A phase I/II trial of sapanisertib in advanced anaplastic and radioiodine refractory differentiated thyroid carcinoma.

BACKGROUND: There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC), and radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) refractory to multi-kinase inhibitors. This multi-center trial evaluated sapanisertib, a next generation oral kinase inhibitor of mTOR complexes 1/2, in ATC and RAIR DTC. METHODS: A safety run-in phase I was followed by non-randomized phase II trial in ATC, with an exploratory cohort in RAIR DTC. Primary endpoint was proportion of patients with ATC who were without disease progression at 4 months. Safety and survival outcomes were key secondary endpoints. RESULTS: Forty-six patients (20 ATC; 26 DTC) were enrolled including 40 (18 ATC; 22 DTC) who received recommended phase II dose of 5 mg daily. Eleven percent (2/18, 95% C.I.: 1.4-34.7%) of patients with ATC were progression-free at 4 months, 22.2% (4/18) had stable disease as best response. Enrollment in the ATC cohort stopped early with 18 patients out of proposed 23 due to overall futility. One confirmed partial response (4.5%, 1/22) occurred in RAIR DTC, with stable disease in 63.6% (14/22) patients. Median progression-free survival was 1.6 (95% C.I.: 0.9-2.8) months and 7.8 (2.0-not reached) months in ATC and DTC, respectively. Grade 3 treatment related adverse events occurred in 30% of patients who received the phase II dose, most common being anorexia, nausea, diarrhea, fatigue, skin rash and hyperglycemia. Genomic alterations in the PI3 K/AKT/mTOR pathway were not associated with response or PFS. CONCLUSIONS: Sapanisertib monotherapy did not meet the primary endpoint of this trial (proportion progression-free at 4 months) in ATC, and did not show clinically meaningfully activity. Clinical trials with alternative therapeutic strategies are needed. CLINICAL TRIAL REGISTRATION: NCT02244463.

Correlation Between Glycemic Control and Serum Thyroglobulin Levels in a Patient With RAI-Refractory Thyroid Cancer.

Diabetes is a risk factor for thyroid cancer development. Serum thyroglobulin (Tg) levels are useful as sensitive and specific tumor markers for monitoring radioiodine (RAI)-refractory thyroid cancer; however, the impact of glycemic control on serum Tg levels is poorly understood. Here, we present a case of a female patient with lung metastases of RAI-refractory thyroid cancer in whom glycemic control may have influenced the serum Tg levels. Despite receiving thyroid-stimulating hormone suppression therapy, her serum Tg levels remained elevated. Subsequently, she developed type 2 diabetes and was administered antidiabetic medications for 6 years. Throughout the course of diabetes management, her serum Tg levels fluctuated according to the level of glycemic control, showing a strong correlation with her hemoglobin A1c levels (r = 0.92, P < .01). Similar to the serum levels of other tumor markers, such as the carcinoembryonic antigen and carbohydrate antigen 19-9, the serum levels of Tg can be influenced by glycemic control. Therefore, serum Tg levels in patients with RAI-refractory thyroid cancer and diabetes should be monitored with attention to glycemic control.

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.

Tenosynovial Giant Cell Tumor of Foot in a Patient with Radioiodine-Refractory Thyroid Cancer: Imaging Findings on FDG-PET/CT, MRI, and Radioiodine Scan.

We herein illustrate a case of benign tenosynovial giant cell tumor, which was incidentally detected as FDG-avid lesion on PET/CT in a patient with radioiodine refractory thyroid cancer, with predominantly non-iodine concentrating disease. The lesion was followed up clinically and with local MRI annually for subsequent 3 years. The utility of hybrid PET-CT imaging, the non-iodine concentration of the tumor along with clinical knowledge, and findings on other imaging and pathological modalities in answering and diagnosing incidental benign musculoskeletal tumors in a patient with known thyroid malignancy are presented here.

Redifferentiation of Differentiated Thyroid Cancer: Clinical Insights from a Narrative Review of Literature.

Background: Patients who have metastatic differentiated thyroid cancer (mDTC) frequently have negative diagnostic and/or post-therapy radioiodine scans. As a result, 131I therapy is frequently no longer considered a therapeutic option for these patients. However, with the knowledge of genomic alterations of patients with mDTC, the use of selected agents in specific patient groups may be used with the intention to re-establish 131I uptake (i.e., redifferentiation) and additional 131I therapy. The objectives of this narrative review are to present definitions of related terminology, a brief overview of the molecular mechanisms of redifferentiating agents, and a narrative review of the literature for redifferentiation in patients who have radioiodine refractory mDTC. Summary: We searched multiple electronic databases and reviewed the relevant English-language literature reported after 2010. Fourteen articles were included in this narrative review. Conclusions: Preliminary data suggest that select agents may offer potential for re-establishing 131I uptake in selected patients with radioiodine refractory mDTC (e.g., negative diagnostic and/or post-therapy radioiodine scans). These agents may also enhance uptake (e.g., uptake enhancement) in patients who have 131I uptake in mDTC on a diagnostic and/or post-therapy radioiodine scan. As a result, this may facilitate higher absorbed dose delivered (Gy (rad]) per 131I activity administered [GBq (mCi)]. This in turn may increase the likelihood of a better therapeutic effect for the planned administered 131I activity or a reduction in the originally planned administered 131I activity, while achieving the same intended therapeutic effect with potentially less untoward effects. Further studies are warranted to confirm these preliminary observations and to confirm acceptable subsequent 131I therapy responses after redifferentiation and/or uptake enhancement.

Proteomic analysis of radioiodine-refractory differentiated thyroid cancer identifies CHI3L1 upregulation in association with dysfunction of the sodium-iodine symporter.

Radioiodine refractory differentiated thyroid cancer (RR-DTC) is the main factor adversely affecting the overall survival rate of patients with thyroid cancer. The aim of the present study was to investigate the underlying molecular mechanism of pathogenesis of RR-DTC and to explore novel therapeutic targets for clinical treatment. A proteomic analysis was performed using the tumor tissues of patients with RR-DTC. A total of 6 metastatic lymph nodes were collected during lymph node dissection, 3 from patients with RR-DTC and 3 from patients with papillary thyroid cancer. The expression of chitinase-3-like 1 (CHI3L1) and sodium-iodine symporter (NIS) in the tumor tissue was detected by immunohistochemistry (IHC). Western blotting was used to detect the expression of CHI3L1, phosphorylated (p)-MEK and p-ERK1/2 in PTC-K1 cells transfected with CHI3L1 overexpression vector. The proteomic analysis identified 665 differentially expressed proteins (DEPs), including 327 upregulated and 338 downregulated proteins in the RR-DTC group, which were enriched in 59 signaling pathways by Kyoto Encyclopedia of Genes and Genomes database analysis. In particular, CHI3L1 was demonstrated to be significantly upregulated in RR-DTC as evidenced by quantitative proteomic analysis and IHC. Western blotting suggested that the overexpression of CHI3L1 activated the MEK/ERK1/2 signaling pathway, which may lead to NIS dysfunction. In conclusion, the present study suggests that CHI3L1 is a potential molecular target for the radiotherapy of patients with RR-DTC.

Molecular basis and targeted therapies for radioiodine refractory thyroid cancer.

Patients diagnosed with radioiodine refractory thyroid cancer (RAIR-TC) are not amenable to novel 131 I therapy due to the reduced expression of sodium iodide symporter (Na+/I- symporter, NIS) and/or the impairment of NIS trafficking to the plasma membrane. RAIR-TC patients have a relatively poor prognosis with a mean life expectancy of 3-5 years, contributing to the majority of TC-associated mortality. Identifying RAIR-TC patients and selecting proper treatment strategies remain challenging for clinicians. In this review, we demonstrate the updated clinical scenarios or the so-called "definitions" of RAIR-TC suggested by several associations based on 131 I uptake ability and tumor response post-131 I therapy. We also discuss current knowledge of the molecular alterations involved in membrane-localized NIS loss, which provides a preclinical basis for the development of targeted therapies, in particular, tyrosine kinase inhibitors (TKIs), redifferentiation approaches, and immune checkpoint inhibitors.

Pre-therapeutic evaluation and practical management of cardiovascular and renal toxicities in patients with metastatic radioiodine-refractory thyroid cancer treated with lenvatinib.

INTRODUCTION: Multi-receptor tyrosine kinase inhibitors with anti-angiogenic activity, particularly lenvatinib, have become the standard treatment for radioiodine-refractory metastatic differentiated thyroid cancer but are associated with a high incidence of toxicity. Although patients treated with lenvatinib have been shown to have a significant improvement in progression-free survival, lenvatinib-associated toxicity may result in dose reductions, dose interruptions or even complete lenvatinib withdrawal, compromising anti-tumor efficacy. AREAS COVERED: The article covers the main cardiological and renal toxicities of lenvatinib, including hypertension, prolonged QT interval, heart failure, arterial and venous thromboembolic events, proteinuria and renal failure, and proposes appropriate management of these events during lenvatinib therapy. We performed a literature review of cardiovascular and renal toxicities of Lenvatinib in radioiodine-refractory differentiated thyroid cancer. We discussed prophylactic and therapeutic management for each toxicity based on literature and clinical expertise. EXPERT OPINION: Specific pre-therapeutic evaluation and close monitoring of patients treated with lenvatinib is necessary to prevent and detect cardiovascular and/or renal toxicities early, and to propose appropriate management. Oncologists who treat patients with lenvatinib should know how to monitor and treat these adverse events, and when to ask for the advice of a specialist (cardiologist or nephrologist).

Use of multikinase inhibitors/lenvatinib concomitant with radioiodine for the treatment of radioiodine refractory differentiated thyroid cancer.

Thyroid cancer is the most frequent endocrine tumor. However, in locally advanced or metastatic disease we have only two types of treatment at our disposal: radioactive iodine (RAI) when the disease is RAI-sensitive and multikinase inhibitors (MKIs), lenvatinib and sorafenib, when the disease becomes RAI-refractory (RR). This review revisits the published data on the potential combination of MKIs/lenvatinib with RAI in RR-differentiated thyroid cancer and evaluates some special situations where this combination may be of particular interest. The combination of MKIs/lenvatinib with RAI could, at least hypothetically, improve the efficacy seen in both treatments alone via a synergistic effect and with a lower rate of toxicity rates. Early preclinical data support this notion, while its generalized use awaits the results of ongoing clinical trials.

Use of multikinase inhibitors/lenvatinib concomitant with antiresorptive therapy for bone metastases from radioiodine-resistant differentiated thyroid cancer.

Bone is the second most common distant metastasis site in differentiated thyroid cancer (DTC) and is normally associated with the presence of other metastases, which are usually radioiodine-resistant. The presence of bone metastasis (BM) determines low survival and greater morbidity due to the frequency of skeletal-related events (SREs), which can be a serious complication of BM. There is evidence that antiresorptive therapy (AT) reduces SREs in other solid tumors, but not yet in DTC BM, for which data are scant. The same is true for systemic therapy with multikinase inhibitors (MKIs). In general, the results for MKI use are well known, although the effect on BM has rarely been evaluated. While MKIs are indicated in current clinical practice guidelines, studies evaluating the benefits and risks of concomitant treatment with MKIs and AT are lacking, and the available data come from small samples in retrospective studies. The objective of this article is to review the latest evidence for concomitant MKIs and AT.

In Silico Screening and Validation of PDGFRA Inhibitors Enhancing Radioiodine Sensitivity in Thyroid Cancer.

Aberrant activation of platelet-derived growth factor receptor α (PDGFRA) has been implicated in tumorigenesis and radioiodine resistance of thyroid cancer, indicating its therapeutic potential. In the present study, we confirmed the association between PDGFRA and radioiodine resistance in thyroid cancer using bioinformatics analysis and constructed a prediction model of PDGFRA inhibitors using machine learning and molecular docking approaches. We then performed a virtual screening of a traditional Chinese medicine (TCM) derived compound library and successfully identified 4',5,7-trimethoxyflavone as a potential PDGFRA inhibitor. Further characterization revealed a significant inhibitory effect of 4',5,7-trimethoxyflavone on PDGFRA-MAPK pathway activation, and that it could upregulate expression of sodium iodide symporter (NIS) as well as improve radioiodine uptake capacity of radioiodine-refractory thyroid cancer (RAIR-TC), suggesting it a potential drug lead for the development of new RAIR-TC therapy.

2-[18F]FDG PET in the Management of Radioiodine Refractory Differentiated Thyroid Cancer in the Era of Thyrosin-Kinases Inhibitors: A Real-Life Retrospective Study.

Purpose To evaluate the role of 2-[18F]FDGPET/CT in the follow-up of radioiodine refractory thyroid cancer (RR-TC). Methods Forty-six 2-[18F]FDGPET/CT scans from 14 RR-TC patients were considered. Thyroid function tests: thyroglobulin (Tg), levothyroxine (LT4), and tyrosine-kinases inhibitors (TKIs) assumptions were recorded. Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) were calculated from each scan and correlated with clinical parameters and the overall survival (OS). Results Baseline TLG and MTV predicted OS (p = 0.027 and p = 0.035), and negative correlation with OS was also confirmed when the same parameters were measured in follow-up scans (p = 0.015 and p = 0.021). Tg also correlated with the OS; (p = 0.014; p = 0.019 and p = 0.009). However, TLG and MTV were not significantly correlated with Tg levels. MTV and TLG variation in time were reduced during TKI therapy (p = 0.045 and p = 0.013). Conclusions 2-[18F]FDGPET/CT confirmed its prognostic role at the first assessment and during the follow-up of RR-TC patients. 2-[18F]FDGPET/CT parameters seem at least partially independent from Tg. TKI therapy resulted in a measurable effect on the variation of 2-[18F]FDGPET/CT parameters over time.

Enhancing Radioiodine Incorporation in BRAF-Mutant, Radioiodine-Refractory Thyroid Cancers with Vemurafenib and the Anti-ErbB3 Monoclonal Antibody CDX-3379: Results of a Pilot Clinical Trial.

Background: Oncogenic activation of mitogen-activated protein kinase (MAPK) signaling is associated with radioiodine refractory (RAIR) thyroid cancer. Preclinical models suggest that activation of the receptor tyrosine kinase erbB-3 (HER3) mitigates the MAPK pathway inhibition achieved by BRAF inhibitors in BRAFV600E mutant thyroid cancers. We hypothesized that combined inhibition of BRAF and HER3 using vemurafenib and the human monoclonal antibody CDX-3379, respectively, would potently inhibit MAPK activation and restore radioactive iodine (RAI) avidity in patients with BRAF-mutant RAIR thyroid cancer. Methods: Patients with BRAFV600E RAIR thyroid cancer were evaluated by thyrogen-stimulated iodine-124 (124I) positron emission tomography-computed tomography (PET/CT) at baseline and after 5 weeks of treatment with oral vemurafenib 960 mg twice daily alone for 1 week, followed by vemurafenib in combination with 1000 mg of intravenous CDX-3379 every 2 weeks. Patients with adequate 124I uptake on the second PET/CT then received therapeutic radioactive iodine (131I) with vemurafenb+CDX-3379. All therapy was discontinued two days later. Treatment response was monitored by serum thyroglobulin measurements and imaging. The primary endpoints were safety and tolerability of vemurafenib+CDX-3379, as well as the proportion of patients after vemurafenb+CDX-3379 therapy with enhanced RAI incorporation warranting therapeutic 131I. Results: Seven patients were enrolled; six were evaluable for the primary endpoints. No grade 3 or 4 toxicities related to CDX-3379 were observed. Five patients had increased RAI uptake after treatment; in 4 patients this increased uptake warranted therapeutic 131I. At 6 months, 2 patients achieved partial response after 131I and 2 progression of disease. Next-generation sequencing of 5 patients showed that all had co-occurring telomerase reverse transcriptase promoter alterations. A deleterious mutation in the SWItch/Sucrose Non-Fermentable (SWI/SNF) gene ARID2 was discovered in the patient without enhanced RAI avidity after therapy and an RAI-resistant tumor from another patient that was sampled off-study. Conclusions: The endpoints for success were met, providing preliminary evidence of vemurafenib+CDX-3379 safety and efficacy for enhancing RAI uptake. Preclinical data and genomic profiling in this small cohort suggest SWI/SNF gene mutations should be investigated as potential markers of resistance to redifferentiation strategies. Further evaluation of vemurafenib+CDX-3379 as a redifferentiation therapy in a larger trial is warranted (ClinicalTrials.gov: NCT02456701).

Radioiodine Refractory Follicular Thyroid Cancer and Surgery for Cervical Relapse.

Compared to its more common counterpart papillary thyroid cancer (PTC), follicular thyroid cancer (FTC) has a less favorable outcome, due to its higher incidence of distant metastases and advanced stages at diagnosis. Despite radioiodine (RAI) avidity, metastatic FTC often progresses after radioiodine treatment (RAIT). We aimed at evaluating the indications and outcomes of surgery for cervical relapse of radioiodine refractory FTC. Patients receiving RAIT between 2005 and 2015 at the University Hospital of Cologne, Germany, were screened. Patients with FTC were identified. Demographics, clinic-pathologic characteristics, treatment, and outcome of patients diagnosed with RAI refractory FTC, who underwent cervical surgery in the course of disease, were analyzed. FTC accounted for 8.8% of all thyroid carcinomas undergoing RAIT. In 35.2% of FTC patients, disease persisted or recurred despite a cumulative mean RAI activity of 18.7 GBq ± 11.6 (follow-up 83.5 ± 56.7 months). Distant metastases were diagnosed in 75% of these patients, as bone (57.6%), lung (54.6%), and liver metastases (12.1%). Cervical relapse occurred in 63.6% of these patients and was treated in 57.1% with surgery with, and without, external beam radiation therapy (EBRT). Despite surgery and EBRT, in 75% of patients, cervical relapse recurred again. In conclusion, surgery for cervical radioiodine refractory FTC relapse is often performed in metastatic setting. With and without EBRT, cure is rare, although metastases can appear radioiodine avid. Early biological marker and systemic treatments for these patients are still needed.

Prevalence and Risk Factors of Developing Fistula or Organ Perforation in Patients Treated with Lenvatinib for Radioiodine-Refractory Thyroid Cancer.

INTRODUCTION: Tyrosine kinase inhibitors represent a better treatment in patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Lenvatinib is usually well-tolerated, but sometimes, it is associated with serious and even life-threatening side effects. The aim of this study was to evaluate the prevalence of and the potential risk factors for fistula and/or organ perforation in RAI-R DTC patients treated with lenvatinib. METHODS: This study included data from advanced and progressive RAI-R DTC patients treated with lenvatinib from February 2011 to February 2020 who were followed up at a single center. The clinical-pathological features and the biochemical and morphological results of the patients were collected at the time of starting lenvatinib and during the follow-up. RESULTS: Fourteen of 95 (14.7%) locally advanced or metastatic RAI-R DTC patients treated with lenvatinib developed a fistula or organ perforation. Nine of 14 (64.3%) patients had tumor infiltration of the trachea, bronchus, esophagus, pleura, or bladder. Five of 14 (35.7%) had a bowel perforation, but only 2 had preexisting diverticulosis. Evaluation of the risk factors for developing a fistula or organ perforation showed that the presence of tumor infiltration and the tumor histology (papillary and poorly differentiated vs. follicular and Hurthle thyroid cancer) were significantly correlated with the development of a fistula or organ perforation (p = 0.003 and p = 0.02, respectively). In the subgroup of patients with tumor infiltration, we found that the papillary thyroid cancer histotype was the only potential predictor of fistula development. External beam radiation therapy (EBRT), the starting dose of lenvatinib, and the duration of treatment were not relevant for the development of fistula. CONCLUSIONS: In metastatic thyroid cancer patients treated with lenvatinib, the presence of tumor infiltration and histological type should be considered as potential risk factors for the development of fistula or organ perforation, although they do not represent an absolute contraindication. Although EBRT and the presence of diverticulosis were not significantly associated with the development of fistula and organ perforation, they should be regarded as potential additional reasons for the development of these complications. According to our findings, there is no reason to start lenvatinib at a lower daily dose when tumor infiltration is present.

Coexistent thyroid and lung cancers resembling "flip-flop" phenomenon.

The "flip-flop" phenomenon may be present in differentiated progressive thyroid cancer. A high suspicion index must be maintained when this phenomenon coexists with a high tumor burden, due to the risk of the appearance of distinct tumors.

Real-World Efficacy and Safety of Multi-Tyrosine Kinase Inhibitors in Radioiodine Refractory Thyroid Cancer.

Background: The management of patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that is refractory to radioiodine (RAI) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib have been approved based on phase 3 clinical trials. Patients and Methods: We aimed at describing the efficacy and safety of TKI treatment of RAI-refractory DTC in a real-world setting at six German referral centers. One hundred and one patients with locally advanced or metastatic RAI-refractory DTC treated with sorafenib, lenvatinib, and/or pazopanib were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated by using the Kaplan-Meier method. Results: Ninety-seven of 101 patients had progressive disease before TKI initiation. The median PFS for first-line treatment with sorafenib (n = 33), lenvatinib (n = 53), and pazopanib (n = 15) was 9 (95% confidence interval 5.2-12.8), 12 (4.4-19.6), and 12 months (4.4-19.6), respectively. The median OS for first-line treatment was 37 (10-64) for sorafenib, 47 (15.5-78.5) for lenvatinib, and 34 months (20.2-47.8) for pazopanib. Serious complications (e.g., hemorrhage, acute coronary syndrome, and thrombosis/venous thromboembolism) occurred in 16 out of 75 (21%) patients taking lenvatinib, in 3 out of 42 (7%) patients taking sorafenib, and in 3 out of 24 (13%) patients taking pazopanib. Conclusions: Sorafenib, lenvatinib, and pazopanib are effective treatment options in the majority of patients with RAI-refractory DTC. The PFS and six-month survival rate in patients treated with lenvatinib und pazopanib appear to compare favorably with sorafenib in the first-line treatment setting. However, a more advanced disease stage at treatment initiation in sorafenib- and pazopanib-treated patients in the era before TKI-approval and the retrospective nature of this study precludes a direct comparison of TKIs.

Effect of Kinase Inhibitors on the Technetium-99m Uptake into Thyroid Carcinoma Cells In Vitro.

BACKGROUND/AIM: We evaluated the potential of the kinase inhibitors sorafenib, lenvatinib and selumetinib on increasing the uptake of technetium-99m into thyroid cancer cells. MATERIALS AND METHODS: Four established cell lines and three patient's cell cultures were treated with 0.1, 1 and 5 µM of sorafenib, lenvatinib and selumetinib for 72 hours. After incubation with 1 MBq of technetium-99m, the radioactivity uptake was measured. RESULTS: The experiments showed heterogeneous results. Maximum technetium-99m uptake increases of 312% (sorafenib), 326% (lenvatinib) and 759% (selumetinib) were obtained using the highest applied concentrations. In some tests, an uptake reduction or no effect was observed. CONCLUSION: Kinase inhibitors have a positive effect on technetium-99m uptake. Due to study limitations, a redifferentiating effect of the drugs could not be definitely proven. Unspecific cytotoxicity might have a confounding effect.

Role of laser ablation in multimodal treatment of radioiodine- refractory bone metastases of thyroid cancer: a retrospective study.

PURPOSE: To assess the efficacy, safety, and pain benefits of imaging-guided laser ablation (IGLA) in patients with radioiodine-refractory (RR) bone metastases from differentiated thyroid carcinoma (DTC). PATIENTS AND METHODS: The institutional medical records of patients with bone metastases from DTC treated with laser ablation (LA) were reviewed retrospectively. Local response, complications, and effects on pain relief were investigated. RESULTS: Six osteolytic lesions in five patients (one male, four females; mean age 65.4 ± 5.1 years, range 58-72) were treated with IGLA. All lesions were osteolytic and all have had previous treatments with high-dose radioiodine therapy followed by external radiotherapy (EBRT). All patients assumed opioid analgesics for severe pain. Overall, the lesions (mean size 5.8 ± 3.2 cm; median 5.0 cm, range 3.0-12.0 cm) underwent nine IGLA sessions (mean 1.8 ± 0.4 sessions; median 2.0 sessions, range 1-2). In four (80%) out five lesions, cross-sectional imaging showed a nearly complete response (CR) while the largest lesion was ablated by 80%. Pain changes were assessed with the Brief Pain Inventory-Short Form, that was administered before IGLA and during a 6-month follow-up. Patients experienced significant reduction in worst pain, average pain, and pain interference. Following IGLA, the average daily opioid requirement rapidly and progressively decreased. Treatments were well-tolerated and no major complications occurred. CONCLUSIONS: IGLA is an effective and safe debulking procedure and provides significant pain relief in patients suffering from DTC bone metastases that are not responsive to standard treatments. So, IGLA could be considered as part of a multimodality management of advanced thyroid cancer with RR metastatic skeletal involvement.

2019 European Thyroid Association Guidelines for the Treatment and Follow-Up of Advanced Radioiodine-Refractory Thyroid Cancer.

The vast majority of thyroid cancers of follicular origin (TC) have a very favourable outcome, but 5-10% of cases will develop metastatic disease. Around 60-70% of this subset, hence less than 5% of all patients with TC, will become radioiodine refractory (RAI-R), with a significant negative impact on prognosis and a mean life expectancy of 3-5 years. Since no European expert consensus or guidance for this challenging condition is currently available, a task force of TC experts was nominated by the European Thyroid Association (ETA) to prepare this document based on the principles of clinical evidence. The task force started to work in September 2018 and after several revision rounds, prepared a list of recommendations to support the treatment and follow-up of patients with advanced TC. Criteria for advanced RAI-R TC were proposed, and the most appropriate diagnostic tools and the local, systemic and palliative treatments are described. Systemic therapy with multikinase inhibitors is fully discussed, including recommendations on how to start it and at which dosage, on the duration of treatment, and on the management of side effects. The appropriate relationship between the specialist and the patient/family as well as ethical issues are covered. Based on the available studies and on personal experience, the experts provided 39 recommendations aimed to improve the management of advanced RAI-R TCs. Above all of them is the indication to treat and follow these patients in a specialized setting which allows the interaction between several specialists in a multidisciplinary team.