Adrenal insufficiency in thyroid cancer patients treated with tyrosine kinase inhibitors and detected by ACTH stimulation test.

PURPOSE: Advanced thyroid cancer patients treated with tyrosine kinase inhibitors (TKI) can develop several adverse events (AEs), including adrenal insufficiency (AI). METHODS: We studied 55 patients treated with TKI for radioiodine-refractory or medullary thyroid cancer. The adrenal function was evaluated during follow-up by performing serum basal ACTH, and basal and ACTH-stimulated cortisol. RESULTS: Twenty-nine/55 (52.7%) patients developed subclinical AI during TKI treatment as demonstrated by a blunted cortisol response to ACTH stimulation. All cases showed normal values of serum sodium, potassium and blood pressure. All patients were immediately treated, and none showed an overt AI. Cases with AI were all negative for adrenal antibodies and did not show any adrenal gland alteration. Other causes of AI were excluded. The onset time of the AI, as measured in the subgroup with a first negative ACTH test, was < 12 months in 5/9 (55.6%), between 12 and 36 months in 2/9 (22.2%) and > 36 months in 2/9 (22.2%) cases. In our series, the only prognostic factor of AI was the elevated, although moderate, basal level of ACTH when the basal and stimulated cortisol were still normal. The glucocorticoid therapy improved fatigue in most patients. CONCLUSIONS: Subclinical AI can be developed in > 50% of advanced thyroid cancer patients treated with TKI. This AE can develop in a wide period ranging from < 12 to > 36 months. For this reason, AI must be looked for throughout the follow-up to be early recognized and treated. A periodic ACTH stimulation test, every 6-8 months, can be helpful.

Radio-iodine refractory thyroid cancer patients: a tailored follow-up based on clinicopathological features.

OBJECTIVE: To report the experience of a single center for the selection of radioiodine-refractory (RAIR) thyroid cancer patients (RAIR-TC) who needed tyrosine kinase inhibitor (TKIs) treatment. PATIENTS AND METHODS: We evaluated all features of 279 RAIR-TC patients both at the time of diagnosis and at the RAIR diagnosis. RESULTS: Ninety-nine patients received indication to TKIs (Group A), while 180 remained under active surveillance (Group B). Group A had greater tumor size, more aggressive histotype, more frequent macroscopic extrathyroidal extension, distant metastases, advanced AJCC stage, and higher ATA risk of recurrence. After RAIR diagnosis, 93.9% of Group A had progression of disease (PD) after which TKIs' therapy was started. The remaining 6.1% of patients had a so severe disease at the time of RAIR diagnosis that TKIs' therapy was immediately started. Among Group B, 42.7% had up to 5 PD, but the majority underwent local treatments. The mean time from RAIR diagnosis to the first PD was shorter in Group A, and the evidence of PD within 25 months from RAIR diagnosis was associated with the decision to start TKIs. CONCLUSIONS: According to our results, a more tailored follow-up should be applied to RAIR-TC patients. A too strict monitoring and too many imaging evaluations might be avoided in those with less-aggressive features and low rate of progression. Conversely, RAIR-TC with an advanced stage at diagnosis and a first PD occurring within 25 months from RAIR diagnosis would require a more stringent follow-up to avoid a late start of TKIs.

Management of patients with extensive locally advanced thyroid cancer: results of multimodal treatments.

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.

Osteonecrosis of the jaw: a rare but possible side effect in thyroid cancer patients treated with tyrosine-kinase inhibitors and bisphosphonates.

Osteonecrosis of the jaw (ONJ) is a rare but very serious disease that can affect both jaws. It is defined as exposed bone in the maxillofacial region that does not heal within 8 weeks after a health care provider identification. ONJ can occur spontaneously or can be due to drugs like bisphosphonates (BPS) and anti-RANK agents, in patients with no history of external radiation therapy in the craniofacial region. Although in phase 3 trials of tyrosine kinase inhibitors (TKIs) used in thyroid cancer (TC) the ONJ was not reported among the most common side effects, several papers reported the association between ONJ and TKIs, both when they are used alone and in combination with a bisphosphonate. The appearance of an ONJ in a patient with metastatic radio-iodine refractory differentiated TC, treated with zoledronic acid and sorafenib, has put us in front of an important clinical challenge: when a ONJ occurred during TKIs treatment, it really worsens the patients' quality of life. We should consider that in the case of ONJ a TKI discontinuation becomes necessary, and this could lead to a progression of neoplastic disease. The most important aim of this review is to aware the endocrinologists/oncologists dealing with TC to pay attention to this possible side effect of BPS and TKIs, especially when they are used in association. To significantly reduced the risk of ONJ, both preventive measures before initiating not only antiresorptive therapy but also antiangiogenic agents, and regular dental examinations during the treatment should always be proposed.

Lenvatinib as a salvage therapy for advanced metastatic medullary thyroid cancer.

PURPOSE: Patients with advanced progressive metastatic medullary thyroid cancer (MTC), show poor prognosis and few available systemic therapeutic options. After the loss of clinical benefit with other tyrosine kinase inhibitors (TKI), we evaluated the use of lenvatinib as salvage therapy. METHODS: Ten patients who experienced the loss of clinical benefit after treatment with at least one previous TKI, were treated with lenvatinib. We assessed patient's response immediately before, at the first (first-EV) and last (last-EV) evaluation, after the beginning of treatment. RESULTS: At first-EV, one patient died, while all the remaining 9 showed a stable disease (SD) in the target lesions. At last-EV, SD was still observed in seven patients, while partial response (PR) and progressive disease (PD), in one patient each. Conversely, analyzing all target and non-target lesions, at first-EV, we observed PR in one patient and SD in eight patients. At last-EV, PR was shown in two patients and SD was shown in seven. Bone metastases showed stable disease control at both first-EV and last-EV in only approximately 60% of cases. Tumor markers (CTN and CEA) decreased at first-EV, while they increased at last-EV. Seven patients experienced at least one dose reduction during treatment with lenvatinib. CONCLUSIONS: In this real-life clinical experience, lenvatinib showed interesting results as salvage therapy in patients with advanced progressive metastatic MTC patients. Its usefulness could be effective in patients without any other available treatment, because previously used or unsuitable, especially with negative RET status with no access to the new highly selective targeted therapies.

mRECIST criteria to assess recurrent thyroid carcinoma treatment response after radiofrequency ablation: a prospective study.

PURPOSE: Surgical removal is recommended for recurrent thyroid carcinomas (RTCs) unable to uptake radioiodine and/or not responsive to chemotherapy. However, repeated neck dissection is difficult for surgeons. Thus, radiofrequency ablation (RFA) was proposed for RTCs. The aim of this prospective study is to assess RTC treatment response after RFA, according to well-established criteria. METHODS: Sixteen lesions in 13 patients were treated by RFA. All patients refused/were excluded from repeated surgery or other conventional therapy. CT and US examinations were performed before RFA to evaluate lesion volume and vascularization. All RFA procedures were performed under US-guidance by an 18-gauge, electrode. Treatment response was evaluated by CT, according to RECIST 1.1 and to mRECIST guidelines; CT examinations were performed during follow-up (6-18 months); the volume of residual vital tumour tissue and the percentage of necrotic tissue were estimated by contrast enhanced CT. RESULTS: RFA was well tolerated by all patients; in two cases laryngeal nerve paralysis was observed. Mean pre-treatment volume was 4.18 ± 3.53 ml. Vital tumour tissue and percentage of necrosis at 6, 12 and 18 months were 0.18 ± 0.25, 0.11 ± 0.13, 0.29 ± 0.40 ml and 91.9 ± 11.1, 90.4 ± 13.3, 80.8 ± 23.1%. According to RECIST 1.1, target lesion response was classified as complete response (CR) in one case, partial response (PR) in 11/16, stable disease in 4/16 cases. According to mRECIST, 11/16 cases were classified as CR and the remaining 5 as PR. CONCLUSION: RFA is a safe procedure to treat the viable tumour tissue and to reduce the RTC volume; as to the criteria to assess treatment response, mRECIST appears to be more accurate.

Use of low-dose radioiodine ablation for Graves' orbitopathy: results of a pilot, perspective study in a small series of patients.

OBJECTIVE: Elimination of thyroid antigens by total thyroid ablation (TTA), namely, thyroidectomy followed by radioiodine, may be beneficial for Graves' Orbitopathy (GO). TTA is usually performed with a 131I dose of 30 mCi. In Italy, this dose must be followed by a 24-h protected hospitalization, with increase in the waiting lists. In contrast, a 15 mCi dose can be given without hospitalization and with lower costs. Here, we investigated whether a lower dose of radioiodine can be used to ablate thyroid remnants in patients with GO, after thyroidectomy. METHODS: The study was performed in two small groups of consecutive thyroidectomized patients (six patients per group) with Graves' hyperthyroidism and GO. Patients underwent ablation with either 15 or 30 mCi of 131I following treatment with recombinant human TSH (rhTSH). The primary outcome was rhTSH-stimulated serum thyroglobulin (Tg) at 6 months. The secondary outcome was baseline Tg at 6 months. RESULTS: Baseline Tg and rhTSH-stimulated Tg after at 6 months did not differ between two groups, suggesting a similar extent of ablation. rhTSH-stimulated Tg was reduced significantly compared with rhTSH-stimulated Tg at ablation in both groups. GO outcome following treatment with intravenous glucocorticoids did not differ between the two groups. CONCLUSIONS: Our findings may provide a preliminary basis for the use of a 15 mCi dose of radioiodine upon rhTSH stimulation in thyroidectomized patients with Graves' hyperthyroidism and GO.

Classical point mutations of RET, BRAF and RAS oncogenes are not shared in papillary and medullary thyroid cancer occurring simultaneously in the same gland.

BACKGROUND: Papillary (PTC) and medullary (MTC) thyroid carcinomas represent two distinct entities, but quite frequently, they may occur simultaneously. AIM: To provide genetic analysis of PTC and MTC occurring in the same patient (PTC/MTC) to elucidate their origin. METHODS: Sequencing analysis of RAS, BRAF and RET oncogenes hot spots mutations in tumoral and normal tissues of 24 PTC/MTC patients. RESULTS: Two of 24 patients (8.3 %) were affected by familial MTC (FMTC) harboring RET germline mutations in all tissues. Eight of 22 (36.4 %) sporadic cases did not show any somatic mutation in the three tissue components. Considering the MTC component, 10/22 (45.4 %) patients did not show any somatic mutation, 7 of 22 (31.8 %) harbored the M918T RET somatic mutation and 4/22 (18.2 %) presented mutations in the H-RAS gene. In an additional case (1/22, 4.6 %), H-RAS and RET mutations were simultaneously present. Considering the PTC component, 1 of 24 (4.2 %) patients harbored the V600E BRAF mutation, 1 of 24 (4.2 %) the T58A H-RAS mutation and 1 of 24 (4.2 %) the M1T K-RAS mutation, while the remaining PTC cases did not show any somatic mutation. In one case, the MTC harbored a RET mutation and the PTC a BRAF mutation. None of the mutations found were present in both tumors. CONCLUSIONS: To our knowledge, this is the first study analyzing a possible involvement of RET, BRAF and RAS oncogene mutations in PTC/MTC. These data clearly suggest that the classical activating mutations of the oncogenes commonly involved in the pathogenesis of PTC and MTC may not be responsible for their simultaneous occurrence.

Detection of metastases from differentiated thyroid cancer by different imaging techniques (neck ultrasound, computed tomography and [18F]-FDG positron emission tomography) in patients with negative post-therapeutic ¹³¹I whole-body scan and detectable serum thyroglobulin levels.

INTRODUCTION: DTC patients having detectable Tg and negative post-therapeutic (131)I-WBS have to be investigated by different imaging techniques to detect metastases. PURPOSE: Comparison of neck US, CT and [18F]-FDG PET scan. METHODS: In 49 DTC patients with biochemical disease, neck was examined by US, CT and [18F]-FDG PET. FNA was performed and Tg was determined by FNA-Tg in selected cases of suspicious lymph nodes. Thorax was examined by CT and PET. Serum Tg was measured on LT4 therapy (basal Tg) and after the stimulation with recombinant human TSH (peak Tg). RESULTS: A thyroid remnant was seen by US, CT and PET in eight patients; recurrences were seen by US, CT and PET in six, five and five patients, respectively. Two metastatic nodes were identified by US and CT but not by PET. Lung micronodules were detected by CT in 7/49 (14.3 %) patients and by FDG PET in three of them. Basal Tg ranged from 0.5-1,725 ng/ml while peak Tg ranged from 0.5 to 2,135 ng/ml: the distribution between positive and negative patients was similar. Bone scan was negative in all cases. CONCLUSIONS: In DTC patients with detectable Tg and negative I-131 post-therapy WBS, imaging examination revealed remnant or metastases in 43 % of cases. Remnant and recurrences were equally detected by the three techniques; US was better than [18F]-FDG PET for lymph node metastases since this latter method can give false both positive and negative results; chest examination is best made by CT versus FDG PET due to its higher spatial resolution.