1.53 vs 1.91 g, P = .007) and the duration of calcium therapy (32.30 vs 45.66 days, P = .003). Having at least 2 well-vascularized parathyroid glands correlates to lower rates of transient hypocalcemia (7.4% vs 21.9%, P = .037) as well as to higher serum calcium (8.70 vs 8.42 mg/dL, P = .027) and parathyroid hormone levels (19.15 vs 11.4 pg/mL, P = .0002) on postoperative day 1., Conclusion: Near-infrared autofluorescence and indocyanine green fluorescence are novel tools that may support the endocrine surgeon in preserving and predicting post-thyroidectomy parathyroid gland function., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) have a worse prognosis with respect to well differentiated TC, and the loss of the capability of up-taking 131 I is one of the main features characterizing aggressive TC. The knowledge of the genomic landscape of TC can help clinicians to discover the responsible alterations underlying more advance diseases and to address more tailored therapy. In fact, to date, the antiangiogenic multi-targeted kinase inhibitor (aaMKIs) sorafenib, lenvatinib, and cabozantinib, have been approved for the therapy of aggressive radioiodine (RAI)-resistant papillary TC (PTC) or follicular TC (FTC). Several other compounds, including immunotherapies, have been introduced and, in part, approved for the treatment of TC harboring specific mutations. For example, selpercatinib and pralsetinib inhibit mutant RET in medullary thyroid cancer but they can also block the RET fusion proteins-mediated signaling found in PTC. Entrectinib and larotrectinib, can be used in patients with progressive RAI-resistant TC harboring TRK fusion proteins. In addition FDA authorized the association of dabrafenib (BRAF V600E inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAF V600E -mutated ATC. These drugs not only can limit the cancer spread, but in some circumstance they are able to induce the re-differentiation of aggressive tumors, which can be again submitted to new attempts of RAI therapy. In this review we explore the current knowledge on the genetic landscape of TC and its implication on the development of new precise therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Elia, Patrizio, Ragusa, Paparo, Mazzi, Balestri, Botrini, Rugani, Benvenga, Materazzi, Spinelli, Antonelli, Fallahi and Ferrari.)

Paragangliomas and pheochromocytomas are rare neuroendocrine tumors, carrying a germ-line mutation in 40% patients. Sclerosis is a rare histological feature in these tumors. We investigated the possible correlations between histological findings, first sclerosis, immunoreactivity for vesicular catecholamine transporters (VMAT1/VMAT2) and patients' genotype in a consecutive series of 57 tumors (30 paragangliomas and 27 pheochromocytomas) from 55 patients. The M-GAPP grading system, sclerosis (0-3 scale) and VMAT1/VMAT2 (0-6 scale) immunoreactivity scores were assessed. Germ-line mutations of Succinate Dehydrogenase genes, RET proto-oncogene and Von Hippel Lindau tumor suppressor gene were searched. A germ-line mutation was found in 25/55 (45.5%) patients, mainly with paraganglioma (N = 14/30, 46,66%). Significant (score ≥ 2) tumor sclerosis was found in 9 (16.1%) tumors, i.e., 7 paragangliomas and 2 pheochromocytomas, most of them (8/9) from patients with a germ-line mutation. M-GAPP score was higher in the mutation status (in 76% of patients involving the SDHx genes, in 12% the RET gene and in the remaining 12% the VHL gene) and in tumors with sclerosis (p < 0.05). Spearman's rank correlation showed a strong correlation of germ-line mutations with M-GAPP (p < 0.0001) and sclerosis (p = 0.0027) scores; a significant correlation was also found between sclerosis and M-GAPP scores (p = 0.029). VMAT1 expression was higher in paragangliomas than in pheochromocytomas (p = 0.0006), the highest scores being more frequent in mutation-bearing patients' tumors (p < 0.01). VMAT2 was highly expressed in all but two negative tumors. Sclerosis and VMAT1 expression were higher in paragangliomas than in pheochromocytomas; tumor sclerosis, M-GAPP and VMAT1 scores were associated to germ-line mutations. Sclerosis might represent a histological marker of tumor susceptibility, prompting to genetic investigations in paragangliomas., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: Selpercatinib is a highly selective RET-inhibitor drug, approved for the treatment of RET-altered lung and thyroid cancers. So far, RET-altered medullary thyroid cancer (MTC) patients treated with selpercatinib showed a remarkable objective response rate and safety profile. However, new treatment emerging adverse events (TEAEs) have been recently reported. The aim of this study was to evaluate the prevalence, features, and clinical management of effusions that are one of these TEAEs., Design: Around 10 of 11 patients with advanced MTC enrolled in the LIBRETTO-201 clinical trial at Endocrinology Unit of the Pisa University Hospital were evaluated for the presence and management of effusions., Methods: We retrospectively evaluated MTC patients treated with selpercatinib. The presence of pleural, pericardial, abdominal, and/or pelvic effusions was evaluated by reviewing the computerized tomography scan performed during the study protocol and up to 24 months of observation., Results: All but one MTC patient experienced previous multikinase inhibitors treatment. Three patients already had effusions before starting selpercatinib treatment. New effusions appeared in eight of ten (80%) patients during the treatment. A chylous nature was documented in patients who underwent fluid aspiration. Whenever a dose reduction was performed, a significant positive effect was observed., Conclusions: Chylous effusions are a new TEAE of selpercatinib treatment. They can appear or worsen at any time during the treatment. For cases with asymptomatic and mild effusions, active surveillance may be appropriate and safe. In symptomatic and/or moderate/severe cases, aspiration of the fluid and a dose reduction can improve this AE, strongly supporting a cause-effect correlation with selpercatinib., Significance Statement: Effusions, particularly of chylous nature, represent emergent and quite frequent adverse events in the management of patients affected by advanced MTC on treatment with the highly selective inhibitor selpercatinib. In this study, we evaluated, in a series of MTC patients treated with selpercatinib, the prevalence of pleural, pericardial, abdominal, and/or pelvic effusions. Insights into the diagnosis and treatment of the effusions are provided as well as suggestions for clinical management.

Background: The Italian Consensus for the Classification and Reporting of Thyroid Cytology (ICCRTC) includes six diagnostic categories (TIR 1/1C, TIR 2, TIR 3A, TIR 3B, TIR 4, and TIR 5), each indicating a different risk of malignancy. The objective of this monocentric retrospective study was to evaluate the distribution of the ICCRTC classes at the authors' institution and assess their cytohistologic correlations., Methods: The authors retrospectively collected 37,371 consecutive cytologic reports of thyroid nodules and described the clinical-pathologic features of the different cytologic categories. The cytologic diagnoses also were compared with histologic outcomes in a subset of patients., Results: The cytologic classes were distributed as follows: nondiagnostic, 15.6%; benign, 66.5%; low-risk indeterminate, 10% (TIR 3A); high-risk indeterminate, 3.5% (TIR 3B); suspicious, 1.7%; and malignant, 2.6%. According to histology, the risk of malignancy was very high in the nondiagnostic category (29.8%), with young male patients more exposed to malignancy, and it was relatively high among benign (7.8%) and indeterminate nodules (32.5% in TIR 3A; 52.1% in TIR 3B), mainly because of the high prevalence of follicular architecture in malignant tumors. On histology, the malignancy rates were 92.4% and 99.3% for the suspicious and malignant categories, respectively; aggressive variants of papillary thyroid carcinoma were mostly diagnosed in these categories., Conclusions: In this series, nondiagnostic nodules showed high prevalence and, surprisingly, high malignancy rates. Malignant tumors with follicular architecture represented a diagnostic pitfall in benign and indeterminate nodules. The suspicious and malignant categories had high specificity for malignancy. Importantly, the ICCRTC had high reliability for identifying preoperatively aggressive histotypes of thyroid carcinoma., (© 2022 The Authors. Cancer Cytopathology published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Energy-based devices are surgical devices increasingly utilized for thyroid surgery, owing to a reduction of operative time and surgical related complications. The aim of the study is to evaluate whether the use of energy-based devices could improve the complication rate in pediatric thyroid surgery., Methods: This is a retrospective observational study. We identified 177 consecutive pediatric patients (Group A) with thyroid diseases, surgically treated by energy-based devices and 237 patients (Group B) treated by conventional clamp and tie technique and matched for sex, age and indication for surgery. Transient and permanent complications rate, operative time and length of hospital stay were compared between the two groups., Results: Patients of Group A experienced a lower complication rate compared to Group B. Particularly, transient (11.3 vs. 19% p < 0.05) and permanent post operative hypoparathyroidism (1.7 vs. 5.5%, p < 0.05) were lower in Group A. Moreover, operative time was also shorter in Group A compared to Group B and this difference was statistically significant in patients who performed total thyroidectomy alone and total thyroidectomy associated with central compartment neck dissection (p < 0.05). Length of hospital stay was lower in Group A than in Group B, but this difference was statistically significant only for microfollicular lesion (p < 0.05)., Conclusion: The use of energy-based devices has a key role in reducing surgical related complications, particularly transient and permanent hypoparathyroidism, operative time and length of hospital stay in pediatric patients treated with thyroid surgery., Level of Evidence: Level III., Type of Study: Retrospective comparative study., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Background: Adrenocortical carcinoma (ACC) is a rare malignant tumor with a poor prognosis. Radical surgical resection with negative margins represents the only opportunity for a potential cure. This review provides a critical assessment of the existing studies regarding the surgical approaches for the treatment of ACC., Methods: This review was performed according to criteria reported in the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The research was carried out using the PubMed electronic library. This review is limited to comparative studies evaluating minimally invasive adrenalectomy (MIA) and open adrenalectomy (OA) in adult patients affected by ACC., Results: A total of 14 studies were selected for the review, reporting that 2574 patients underwent adrenal surgery for ACC: 1779 (69.1%) by means of OA and 795 (30.8%) by means of MIA. Six studies considered OA to be superior to MIA, whereas eight studies reported that MIA is as effective as OA in highly selected cases. All studies were retrospective with a heterogenous selection of patients., Conclusions: Data regarding the management of MIA are scarce, heterogenous, and mainly based on retrospective studies. OA remains the gold standard approach for the management of ACC; however, MIA may play a role in selected cases treated in high volume institutions with experienced surgeons.

Background: Postoperative hypocalcemia is a frequent complication after thyroidectomy. Hypoparathyroidism may develop as transient (TtHP), with normalization within six months from surgery, or permanent (PtHP) if the patient requires replacement therapy. We analyzed factors associated with the development of postoperative hypoparathyroidism and in detail PtHP following thyroid surgery in a pediatric population., Procedure: A retrospective multicenter study analyzing 326 patients was carried out. We recorded gender, age, tumor size, thyroiditis, extrathyroidal extension, lymph node dissection (central/lateral compartment, unilateral/bilateral), parathyroid autotransplantation, and histology. Additionally, calcium levels were acquired postoperatively., Results: We analyzed pediatric patients ≤18 years who underwent thyroidectomy clustered into age groups (≤15 or > 15). Patients' mean follow-up was 5.8 years (1-11 years). Postoperative hypoparathyroidism occurred in 36 (11.0%): 20 cases (6.13%) developed PtHP. Postoperative hypoparathyroidism was more frequent in younger patients (P = 0.014), in larger tumors (P < 0.001), in case of extrathyroidal extension (P = 0.037), and in central compartment (P = 0.020) and bilateral lymph node dissection (P = 0.030). PtHP was more frequent in older patients (P = 0.014), in case of thyroiditis (P < 0.001), and extrathyroidal extension (P < 0.001). Concerning the first postoperative calcium level measurement, in the postoperative hypoparathyroidism group, we registered a 8.17 mg/dL value with 14% pre/postoperative decrease (Δ Ca ), whereas in PtHP patient group calcium level was 7.91 mg/dL with 16.7% Δ Ca ., Conclusions: The risk of postoperative hypoparathyroidism is related to younger age, tumor size, central compartment and bilateral lymph node dissection, extrathyroidal extension, and decrease in postoperative calcium levels. The risk of PtHP is related to older age, thyroiditis, extrathyroidal extension, and decrease in postoperative calcium levels., (© 2022 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Fewer than 100 cases of amiodarone-induced thyrotoxicosis (AIT) managed surgically have been reported worldwide. This study aims to assess the outcome of thyroidectomy under general anesthesia in a relatively large case series. A retrospective analysis of the clinical records of 53 patients who underwent thyroidectomy for AIT between 1995 and 2019 was conducted. There were 48 (90%) males and 5 females with an average age of 63.7 years. Type 1 and 2 AIT were present in 35 (66%) and 18 (34%) of patients, respectively. The mean preoperative ejection fraction (EF) was 45 ± 13%. Salvage surgery was performed in 6 (11%) patients due to decompensating heart failure and/or malignant arrhythmias. 35 (66%) patients underwent urgent surgery due to a predicted late response to medical therapy and/or the need to discontinue it. Elective surgery was performed in the remainder. A considerable improvement in mean EF occurred 12 months post-surgery (44% vs. 49%; p < 0.001). The overall survival rate following thyroidectomy was 96% at 12 months, and 83% at 5 years. No survival differences were observed based on systolic function. Cardiac-specific mortality was 11%, and these patients demonstrated a considerably shorter survival post-surgery compared to those who died of a non-cardiac cause (27 ± 18 vs. 77.5 ± 54 months; p < 0.05). Total thyroidectomy can be safely performed under general anesthesia despite severe cardiac disease. It considerably improves cardiac function and confers a survival advantage. Therefore, it should be considered early in the treatment plan of select cases., (© 2022. Italian Society of Surgery (SIC).)

Context: Measurement of driver mutations in circulating tumoral DNA (ctDNA) obtained by liquid biopsy has been shown to be a sensitive biomarker in several human tumors., Objective: The aim of this study was to evaluate the clinical relevance of pre- and post-operative ctDNA in sporadic medullary thyroid cancer (sMTC)., Methods: We studied pre- and post-operative ctDNA in 26 and 23 sMTC patients, respectively. ctDNA results were correlated to serum calcitonin (Ct), carcinoembryonic antigen (CEA), and other clinical/pathological features., Results: Twenty-six of 29 (89.7%) sMTCs were mutated either for RET or RAS and 3/29 (10.3%) were negative. Four of 26 (15.4%) cases showed positive pre-operative ctDNA with a significantly higher presence of RET M918T mutation (P = 0.0468). Patients with positive pre-operative ctDNA showed a higher variation allele frequency value of the somatic driver mutation (P = 0.0434) and a higher frequency of persistent disease (P = 0.0221). Post-operative ctDNA was positive only in 3/23 (13%) sMTCs and no one was positive for pre-operative ctDNA. Higher values of both Ct (P = 0.0307) and CEA (P = 0.0013) were found in positive ctDNA cases. Finally, the 7 cases harboring either pre- or post-operative positive ctDNA had a persistent disease (P = 0.0005) showing a higher post-operative serum Ct when compared with cases with negative ctDNA (P = 0.0092)., Conclusions: Pre-operative ctDNA in medullary thyroid cancer is not useful for diagnostic purposes, but it can be useful for predicting the outcome of the disease. In our series, post-operative ctDNA showed a potential for monitoring the response to therapies, but further studies are required to confirm our results., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Although the majority of RET alterations are single nucleotide variants (SNV), small deletions and/or insertions have been reported at variable prevalence. No information about the efficacy of RET-specific inhibitors in patients harboring RET indels has been provided., Objective: We present an update on the prevalence of RET indels in medullary thyroid cancer (MTC) and describe the efficacy of selpercatinib in patients with advanced MTC with RET indels., Methods: The MTC tissues of 287 patients were analyzed using an Ion S5 targeted sequencing. The functional role of the reported indels have been evaluated by MutationTaster. Clinical and pathological data of MTC patients harboring a RET indel were collected and analyzed. Two patients with a RET indel were treated with selpercatinib., Results: Among 178 RET-positive cases, 147 (82.6%) harbored a SNV and 31 (17.4%) a RET in-frame indel. Nine indels were not previously reported and were found to be disease causing by MutationTaster. Patients harboring an indel were found to have an aggressive disease and 2 of them were treated with selpercatinib, experiencing a good response to the treatment., Conclusion: These data show that RET indels are not infrequent and correlate with an aggressive disease. Two RET indel-positive patients showed a partial response to the treatment with a highly selective RET inhibitor; thus, these RET indels can be considered actionable mutations. In order to not miss these alterations, the analysis of the full gene is recommended., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)