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The adoption of High Temperature Superconductors (HTS) tapes is becoming a suitable and interesting alternative to copper for windings in transformers, thanks to the improvement in performance and the lowering of costs. Of course, optimized designs, different with respect to usual layouts, must be considered, due to the additional requirements of HTS tapes, such as minimization of orthogonal magnetic fields and consideration of additional losses in the HTS. In the framework of a scientific cooperation among some Italian Universities and private companies, a test model for a 10 KVA transformer with HTS secondary windings has been developed, and validated against a demonstrative prototype, manufactured during the project. In the paper, the device model performance is assessed, with particular care to the HTS losses modeling, and some comparisons to the experimental results are presented. [ABSTRACT FROM AUTHOR]

Simple Summary: The clinical behavior of medullary thyroid carcinoma is heterogeneous and can be influenced by several clinical, biochemical and molecular factors. The role of age as a prognostic factor remains controversial. In our cohort of 432 sporadic medullary thyroid carcinoma, no differences in histologic features at diagnosis and in number and type of therapies performed during the follow-up were detected when dividing the patients according to age (< and ≥ 65 years). Younger patients had a longer follow-up and survival time, compared to the older patients. However, in dead patients, no differences in the aggressiveness of the disease at presentation and treatments performed during the follow-up were found between the two age groups. Sporadic medullary thyroid carcinoma (MTC) is a rare malignancy with a heterogeneous clinical course. Several potential prognostic factors have been investigated, but the impact of some of these is controversial, such as age at diagnosis. We evaluated the data of 432 sporadic MTC patients followed-up for a median of 7.4 years. Patients were divided and compared according to their age at diagnosis in group A (<65 years—n = 338, 78.2%) and group B (≥65 years—n = 94, 21.8%). No differences were detected between the two groups. Median follow-up time was significantly longer in patients <65 than ≥65 years. We observed 41 (9.5%) cancer-related death events. The death rate was similar between the two age groups. However, the Kaplan Meier curve showed a longer survival time for younger patients compared to older patients [HR 2.5 (CI 95%: 1.27–4.94), p < 0.01]. Nevertheless, no differences in the aggressiveness of the disease at presentation and in the number and type of treatments performed were found in the two subgroups of dead patients. In patients with sporadic MTC, age at diagnosis did not correlate with any clinical and pathological features. Cancer-related death events are similar in older and younger patients, but survival time is longer in the younger. [ABSTRACT FROM AUTHOR]

Copy number variations (CNV) of the RET gene have been described in 30% of Medullary Thyroid Cancer (MTC), but no information is available about their role in this tumor. This study was designed to clarify RET gene CNV prevalence and their potential role in MTC development. RET gene CNV were analyzed in 158 sporadic MTC cases using the ION Reporter Software (i.e., in silico analysis) while the multiplex ligation-dependent probe amplification assay (i.e., in vitro analysis) technique was performed in 78 MTC cases. We identified three categories of RET ploidy: 137 in 158 (86.7%) cases were diploid and 21 in 158 (13.3%) were aneuploid. Among the aneuploid cases, five out of 21 (23.8%) showed an allelic deletion while 16 out of 21 (76.2%) had an allelic amplification. The prevalence of amplified or deleted RET gene cases (aneuploid) was higher in RET positive tumors. Aneuploid cases also showed a higher allelic frequency of the RET driver mutation. The prevalence of patients with metastatic disease was higher in the group of aneuploid cases while the higher prevalence of disease-free patients was observed in diploid tumors. A statistically significant difference was found when comparing the ploidy status and mortality. RET gene CNVs are rare events in sporadic MTC and are associated with RET somatic mutation, suggesting that they could not be a driver mechanism of tumoral transformation per se. Finally, we found a positive correlation between RET gene CNV and a worse clinical outcome. [ABSTRACT FROM AUTHOR]

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.)

Highly selective RET inhibitor selpercatinib has demonstrated notable efficacy in advanced/progressive RET-mutant medullary thyroid cancer (MTC) patients. However, despite a more tolerable toxicity profile than multikinase inhibitors, peculiar adverse events (AEs) have been described. Obliterative bronchiolitis (OB) is a respiratory disease characterized by inflammation and fibrosis in small conducting airways. We evaluated a 70-year-old man with advanced RET-mutant MTC who developed OB during treatment with selpercatinib. Radiological features of OB occurred early and persisted during selpercatinib treatment, with a waxing and waning pattern. Notably, a partial response of MTC was achieved during the treatment, and selpercatinib was never reduced or interrupted. The almost complete absence of symptoms and the fluctuating trend, without specific treatment for OB, suggested that it is necessary to carefully evaluate the risks mediated by this AE with the risks of modifying or discontinuing the anti-cancer therapy.

Context: The active surveillance (AS) program for papillary thyroid carcinoma (≤ 1 cm) at low-risk (mPTC) showed a low percentage of progression., Objective: The aim of this study was to find a molecular signature of cases that showed disease progression during AS, which would allow their early identification., Methods: We performed next generation sequencing of 95 fine needle aspiration cytology specimens from cases prospectively enrolled in the AS program to analyze key somatic driver alterations or gene fusions implicated in PTC tumorigenesis. TERT promoter analysis was performed using Sanger sequencing or droplet digital PCR., Results: BRAF p.V600E was found in 66.3% (63/95) of mPTC and was the most common somatic alteration, followed by RAS oncogene mutations detected in 3.2% of mPTC (3/95: 2 NRAS and 1 KRAS) and gene fusions detected in 3.2% of mPTC (3/95: 1 RET-PTC1, 1 TFG-NTRK1, 1 ALK imbalance). No TERT promoter mutations (C228T and C250T) were found in the analyzed mPTC (84/95). The comparison between the molecular profile and the clinical outcome of the mPTC (stable versus progressive disease) showed no correlation (p-value=0.6) and did not identify a molecular signature able to identify progressive mPTC., Conclusions: The molecular profile of mPTC is like that of bigger PTC with the exception that none of them showed a TERT promoter mutation. The identification of the most common driver mutations, such as BRAF, RAS, or gene fusions, is not helpful for the early identification of mPTC that will show disease progression during follow-up in the AS program., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Objective: The aim of this study was to assess the clinical impact of hand-foot syndrome (HFS) during treatment with two multikinase inhibitors, sorafenib and lenvatinib, in a large group of patients with advanced thyroid cancer. Moreover, we looked for possible associations between HFS occurrence and clinical and pathological features., Methods: We retrospectively evaluated 239 patients with advanced thyroid cancer: 165 treated with lenvatinib and 74 with sorafenib. Statistical analyses were performed to verify which features could be correlated with HFS development., Results: HFS was observed in 35/74 (47.4%) and in 43/165 (26.7%) patients treated with sorafenib or lenvatinib, respectively. The median latency from the drug beginning and HFS appearance was 27 days for sorafenib and 2.9 months for lenvatinib. G3/G4 toxicity was observed in 16/35 (45.7%) patients treated with sorafenib and only in 3/43 (7%) treated with lenvatinib. Drug dose reduction due to HFS was required in 19/74 (25.7%) and 3/165 (1.8%) patients treated with sorafenib and lenvatinib, respectively. HFS occurrence was significantly associated with a longer duration of therapy in both groups., Conclusion: HFS was a frequent adverse event during both lenvatinib and sorafenib therapy, with a higher frequency and toxicity grade during sorafenib treatment. HFS was the most frequent reason for drug reduction or discontinuation in patient treated with sorafenib. Early diagnosis of HFS is important to allow early intervention, possibly in a multidisciplinary setting, and to avoid treatment discontinuation, which is highly relevant to obtain the maximum effectiveness of systemic therapy.

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.)

Introduction: The treatment of differentiated thyroid cancer (DTC) has been changing. In low (LR) and intermediate (IR) risk DTC, surgery is becoming more conservative and the usefulness of radioiodine ( 131 I) has been questioned. An increasing number of patients are treated with lobectomy or total thyroidectomy (TTx), but without 131 I. Consequently, the management and the follow-up of these patients need to be revised., Evidence Acquisition: We reviewed the available data about the management of these growing categories of patients. We focused on the emerging roles of the conventional tools in the follow-up [thyroglobulin (Tg), thyroglobulin antibodies (TgAb) and neck ultrasound (US)]. Moreover, we evaluated the changes in the use of levothyroxine (L-T4) therapy, and the role of the ongoing risk re-stratification., Evidence Synthesis: Tg, TgAb and neck US continue to represent the cornerstone of the follow-up, however, a change in their interpretation is needed. In particular, the absolute value of Tg and TgAb lost their clinical meaning, while their trend over time acquired a greater value. At variance, the diagnostic role of neck US is becoming very relevant for the early identification of the local recurrences. In addition, L-T4 therapy should be personalized according with the type of surgery, the age of patients and their comorbidities., Conclusions: Management of DTC treated with lobectomy or TTx but without 131 I is worldwide changing. The evidences suggest that in this setting of patients with LR or IR of recurrences, a relaxed surveillance could represent the most reasonable choice.

Purpose of Review: In this review, we evaluate recent findings related to the association between obesity and thyroid cancer., Recent Findings: During the last several decades, the prevalence of obesity and thyroid cancer have been increasing in parallel on a global scale. Current evidence suggests that the growing incidence of differentiated thyroid cancer (DTC) is pathogenically linked to the spread of obesity, but the biological mechanisms that may explain this connection have been only partially described. Furthermore, unlike other tumors, data on the impacts of obesity on the aggressiveness of DTC and response to treatment of DTC remain conflicting., Summary: Emergent knowledge regarding the links between obesity and thyroid cancer suggests a relevant role for obesity as a risk factor for DTC, with no apparent impact on its aggressiveness.

Objective: Prophylactic central compartment lymph node dissection (pCCND) results in a higher percentage of surgical-related complications. To date, no evidence of the impact of pCCND on the clinical outcome of papillary thyroid carcinoma (PTC) patients with synchronous ipsilateral cervical lymph node metastases has been reported., Methods: We evaluated all consecutive patients affected by PTC and synchronous ipsilateral cervical, but without evidence of central compartment, lymph node metastases. We selected 54 consecutive patients (group A) treated by total thyroidectomy, ipsilateral cervical lymph node dissection, and pCCND and 115 patients (group B) matched for sex, age at diagnosis, number and dimension of the metastatic lateral cervical lymph nodes, without pCCND. Clinical outcome after a median of 5 years and surgical-related complications were assessed., Results: The two groups were completely similar in terms of clinical features. Clinical outcomes showed a higher percentage of biochemical and indeterminate but not structural response in group B. Group B required significantly more radioiodine treatments, but no difference was shown in the need to repeat surgery for recurrences. Conversely, the prevalence of permanent hypoparathyroidism was significantly higher in group A (14.8%) than in group B (4.3%)., Conclusion: In PTC patients with synchronous ipsilateral cervical lymph node metastases, in absence of clinically evident lymph node metastases of the central compartment, performing pCCND does not improve the 5-year outcome in terms of structural disease, despite a greater number of 131 I treatments. However, pCCND is severely affected by a higher percentage of permanent hypoparathyroidism, even in the hands of expert surgeons., Abbreviations: IQR = interquartile range; pCCND = prophylactic central compartment lymph node dissection; PTC = papillary thyroid carcinoma; Tg = thyroglobulin; US = ultrasound., (© 2020 American Association of Clinical Endocrinologists. Published by Elsevier, Inc. All rights reserved.)

Objective: In intermediate risk (IR) differentiated thyroid cancer (DTC) patients, selective use of radioiodine (131-I) for remnant ablation and/or as adjuvant therapy (RRA) is advocated. The recently suggested postoperative evaluation could delay the use of RRA. The aim of this study was to evaluate if a delayed RRA can worsen the clinical outcome of IR-DTC patients. Methods: Four hundred and fourteen consecutive IR-DTC patients were divided according to the time elapsed from surgery to RRA, <6 months (group A, 186/414 [44.9%]), or ≥6 months (group B, 228/414 [55.1%]). Clinical and biochemical data were collected, and clinical outcome was analyzed at the first evaluation (EV) after RRA (first-EV) and after a median of 6 years of follow-up (last-EV). Results: No difference in the clinical outcome of group A and B was found. Since a different activity of 131-I could have an impact on the outcome, we separately analyzed the groups according to the 131-I activity (low-activity group: 1,110 MBq/30 mCi [n = 320], and high-activity group: 3,700 MBq/100 mCi [n = 94]), further subdivided according to the time elapsed from surgery to RRA. No major differences were found in both the low- and high-activity groups when comparing the features of their subgroups A and B, as far as in their clinical outcome. Conclusion: The time elapsed between surgery and the first 131-I treatment does not influence the clinical outcome of IR-DTC patients. This finding allows a more relaxed attitude in the decision making process whether to perform the RRA in IR-DTC cases in which a selective use of 131-I is recommended. Abbreviations: ATA = American Thyroid Association; DTC = differentiated thyroid cancer; EV = evaluation; HR = high risk; 131-I = radioiodine; IR = intermediate risk; LR = low risk; rhTSH = recombinant human thyroid-stimulating hormone; RRA = radioiodine for remnant ablation; Tg = thyroglobulin; TgAb = thyroglobulin autoantibody; US = ultrasound.

Background: Thyroglobulin (Tg) antibodies (TgAb) can interfere with Tg measurement and can be used as "Tg surrogate" in patients with differentiated thyroid cancer (DTC) treated with total thyroidectomy (TTx) and radioiodine remnant ablation (RRA). In contrast, few data, and in patients usually followed for a short-term follow-up, have been reported about the changes of TgAb levels in patients treated with TTx but without RRA. The aims of this study were to evaluate the changes of TgAb levels in DTC patients treated with TTx but not RRA and to identify the factors that influence these changes., Methods: The change in TgAb levels in 107 DTC (<1 cm) patients submitted to TTx but not RRA was evaluated. Patients were followed for a median of 6.3 years, and all had at least three determinations of TgAb and neck ultrasound (nUS)., Results: TgAb levels showed a progressive decrease during follow-up. Initial TgAb levels and degree of lymphocytic infiltration influenced the time but not the rate of TgAb disappearance. No influence on time and rate of the decrease in TgAb was observed when the association with thyroperoxidase antibodies (TPOAb) levels were considered. A TgAb cutoff value of 61.9 IU/mL at first postoperative evaluation was a good indicator for disappearance of the TgAb within six years. No tumor recurrence was observed in the series. In one case, the progressive increase in TgAb anticipated the reappearance of benign thyroid tissue with lymphocytic infiltration., Conclusions: TgAb levels decline in the majority of DTC patients treated with TTx but not ablated with radioiodine. The levels decrease rapidly after the surgical treatment and continue to decrease over time. The time of disappearance is influenced by the initial TgAb levels and the degree of lymphocytic infiltration. No influence of the actual TPOAb levels has been observed. An increase in TgAb levels should not be overlooked, since it can indicate the presence or reappearance of either normal thyroid tissue or tumor recurrence.

The last ten years have been characterized by the introduction in the clinical practice of new drugs named tyrosine kinase inhibitors for the treatment of several human tumors. After the positive conclusion of two international multicentric, randomized phase III clinical trials, two of these drugs, sorafenib and lenvatinib, have been recently approved and they are now available for the treatment of advanced and progressive radioiodine refractory thyroid tumors. We have been involved in most clinical trials performed with different tyrosine kinase inhibitors in different histotypes of thyroid cancer thus acquiring a lot of experience in the management of both drugs and their adverse events. Aim of this review is to give an overview of both the rationale for the use of these inhibitors in thyroid cancer and the major results of the clinical trials. Some suggestions for the management of treated patients in the real life are also provided., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chemoresistance is a major obstacle to effective therapy against colorectal cancer (CRC) and may lead to deadly consequences. The metabolism of CRC cells depends highly on the p38 MAPK pathway, whose involvement in maintaining a chemoresistant behavior is currently being investigated. Our previous studies revealed that p38α is the main p38 isoform in CRC cells. Here we show that p38α pharmacological inhibition combined with cisplatin administration decreases colony formation and viability of cancer cells and strongly increases Bax-dependent apoptotic cell death by activating the tumor suppressor protein FoxO3A. Our results indicate that FoxO3A activation up-regulates transcription of its target genes (p21, PTEN, Bim and GADD45), which forces both chemosensitive and chemoresistant CRC cells to undergo apoptosis. Additionally, we found that FoxO3A is required for apoptotic cell death induction, as confirmed by RNA interference experiments. In animal models xenografted with chemoresistant HT29 cells, we further confirmed that the p38-targeted dual therapy strategy produced an increase in apoptosis in cancer tissue leading to tumor regression. Our study uncovers a major role for the p38-FoxO3A axis in chemoresistance, thereby suggesting a new therapeutic approach for CRC treatment; moreover, our results indicate that Bax status may be used as a predictive biomarker., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)