Impact of systemic treatments for advanced thyroid cancer on the adrenal cortex.

Background: Fatigue is a frequent adverse event during systemic treatments for advanced thyroid cancer, often leading to reduction, interruption, or discontinuation. We were the first group to demonstrate a correlation between fatigue and primary adrenal insufficiency (PAI). Aim: The objective was to assess the entire adrenal function in patients on systemic treatments. Methods: ACTH, cortisol and all the hormones produced by the adrenal gland were evaluated monthly in 36 patients (25 on lenvatinib, six on vandetanib, and five on selpercatinib). ACTH stimulation tests were performed in 26 cases. Results: After a median treatment period of 7 months, we observed an increase in ACTH values in 80-100% of patients and an impaired cortisol response to the ACTH test in 19% of cases. Additionally, dehydroepiandrosterone sulphate, ∆-4-androstenedione and 17-OH progesterone levels were below the median of normal values in the majority of patients regardless of the drug used. Testosterone in females and oestradiol in males were below the median of normal values in the majority of patients on lenvatinib and vandetanib. Finally, aldosterone was below the median of the normal values in most cases, whilst renin levels were normal. Metanephrines and normetanephrines were always within the normal range. Replacement therapy with cortisone acetate improved fatigue in 14/17 (82%) patients with PAI. Conclusion: Our data confirm that systemic treatments for advanced thyroid cancer can lead to impaired cortisol secretion. A reduction in the other hormones secreted by the adrenal cortex has been first reported and should be considered in the more appropriate management of these fragile patients.

Vitamin D levels and lipid profile in children and adolescents: a tight correlation.

INTRODUCTION: Vitamin D is an essential hormone for humans, playing an important role in musculoskeletal and calcium homeostasis. Its deficiency/insufficiency seems to contribute to the development of cardiometabolic diseases in adults: this correlation appears less clear for children and adolescents. The aim of this paper was to review literature data on the relationship between vitamin D and lipid profile alterations in pediatric population. EVIDENCE ACQUISITION: We carried out a comprehensive research in electronic databases, including MEDLINE and PubMed up to December 2022, for cross-sectional or prospective studies that investigated the correlation between serum vitamin D levels and lipid profile in children and adolescents. At the end of the process, 37 articles were included in this review. EVIDENCE SYNTHESIS: According to our findings, vitamin D deficiency/insufficiency is strongly associated with lower high-density lipoprotein (HDL) cholesterol levels and higher levels of triglycerides and total cholesterol. Data about low-density lipoproteins (LDL) cholesterol are inconsistent. The potential role of vitamin D supplements for the prevention of cardiometabolic disease currently remains a speculation. CONCLUSIONS: An increasing number of studies shows how hypovitaminosis D in the pediatric age may play a role in the pathogenesis of metabolic disorders and lipid profile alterations. Data regarding the potential role of vitamin D supplements for the prevention of cardiometabolic disease are currently controversial. Further studies are needed to evaluate the causality of this association and to assess the underlying pathogenetic mechanisms.

A Prospective Multicenter Study Examining the Relationship Between Thyroid Cancer Treatment Outcomes and the Presence of Autoimmune Thyroiditis.

Background: There is some controversy on the potential relationship between autoimmune processes and clinicopathologic features as well as prognosis of differentiated thyroid cancer (DTC), and the evidence is limited by its largely retrospective nature. We examined the relationship between the presence of autoimmune thyroiditis (AT) and 1-year thyroid cancer treatment outcomes in a large multicenter study using prospectively collected data. Methods: We included data from consecutive DTC patients enrolled in the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339). We divided the groups according to the presence (AT) or absence (no autoimmune thyroiditis [noAT]) of associated AT. We used propensity score matching to compare the clinical features and outcomes between the two groups at 1-year follow-up. Results: We included data from 4233 DTC patients, including 3172 (75%) females. The American Thyroid Association (ATA) risk levels were as follows: 51% (2160/4233) low risk, 41.3% (1750/4233) intermediate risk, and 7.6% (323/4233) high risk. There were 1552 patients (36.7%) who had AT. Before propensity score matching, AT patients were significantly younger and had a smaller and bilateral tumor (p < 0.0001). Patients with AT more frequently fell into the low- and intermediate-risk categories, while the ATA high risk was more frequent among noAT patients (p = 0.004). After propensity score matching, patients with AT more frequently showed evidence of disease (structural/biochemical incomplete response) versus excellent/indeterminate response, compared with patients without AT (7.3% vs. 4.5%, p = 0.001), with an odds ratio of 1.86 ([confidence interval: 1.3-2.6], p = 0.0001). However, when considering only structural persistence as the outcome, no statistically significant differences were observed between patients with or without AT (3.4% vs. 2.7%, p = 0.35). The elevated risk associated with the ATA intermediate and high risk at diagnosis remained consistently statistically significant. Conclusions: In this large prospective series, biochemical persistence was more frequent, at 1-year follow-up, in AT patients. However, there was no significant association between the presence of AT and structural persistence of disease. These findings may be explained by the presence of a residual thyroid tissue.

Changes in Urinary Iodine Levels Following Bariatric Surgery.

OBJECTIVE: Obesity has become an epidemic in the United States. Although bariatric surgery can effectively achieve weight loss by altering the gastrointestinal tract, it commonly results in micronutrient deficiency, requiring supplementation. Iodine is an essential micronutrient for the synthesis of thyroid hormones. We aimed to investigate changes in urinary iodine concentrations (UIC) in patients following bariatric surgery. METHODS: 85 adults who underwent either laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass surgery were enrolled. At baseline and 3 months after surgery, we evaluated spot UIC and serum thyroid stimulating hormone (TSH), vitamin D, vitamin B12, ferritin, and folate levels. Participants provided a 24-hour diet recall for iodine-rich foods and information about multivitamin use at each time point. RESULTS: There was a significant increase in median UIC (201 [120.0 - 288.5] vs 334.5 [236.3 - 740.3] µg/L; P < .001), a significant decrease in mean body mass index (44.0 ± 6.2 vs 35.8 ± 5.9; P < .001) and a significant decrease in TSH levels (1.5 [1.2 - 2.0] vs 1.1 [0.7 - 1.6] uIU/mL; P < .001) at 3 months postoperatively compared to baseline. Body mass index, UIC, and TSH levels before and after surgery did not differ based on the type of weight loss surgery. CONCLUSION: In an iodine-sufficient area, bariatric surgery does not cause iodine deficiency nor clinically significant changes in thyroid function. Different surgical procedures with different anatomical alterations in the gastrointestinal tract do not significantly affect iodine status.

Management of hypertension during lenvatinib for advanced thyroid cancer: a suggested diagnostic and therapeutic algorithm.

Background: Hypertension (HTN) is the most frequent adverse event during treatment with lenvatinib (LEN), but data on its best management are limited. Aim: The objective of this study was to assess incidence, features and best management of LEN-related HTN in a consecutive single tertiary-care centre cohort. Methods: Twenty-nine patients were followed up for a mean time of 29.8 months (6-77 months). Results: After a mean follow-up of 6.8 months, HTN was recorded in 76% of cases, as a de novo occurrence in half of them. HTN significantly correlated with LEN dose and was of grade 1, grade 2 and grade 3 in 5%, 50% and 45% of patients, respectively. The majority (77%) of patients with HTN developed proteinuria. There was no correlation between HTN and proteinuria or clinical features or best morphological response or any other adverse event (AE), with the exception of diarrhoea. Patients with or without pre-existing HTN or any other cardiovascular disease had a similar incidence of HTN during LEN, thus excluding the impact of this potential predisposing factor. After evaluation by a dedicated cardiologist, medical treatment was introduced in 21/22 patients (polytherapy in 20 of them). The most frequently used drugs were calcium channel blockers (CCBs) due to their effect on vasodilation. In case of poor control, CCBs were associated with one or more anti-hypertensive drug. Conclusion: HTN is a frequent and early AE in patients on LEN treatment. We suggest a diagnostic and therapeutic algorithm to be applied in clinical practice to allow efficient HTN control and improve patient compliance, reducing LEN discontinuation.

Endocrine-related adverse conditions induced by tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) have improved outcome for many tumors. Although better tolerated than cytotoxic chemotherapy, they may cause several adverse events (AEs) and various endocrine-related toxicities have been reported under TKI treatment. The toxicity profile varies between the different TKI compounds. This review focuses on the main endocrinopathies caused by TKIs. Thyroid dysfunction and, in particular, hypothyroidism are the most frequent and best described. Several potential mechanisms have been hypothesized, including thyroid gland dysfunction, hormone metabolism impairment and hypothalamus-pituitary-thyroid axis imbalance. TKIs have been reported to influence almost all glands. In particular, they are associated with adrenal insufficiency, growth retardation due to growth hormone (GH) and/or insulin-like growth factor-1 (IGF1) deficiency, hypogonadism, and male and female fertility impairment. TKIs may affect bone metabolism, in particular decreasing osteoclastogenesis and bone turnover and, in turn, they may cause secondary hyperparathyroidism. Hypocalcemia has been reported under lenvatinib and vandetanib treatment and parathyroid hormone (PTH)-dependent and PTH-independent mechanisms have been hypothesized. Metabolic alterations during TKI treatment range from hypoglycemia with imatinib and dasatinib to hyperglycemia with nilotinib; dyslipidemia improved with imatinib and worsened with nilotinib, sunitinib, pazopanib, sorafenib, and famitinib. Endocrine-related AEs should be managed by dedicated endocrinologists. Hormone deficiencies are easily managed by replacement therapy, while endocrine hyperfunction may be improved by symptomatic treatment. Severe situations should be managed in coordination with the oncologist, trying to limit the need for TKI dose reduction or interruption.

Hypocalcemia During Lenvatinib Treatment for Advanced Thyroid Cancer: Clinical Features and Management in a Real-Life Setting.

Background: Several toxicities are recorded during treatment of advanced thyroid cancer (TC) with antiangiogenic drugs, including lenvatinib (LEN). Hypocalcemia was reported in registration studies, but little data are available from real-life cohorts. The aim of our study was to describe the incidence, characteristics, and the management of hypocalcemia in patients on LEN treatment. Methods: This is a retrospective cohort study of consecutive patients with advanced TC, treated with LEN for at least six months at a single tertiary center in Italy. Phosphocalcic metabolism was evaluated during treatment. Results: We included 25 patients treated for a mean of 29 ± 19 months (range 6-68 months). Hypocalcemia occurred in 6 of the 25 patients (24% [95% confidence interval 9.36-45.13%]), being of grade ≥3 in 2 of the 25 patients (8%), and recurrent in 4 of 6 patients (67%). The median time to hypocalcemia onset was 3 months (range 0.5-13 months) from starting LEN. No differences were found between patients who developed or not hypocalcemia regarding either starting/mean dose of LEN or clinicopathological characteristics. During the hypocalcemic crisis, the 2 patients with grade ≥3 hypocalcemia had low magnesium and low or inappropriately normal parathormone (PTH) levels, while 2 of 3 patients with grade 2 hypocalcemia had a secondary hyperparathyroidism. Hypocalcemia was managed with calcium oral supplementation in most cases, although up to 10% of patients required intravenous calcium treatment and transient LEN withdrawal. Conclusions: In this relatively small cohort, we observed an incidence of hypocalcemia of 24%, which is higher than that reported in the registration trial (6.9%). Both PTH-dependent and PTH-independent mechanisms explained hypocalcemia in the present cohort. Monitoring of serum calcium levels is strongly advised during the first year of LEN treatment, as hypocalcemia may be severe. More research is needed to confirm our findings and inform possible risk factors for hypocalcemia in advanced TC patients treated with LEN.

Persistent Thyroid Carcinoma and Pregnancy: Outcomes in an Italian Series and Review of the Literature.

Scanty data are available on the progression risk in patients with persistent thyroid cancer (TC) before pregnancy. We aimed to evaluate this topic in our series and to review available literature data. This was a retrospective study performed in a tertiary care Italian TC center. We included 8 patients with persistent papillary TC who became pregnant after initial treatments (mean time interval of 62 months). Seven patients had the structural disease (lung and/or neck node metastases), while one patient had biochemical persistence. During a mean follow-up of 97 months, none of the patients showed disease progression either during pregnancy or during a follow-up of at least 12 months after delivery, and no additional treatments were needed. A sequential biochemical evaluation showed that thyroglobulin levels can significantly increase during pregnancy, returning to preconception levels after delivery. In conclusion, our data confirm that pregnancy is not associated with disease progression in patients with stable local and/or distant persistence before conception. Thus, pregnancy should not be contraindicated in metastatic women, although a precise clinical characterization, including the disease stage at diagnosis, the ATA risk class, and the dynamic risk stratification, should be conducted before conception.

Unilateral Surgery for Medullary Thyroid Carcinoma: Seeking for Clinical Practice Guidelines.

Optimized preoperative diagnostic tools with calcitonin tests, ultrasound features, functional imaging modalities, and genetic testing to detect hereditary forms have led to an increased rate of earlier diagnosis and surgery for medullary thyroid cancer (MTC). This helps to adapt the primary surgery to the tumor stage and avoid surgical overtreatment for localized tumor growth, i.e., deviating from the regularly recommended thyroidectomy with bilateral central lymph node dissection in favor of a limited unilateral approach. To limit primary surgical therapy, it is crucial that the MTC is clinically unifocal, sporadic, and confined to the thyroid, and that calcitonin levels indicate biochemical recovery after surgery. The main requirement for such a limited approach is the availability of frozen section studies that reliably indicate (i) R0 resection of the MTC, (ii) absence of infiltration of the organ capsule, (iii) lack of desmoplasia (i.e., evidence of the metastatic potential of the MTC), (iiii) absence of contralateral disease or precancerous lesions. Informed consent is mandatory from the patient, who has been fully informed of the advantages, disadvantages, and potential risks of not undergoing the "classic" surgical procedure. The aim of this article is to review the guidelines for the management of early-stage MTC.

Daily Management of Patients on Multikinase Inhibitors' Treatment.

In a minority of differentiated thyroid cancer (TC) cases and in a large percentage of poorly differentiated TCs (PDTCs) and anaplastic TCs (ATCs), the prognosis is poor due to the lack of response to conventional treatments. In the last two decades, multikinase inhibitor (MKI) compounds have been developed and demonstrated to be very effective in these aggressive cases. Besides the great efficacy, several adverse events (AEs) have been reported in virtually all patients treated with MKIs, largely overlapping between different compounds and including hypertension, diarrhea, anorexia, decreased weight, fatigue, and proteinuria. Most grade 3-4 adverse reactions occur during the first 6 months of treatment and require dosage reduction and/or drug discontinuation. Due to severity of the AEs related to the treatment with MKIs, a multidisciplinary team is definitely required for the daily management of these patients, for the evaluation of the disease status, and the psychophysical condition. Moreover, it is crucial that the patients could have a facilitated access to reach either specialist doctors or nurses who must have been trained to follow them for their individual clinical complications. The follow-up visits should take place at monthly intervals until the sixth month and then every 1-2 months until the completion of the first year of treatment. The flow chart followed at our tertiary center is reported in the present review as a real-life-based example for the follow-up of patients with advanced TC on MKI treatment.

Lenvatinib-induced hypocalcaemia due to transient primary hypoparathyroidism.

CONTEXT: Radioiodine refractory differentiated thyroid cancer can be effectively treated with multi-tyrosine-kinase inhibitors (MKIs). Hypocalcaemia has been reported among the side effects of these drugs, but little is known about its pathophysiology and clinical relevance. CASE REPORT: We report the case of a 78-years-old woman with an aggressive papillary thyroid cancer infiltrating perithyroidal structures. The extent of surgery was limited to hemithyroidectomy, RAI treatment could not be performed, and she started lenvatinib treatment. After 4 months of therapy, the patient accessed the Emergency Department for a grade III hypocalcaemia (corrected serum calcium: 6.6 mg/dL, n.v. 8.1-10.4 mg/dL), due to primary hypoparathyroidism (serum PTH: 12.6 ng/L, n.v. 13-64 ng/L). The patient was treated with intravenous calcium infusions and vitamin D supplementation. After discharge, the oral dose of carbonate calcium (CaCO3) was of 6 g/day, and was titrated according to blood exams. Two weeks after discharge, while taking CaCO3 at the dose of 3 g/day, the patient experienced symptomatic grade II hypercalcemia (corrected serum calcium: 11.6 mg/dL), associated to the spontaneous reprise of PTH secretion, and leading to oral calcium withdrawal. During the subsequent follow-up, the patient remained eucalcemic without calcium supplementation. CONCLUSIONS: Though hypocalcaemia has been described as potential side effect of MKI treatment, this is the first report of a lenvatinib-induced primary hypoparathyroidism, in a patient with a documented normal parathyroid function after surgery. The periodical assessment of calcium-phosphorus metabolism is thus warranted to prevent this potentially lethal side effect, in both post-surgical hypoparathyroid and euparathyroid patients.

Can preoperative 25-hydroxyvitamin D levels predict transient hypocalcemia after total thyroidectomy?

Transient postoperative hypocalcemia is a common complication after total thyroidectomy. Evidence on contributing metabolic factors is contradictory. Our work aims to define the role of preoperative 25-hydroxyvitaminD levels in developing transient postoperative hypocalcemia. 183 consecutive patients who underwent total thyroidectomy at our institution (May 2017-December 2019) were included in the retrospective study. We reported gender, age, estimated glomerular filtration rate, creatinine, preoperative 25-hydroxyvitaminD, serum pre- and postoperative calcium, pre- and postoperative PTH levels and transient postoperative hypocalcemia occurrences. We compared variables both among patients with and without transient postoperative hypocalcemia and between patients with different 25-hydroxyvitaminD levels (< 10 ng/ml deficitary; 11-30 ng/ml insufficient; > 30 ng/ml, normal). A binomial logistic regression model evaluating the risk for transient postoperative hypocalcemia was elaborated. Patients with transient postoperative hypocalcemia had lower levels of postoperative PTH (p < 0.001) and more frequently normal or deficitary 25-hydroxyvitaminD levels (p = 0.05). When comparing patients according to their 25-hydroxyvitaminD levels, insufficiency was associated with a lower rate of transient postoperative hypocalcemia (p = 0.05); deficiency was associated with higher preoperative PTH (p = 0.021), postoperative PTH (p = 0.043) and estimated glomerular filtration rate (p = 0.031) and lower serum creatinine (p = 0.014). In the regression model higher preoperative PTH (OR = 1.011, p = 0.041) and 25-hydroxyvitaminD deficiency (OR = 0.343, p = 0.011) significantly predicted transient postoperative hypocalcemia. Data analysis revealed a correlation between transient postoperative hypocalcemia and 25-hydroxyvitaminD levels: our work points towards the possibility to stratify the risk of transient postoperative hypocalcemia according to patients' preoperative 25-hydroxyvitaminD status.

Post-Surgical Ablative or Adjuvant Radioiodine Therapy Has No Impact on Outcome in 1-4 cm Differentiated Thyroid Cancers without Extrathyroidal Extension.

Whether to conduct remnant ablation or adjuvant radioactive iodine (RAI) therapy in patients with intrathyroidal differentiated thyroid carcinoma (DTC), sized 1.1-4 cm, is debated. We evaluated the impact of RAI on outcome in this category of DTCs. We retrospectively enrolled 308 patients submitted to total thyroidectomy: 198 had tumors sized 1.1-2 cm (Group 1) and 110 of 2.1-4 cm (Group 2). Both groups were divided into patients receiving and not receiving RAI after surgery. RAI+ and RAI- patients did not significantly differ, regarding several clinical and pathological features. Final outcome was defined according to dynamic risk stratification. Remission was observed in the majority of Group 1 and Group 2 patients and outcome did not significantly differ between RAI+ and RAI- patients: respectively, 95.8% vs. 93.7% in Group 1, and 87.7% vs. 86.5% in Group 2. The majority of persistent cases, either RAI+ or RAI-, received therapeutic RAI administration, and about 50% of RAI- cases had an excellent response at final follow up, whereas no RAI+ persistent patients had a beneficial effect. Our findings demonstrate that patients with an intrathyroidal DTC sized 1.1-4 cm do not benefit from RAI. The outcome of these patients remains favorable, and the few patients with persistent diseases can be treated with RAI during follow up.

High Prevalence and Conservative Management of Acute Cholecystitis during Lenvatinib for Advanced Thyroid Cancer.

INTRODUCTION: Lenvatinib (LEN) is a multitarget tyrosine kinase inhibitor currently used for advanced, radioiodine refractory differentiated thyroid cancer (RAI-R DTC). Among adverse events (AEs), nausea, vomiting, and decreased appetite have been frequently described. We aimed to evaluate the prevalence, the clinical presentation, and the effectiveness of conservative treatment of gallbladder disorders in a consecutive series of patient treated with LEN. METHODS: Patients with RAI-R DTC experiencing clinical symptoms suggestive for gallbladder disorders during LEN treatment were evaluated with laboratory investigations and contrast-enhanced abdominal computed tomography (CT) and ultrasound scan (US). RESULTS: After a median time of 2 months from the start of treatment, 5/13 patients (38.4%) complained of gastrointestinal symptoms, with increased biliary enzymes levels, especially γGT, and CT/US suggestive of acute cholecystitis (AC). The onset of symptoms and the peak of γGT levels frequently corresponded to the highest reduction in body weight during the first months of treatment. All patients were treated with supportive care and, when appropriate, with ursodeoxycholic acid; in 4 patients, LEN dose reduction or short interruption was needed, too. CONCLUSIONS: In patients with RAI-R DTC treated with LEN, a high prevalence of AC in the first months of treatment was documented. Mainly due to the low specificity of symptoms such as anorexia, nausea, and vomiting, this AE is likely to be frequently misdiagnosed. The onset of the disease was associated to the weight loss observed during the first months of treatment and contributes to further decrease in body weight. Therefore, particularly during the first months of treatment, or at any time of huge reduction of body weight, monitoring of γGT and US is crucial for prompt diagnosis and treatment. Conservative medical treatment and LEN dosage titration, together with dietary and rehabilitative supports, can limit or avoid the need for drug withdrawal and cholecystectomy.

Total Thyroidectomy Versus Lobectomy for Thyroid Cancer: Single-Center Data and Literature Review.

BACKGROUND: Controversies remain about the ideal risk-based surgical approach for differentiated thyroid cancer (DTC). METHODS: At a single tertiary care institution, 370 consecutive patients with low- or intermediate-risk DTC were submitted to either lobectomy (LT) or total thyroidectomy (TT) and were followed up. RESULTS: Event-free survival by Kaplan-Meier curves was significantly higher after TT than after LT for the patients with either low-risk (P = 0.004) or intermediate-risk (P = 0.032) tumors. At the last follow-up visit, the prevalence of event-free patients was higher in the TT group than in the LT low-risk group (95% and 87.5%, respectively; P = 0.067) or intermediate-risk group (89% and 50%; P = 0.008). No differences in persistence prevalence were found among microcarcinomas treated by LT or TT (low risk, P = 0.938 vs. intermediate-risk, P = 0.553). Nevertheless, 15% of the low-risk and 50% of the intermediate-risk microcarcinomas treated by LT were submitted to additional treatments. On the other hand, macrocarcinomas were significantly more persistent if treated with LT than with TT (low-risk, P = 0.036 vs. intermediate-risk, P = 0.004). Permanent hypoparathyroidism was more frequent after TT (P = 0.01). After LT, thyroglobulin (Tg)/thyroid-stimulating hormone (TSH) had shown decreasing trend in 68% of the event-free patients and an increasing trend in the persistent cases. CONCLUSIONS: Lobectomy can be proposed for low-risk microcarcinomas, although in a minority of cases, additional treatments are needed, and a longer follow-up period usually is required to confirm an event-free outcome compared with that for patients treated with TT. On the other hand, to achieve an excellent response, TT should be favored for intermediate-risk micro- and macro-DTCs despite the higher frequency of postsurgical complications.

Lenvatinib as first-line treatment for advanced thyroid cancer: long progression-free survival.

PURPOSE: Lenvatinib (LEN) has been approved for the treatment of patients with progressive radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Real-life studies reported a lower progression-free survival (PFS) than the registration study, likely due to the more advanced stage of tumors, the more frequent pretreatment with other TKIs, the limited follow-up, and the worse clinical condition of the patients included. METHODS: We evaluated the clinical data of our cohort of 13 consecutive patients, all receiving LEN as a first-line TKI treatment, and followed-up in a single tertiary Center. RESULTS: All patients had an ECOG of 0-1 and regional or distant metastases were documented in 61.5% and 77% of patients, respectively. Median PFS was 22 months (95% CI 14-35) with partial response in 69% and stable disease in 31% of patients. All patients experienced at least one adverse event (AE), the most frequent being fatigue, anorexia, diarrhea, and hypertension. The daily dose was reduced in 70% of patients and only one patient (7.7%) discontinued the drug for AEs. CONCLUSION: In this series of RAI-R DTC patients, with the unique features to have an ECOG 0 or 1 and to be naive for TKI treatments, PFS was the longest among all real-life published so far, with the highest rate of patients with partial response and one of the lowest drug discontinuation rate for AEs. The correct timing of treatment start, the tailoring of the dose, and a proper management of the AEs may have a significant impact on the treatment response to LEN.

Recent advances in the management of anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is undoubtedly the thyroid cancer histotype with the poorest prognosis. The conventional treatment includes surgery, radiotherapy, and conventional chemotherapy. Surgery should be as complete as possible, securing the airway and ensuring access for nutritional support; the current standard of care of radiotherapy is the intensity-modulated radiation therapy; chemotherapy includes the use of doxorubicin or taxanes (paclitaxel or docetaxel) generally with platin (cisplatin or carboplatin). However, frequently, these treatments are not sufficient and a systemic treatment with kinase inhibitors is necessary. These include multitarget tyrosine kinase inhibitors (Lenvatinib, Sorafenib, Sunitinib, Vandetanib, Axitinib, Pazopanib, Pyrazolo-pyrimidine compounds), single target tyrosine kinase inhibitors (Dabrafenib plus Trametinib and Vemurafenib against BRAF, Gefitinib against EGFR, PPARγ ligands (e.g. Efatutazone), Everolimus against mTOR, vascular disruptors (e.g. Fosbretabulin), and immunotherapy (e.g. Spartalizumab and Pembrolizumab, which are anti PD-1/PD-L1 molecules). Therapy should be tailored to the patients and to the tumor genetic profile. A BRAF mutation analysis is mandatory, but a wider evaluation of tumor mutational status (e.g. by next-generation sequencing) is desirable. When a BRAFV600E mutation is detected, treatment with Dabrafenib and Trametinib should be preferred: this combination has been approved by the Food and Drug Administration for the treatment of patients with locally advanced or metastatic ATC with BRAFV600E mutation and with no satisfactory locoregional treatment options. Alternatively, Lenvatinib, regardless of mutational status, reported good results and was approved in Japan for treating unresectable tumors. Other single target mutation agents with fair results are Everolimus when a mutation involving the PI3K/mTOR pathway is detected, Imatinib in case of PDGF-receptors overexpression, and Spartalizumab in case of PD-L1 positive tumors. Several trials are currently evaluating the possible beneficial role of a combinatorial therapy in ATC. Since in this tumor several genetic alterations are usually found, the aim is to inhibit or disrupt several pathways: these combination strategies use therapy targeting angiogenesis, survival, proliferation, and may act against both MAPK and PI3K pathways. Investigating new treatment options is eagerly awaited since, to date, even the molecules with the best radiological results have not been able to provide a durable disease control.