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Hyperthyroidism is characterised by increased thyroid hormone synthesis and secretion from the thyroid gland, whereas thyrotoxicosis refers to the clinical syndrome of excess circulating thyroid hormones, irrespective of the source. The most common cause of hyperthyroidism is Graves' disease, followed by toxic nodular goitre. Other important causes of thyrotoxicosis include thyroiditis, iodine-induced and drug-induced thyroid dysfunction, and factitious ingestion of excess thyroid hormones. Treatment options for Graves' disease include antithyroid drugs, radioactive iodine therapy, and surgery, whereas antithyroid drugs are not generally used long term in toxic nodular goitre, because of the high relapse rate of thyrotoxicosis after discontinuation. β blockers are used in symptomatic thyrotoxicosis, and might be the only treatment needed for thyrotoxicosis not caused by excessive production and release of the thyroid hormones. Thyroid storm and hyperthyroidism in pregnancy and during the post-partum period are special circumstances that need careful assessment and treatment.

In a phase 3, placebo-controlled study, lenvatinib was associated with a significant increase in progression-free survival (18.3 months vs. 3.6 months). Toxic effects with lenvatinib were substantial and included hypertension, diarrhea, and unexplained death. The 10-year survival rate among patients with differentiated thyroid cancer that is refractory to radioiodine (iodine-131) therapy is 10% from the time of detection of metastasis. 1 – 3 Although treatment options have historically been limited, efforts have first targeted vascular endothelial growth factor (VEGF) and its receptor (VEGFR), since this signaling network has been associated with the aggressiveness and metastasis of thyroid cancer. 4 – 6 However, other molecular pathways of tumor growth and maintenance beyond VEGF-driven angiogenesis contribute to the pathogenesis of thyroid cancer, including BRAF, NRAS, HRAS, RET/PTC, fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR). 7 – 16 Because . . .

This trial compared two thyrotropin-stimulation methods and two 131I doses for postoperative ablation in patients with low-risk thyroid cancer. Rates of ablation were similar in all treatment groups. Doses lower than those currently recommended may be adequate for this condition. Radioiodine ( 131 i) is administered to patients with thyroid cancer after total thyroidectomy for three reasons 1 – 3 : first, to eradicate normal-thyroid remnants (ablation) in order to achieve an undetectable serum thyroglobulin level; second, to irradiate any neoplastic focus in order to decrease the risk of recurrence; and third, to perform 131 I total-body scanning for persistent carcinoma. Successful ablation is defined by the combination of undetectable serum thyroglobulin levels after thyrotropin stimulation and normal results on neck ultrasonography 6 to 12 months after 131 I administration. 2 , 3 When these criteria are met, approximately 1% of patients have a recurrence. 4 – 6 In . . .

In this trial, low-dose radioiodine was as effective as high-dose radioiodine in patients with differentiated thyroid tumors, and recombinant human thyrotropin (thyrotropin alfa) was as effective as thyroid hormone withdrawal. Thyroid cancer is the most frequently occurring endocrine cancer, with more than 2100 new cases each year in the United Kingdom and more than 48,000 in the United States. 1 , 2 Most cases are differentiated thyroid cancer, which is associated with a high 10-year survival rate (90 to 95%). 3 Many patients with differentiated thyroid cancer undergo radioiodine ablation to remove residual normal thyroid tissue after surgery. Some nonrandomized studies have suggested that radioiodine ablation reduces rates of death and recurrence. 4 – 7 However, there is uncertainty over the dose (administered activity) of radioiodine required for effective ablation. A systematic review of randomized . . .

In this randomized phase 3 trial involving patients with low-risk differentiated thyroid cancer undergoing thyroidectomy, a follow-up strategy that did not involve the use of radioiodine was noninferior to the use of radioiodine in the response to treatment at 3 years.

Diffuse intrinsic pontine glioma is one of the deadliest central nervous system tumours of childhood, with a median overall survival of less than 12 months. Convection-enhanced delivery has been proposed as a means to efficiently deliver therapeutic agents directly into the brainstem while minimising systemic exposure and associated toxic effects. We did this study to evaluate the safety of convection-enhanced delivery of a radioimmunotherapy agent targeting the glioma-associated B7-H3 antigen in children with diffuse intrinsic pontine glioma. We did a phase 1, single-arm, single-centre, dose-escalation study at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients were aged 3–21 years and had diffuse intrinsic pontine glioma as diagnosed by consensus of a multidisciplinary paediatric neuro-oncology team; a Lansky (patients <16 years of age) or Karnofsky (patients ≥16 years) performance score of at least 50 at study entry; a minimum weight of 8 kg; and had completed external beam radiation therapy (54·0–59·4 Gy at 1·8 Gy per fraction over 30–33 fractions) at least 4 weeks but no more than 14 weeks before enrolment. Seven dose-escalation cohorts were planned based on standard 3 + 3 rules: patients received a single infusion of 9·25, 18·5, 27·75, 37, 92·5, 120·25, or 148 MBq, respectively, at a concentration of about 37 MBq/mL by convection-enhanced delivery of the radiolabelled antibody [124I]-8H9. The primary endpoint was identification of the maximum tolerated dose. The analysis of the primary endpoint was done in the per-protocol population (patients who received the full planned dose of treatment), and all patients who received any dose of study treatment were included in the safety analysis. This study is registered with ClinicalTrials.gov, number NCT01502917, and is ongoing with an expanded cohort. From April 5, 2012, to Oct 8, 2016, 28 children were enrolled and treated in the trial, of whom 25 were evaluable for the primary endpoint. The maximum tolerated dose was not reached as no dose-limiting toxicities were observed. One (4%) of 28 patients had treatment-related transient grade 3 hemiparesis and one (4%) had grade 3 skin infection. No treatment-related grade 4 adverse events or deaths occurred. Estimated volumes of distribution (Vd) were linearly dependent on volumes of infusion (Vi) and ranged from 1·5 to 20·1 cm3, with a mean Vd/Vi ratio of 3·4 (SD 1·2). The mean lesion absorbed dose was 0·39 Gy/MBq 124I (SD 0·20). Systemic exposure was negligible, with an average lesion-to-whole body ratio of radiation absorbed dose higher than 1200. Convection-enhanced delivery in the brainstem of children with diffuse intrinsic pontine glioma who have previously received radiation therapy seems to be a rational and safe therapeutic strategy. PET-based dosimetry of the radiolabelled antibody [124I]-8H9 validated the principle of using convection-enhanced delivery in the brain to achieve high intra-lesional dosing with negligible systemic exposure. This therapeutic strategy warrants further development for children with diffuse intrinsic pontine glioma. National Institutes of Health, The Dana Foundation, The Cure Starts Now, Solving Kids' Cancer, The Lyla Nsouli Foundation, Cookies for Kids' Cancer, The Cristian Rivera Foundation, Battle for a Cure, Cole Foundation, Meryl & Charles Witmer Charitable Foundation, Tuesdays with Mitch Charitable Foundation, and Memorial Sloan Kettering Cancer Center.

Patients with differentiated thyroid cancer can often be treated with postoperative radioiodine (also called radioiodine ablation) after total thyroidectomy. The IoN trial was designed to assess whether recurrence-free survival was non-inferior after no ablation compared with ablation in patients with low-risk differentiated thyroid cancer. IoN was a multicentre, non-inferiority, phase 3 randomised trial conducted at 33 UK cancer centres. Eligible patients had complete (R0) resection following total thyroidectomy; stage pT1, pT2, pT3 (according to Tumour, Node, Metastasis staging version 7 [TNM7]), or pT3a (according to TNM8) disease; and N0, Nx, or N1a disease. Participants were randomly assigned (1:1) by minimisation, using a central electronic system, to have either 1·1 GBq ablation or no ablation, following thyroidectomy. Stratification factors were centre, age, T stage, and nodal status. Patients had annual neck ultrasound scans and 6-monthly serum thyroglobulin measurements. The primary endpoint was 5-year recurrence-free survival, defined by the absence of locoregional recurrent or persistent structural disease, distant metastases, or death from thyroid cancer. Non-inferiority was assessed with a margin of 5 percentage points. Per-protocol and intention-to-treat (ITT) analyses were done for the primary endpoint, and safety was analysed in the per-protocol population. The trial is registered with ClinicalTrials.gov (NCT01398085), ISRCTN (ISRCTN80416929), and EUDRACT (2011–000144–21), and is still in active follow-up. We recruited 504 patients (including 390 [77%] female patients and 114 [23%] male patients) between June 26, 2012 and March 18, 2020 and randomly assigned 251 to receive no ablation and 253 to receive ablation (ITT population). 249 patients in the no ablation group did not have ablation and 231 in the ablation group had ablation (per-protocol population). Median follow-up was 6·8 years (IQR 5·6–8·6) in the no ablation group and 6·6 years (4·8–8·5) in the ablation group; 17 recurrences (eight in the no ablation group and nine in the ablation group; ITT population) occurred during follow-up. 5-year recurrence-free rates were 97·9% (95% CI 96·1–99·7) in the no ablation group versus 96·3% (93·9–98·7) in the ablation group in the ITT analysis, and 97·9% (96·1–99·7) versus 96·9% (94·7–99·1) in the per-protocol analysis. The 5-year absolute risk difference was 0·5 percentage points (95% CI –2·2 to 3·2, pnon-inferiority=0·033; ITT analysis), showing that non-inferiority was reached. The observed recurrence rate was higher among patients with pT3 or pT3a tumours (four [9%] of 46 patients overall with pT3 or pT3a tumours vs 13 [3%] of 458 with pT1 or pT2 tumours), or N1a tumours (six [13%] of 47 with N1a vs 11 [2%] of 457 with N0 or Nx), but they were similar among those who did not receive ablation. Adverse events were similar between the groups, the most common being fatigue (63 [25%] of 249 in the no ablation group vs 65 [28%] of 231 in the ablation group), lethargy (34 [14%] vs 32 [14%]), and dry mouth (24 [10%] vs 21 [9%]), and there were no treatment-related deaths. The IoN trial shows that ablation (or postoperative radioiodine) can be avoided for patients with pT1, pT2, and N0 or Nx tumours with no adverse features. Many patients with low-risk differentiated thyroid cancer worldwide can safely avoid postoperative radioiodine and its related hospitalisation and side-effects, which in turn results in lower health-care costs. Cancer Research UK.

About half of patients with papillary thyroid cancer have tumours with activating BRAF(V600E) mutations. Vemurafenib, an oncogenic BRAF kinase inhibitor approved for BRAF-positive melanoma, showed clinical benefit in three patients with BRAF(V600E)-positive papillary thyroid cancer in a phase 1 trial. We aimed to establish the activity of vemurafenib in patients with BRAF(V600E)-positive papillary thyroid cancer. We did an open-label, non-randomised, phase 2 trial at ten academic centres and hospitals worldwide in patients aged 18 years or older with histologically confirmed recurrent or metastatic papillary thyroid cancer refractory to radioactive iodine and positive for the BRAF(V600E) mutation. Participants either had never received a multikinase inhibitor targeting VEGFR (cohort 1) or had been treated previously with a VEGFR multikinase inhibitor (cohort 2). Patients received vemurafenib 960 mg orally twice daily. The primary endpoint was investigator-assessed best overall response in cohort 1 (confirmed on two assessments 4 weeks or longer apart). Analyses were planned to have a minimum median follow-up of 15 months (data cutoff April 18, 2014) and were done in safety, intention-to-treat, and per-protocol populations. This trial is closed and is registered at ClinicalTrials.gov, number NCT01286753. Between June 23, 2011, and Jan 15, 2013, 51 patients were enrolled to the study, 26 in cohort 1 and 25 in cohort 2. Median duration of follow-up was 18·8 months (IQR 14·2-26·0) in cohort 1 and 12·0 months (6·7-20·3) in cohort 2. Partial responses were recorded in ten of 26 patients in cohort 1 (best overall response 38·5%, 95% CI 20·2-59·4). Grade 3 or 4 adverse events were recorded in 17 (65%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2; the most common grade 3 and 4 adverse events were squamous cell carcinoma of the skin (seven [27%] in cohort 1, five [20%] in cohort 2), lymphopenia (two [8%] in each cohort), and increased γ-glutamyltransferase (one [4%] in cohort 1, three [12%] in cohort 2). Two individuals in cohort 2 died due to adverse events, one from dyspnoea and one from multiorgan failure, but neither was treatment related. Serious adverse events were reported for 16 (62%) of 26 patients in cohort 1 and 17 (68%) of 25 patients in cohort 2. Vemurafenib showed antitumour activity in patients with progressive, BRAF(V600E)-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients. F Hoffmann-La Roche.

Exosomes are nanoscale monolayer membrane vesicles that are actively endogenously secreted by mammalian cells. Currently, multifunctional exosomes with tumor-targeted imaging and therapeutic potential have aroused widespread interest in cancer research. Herein, we developed a multifunctional HEK-293T exosome-based targeted delivery platform by engineering HEK-293T cells to express a well-characterized exosomal membrane protein (Lamp2b) fused to the αv integrin-specific iRGD peptide and tyrosine fragments. This platform was loaded with doxorubicin (Dox) and labeled with radioiodine-131 ( 131 I) using the chloramine-T method. iRGD exosomes showed highly efficient targeting and Dox delivery to integrin αvβ3-positive anaplastic thyroid carcinoma (ATC) cells as demonstrated by confocal imaging and flow cytometry in vitro and an excellent tumor-targeting capacity confirmed by single-photon emission computed tomography-computed tomography after labeling with 131 I in vivo. In addition, intravenous injection of this vehicle delivered Dox and 131 I specifically to tumor tissues, leading to significant tumor growth inhibition in an 8505C xenograft mouse model, while showing biosafety and no side effects. These as-developed multifunctional exosomes (denoted as Dox@iRGD-Exos- 131 I) provide novel insight into the current treatment of ATC and hold great potential for improving therapeutic efficacy against a wide range of integrin αvβ3-overexpressing tumors. Graphical Abstract

Thyrotoxicosis causes a variety of symptoms and adverse health outcomes. Hyperthyroidism refers to increased thyroid hormone synthesis and secretion, most commonly from Graves' disease or toxic nodular goitre, whereas thyroiditis (typically autoimmune, viral, or drug induced) causes thyrotoxicosis without hyperthyroidism. The diagnosis is based on suppressed serum concentrations of thyroid-stimulating hormone (TSH), accompanied by free thyroxine and total or free tri-iodothyronine concentrations, which are raised (overt hyperthyroidism) or within range (subclinical hyperthyroidism). The underlying cause is determined by clinical assessment, detection of TSH-receptor antibodies and, if necessary, radionuclide thyroid scintigraphy. Treatment options for hyperthyroidism include antithyroid drugs, radioactive iodine, and thyroidectomy, whereas thyroiditis is managed symptomatically or with glucocorticoid therapy. In Graves' disease, first-line treatment is a 12–18-month course of antithyroid drugs, whereas for goitre, radioactive iodine or surgery are preferred for toxic nodules or goitres. Evidence also supports long-term treatment with antithyroid drugs as an option for patients with Graves' disease and toxic nodular goitre.