Diagnosis and management of parathyroid carcinoma: a state-of-the-art review.

Parathyroid carcinoma is one of the least common endocrine malignancies and accounts for approximately 1% of all patients with primary hyperparathyroidism. A systematic review of peer-reviewed literature published between January 2000 and March 2022 via Medline, Embase, Cochrane Central Register of Controlled Trials, EudraCT, ClinicalTrials.gov, CINAHL and SCOPUS was conducted. Manuscripts were eligible if they included data on adult non-pregnant populations with parathyroid carcinoma. No restrictions regarding interventions, comparators or duration of follow-up were imposed. Single case reports, reviews or meta-analyses were excluded. Outcomes of interest were molecular pathogenesis, clinical presentation, differential diagnosis, treatment, follow-up and overall survival. Study quality was evaluated using the Newcastle-Ottawa Scale for observational studies. This review included 75 studies from 17 countries, reporting on more than 3000 patients with parathyroid carcinoma. CDC73 mutation has been recognised as playing a pivotal role in molecular pathogenesis. Parathyroid carcinoma typically presents with markedly increased calcium and parathyroid hormone levels. The most frequently described symptoms were bone and muscle pain or weakness. En bloc resection remains the gold standard for the surgical approach. The 5-year overall survival ranged from 60 to 93%, with resistant hypercalcaemia a significant cause of mortality. Emerging evidence indicating that targeted therapy, based on molecular biomarkers, presents a novel treatment option. The rarity of PC and need for personalised treatment warrant multidisciplinary management in a 'centre of excellence' with a track record in PC management.

Postradioiodine Graves' management: The PRAGMA study.

OBJECTIVE: Thyroid status in the months following radioiodine (RI) treatment for Graves' disease can be unstable. Our objective was to quantify frequency of abnormal thyroid function post-RI and compare effectiveness of common management strategies. DESIGN: Retrospective, multicentre and observational study. PATIENTS: Adult patients with Graves' disease treated with RI with 12 months' follow-up. MEASUREMENTS: Euthyroidism was defined as both serum thyrotropin (thyroid-stimulating hormone [TSH]) and free thyroxine (FT4) within their reference ranges or, when only one was available, it was within its reference range; hypothyroidism as TSH ≥ 10 mU/L, or subnormal FT4 regardless of TSH; hyperthyroidism as TSH below and FT4 above their reference ranges; dysthyroidism as the sum of hypo- and hyperthyroidism; subclinical hypothyroidism as normal FT4 and TSH between the upper limit of normal and <10 mU/L; and subclinical hyperthyroidism as low TSH and normal FT4. RESULTS: Of 812 patients studied post-RI, hypothyroidism occurred in 80.7% and hyperthyroidism in 48.6% of patients. Three principal post-RI management strategies were employed: (a) antithyroid drugs alone, (b) levothyroxine alone, and (c) combination of the two. Differences among these were small. Adherence to national guidelines regarding monitoring thyroid function in the first 6 months was low (21.4%-28.7%). No negative outcomes (new-onset/exacerbation of Graves' orbitopathy, weight gain, and cardiovascular events) were associated with dysthyroidism. There were significant differences in demographics, clinical practice, and thyroid status postradioiodine between centres. CONCLUSIONS: Dysthyroidism in the 12 months post-RI was common. Differences between post-RI strategies were small, suggesting these interventions alone are unlikely to address the high frequency of dysthyroidism.

Antigen-Specific Immunotherapy with Thyrotropin Receptor Peptides in Graves' Hyperthyroidism: A Phase I Study.

Background: Graves' disease is one of the most common autoimmune conditions, but treatment remains imperfect. This study explores the first-in-human use of antigen-specific immunotherapy with a combination of two thyrotropin receptor (TSHR) peptides (termed ATX-GD-59) in Graves' hyperthyroidism. Methods: Twelve participants (11 female) with previously untreated mild to moderate Graves' hyperthyroidism were enrolled in a Phase I open label trial to receive 10 doses of ATX-GD-59 administered intradermally over an 18-week period. Adverse events, tolerability, changes in serum free thyroid hormones, and TSHR autoantibodies were measured. Results: Ten subjects received all 10 doses of ATX-GD-59, five (50%) of whom had free triiodothyronine within the reference interval by the 18-week visit. Two further subjects had improved free thyroid hormones by the end of the study (7/10 responders), whereas three subjects showed worsening thyrotoxicosis during the study. Serum TSHR autoantibody concentrations reduced during the study and correlated with changes in free thyroid hormones (r = 0.85, p = 0.002 for TSHR autoantibody vs. free triiodothyronine). Mild injection-site swelling and pain were the most common adverse events. Conclusions: These preliminary data suggest that ATX-GD-59 is a safe and well-tolerated treatment. The improvement in free thyroid hormones in 70% of subjects receiving the medication suggests potential efficacy as a novel treatment for Graves' hyperthyroidism.

Thyrotoxicosis - investigation and management .

Graves' disease (GD) and toxic nodular (TN) goitre account for most cases of thyrotoxicosis associated with hyperthyroidism. Hyperthyroidism is confirmed with measurement of a suppressed serum thyrotropin concentration (TSH) and elevated free thyroid hormones. The three therapeutic options are antithyroid drugs, radioactive iodine and surgery. Thionamides achieve long-term remission in 35% of cases. Many centres administer fixed doses of iodine-131; larger doses result in improved rates of cure at the cost of hypothyroidism. Surgery is usually considered for patients who have a large goitre, compressive symptoms or significant ophthalmopathy.

Management of primary hypothyroidism: statement by the British Thyroid Association Executive Committee.

The management of primary hypothyroidism with levothyroxine (L-T4) is simple, effective and safe, and most patients report improved well-being on initiation of treatment. However, a proportion of individuals continue to suffer with symptoms despite achieving adequate biochemical correction. The management of such individuals has been the subject of controversy and of considerable public interest. The American Thyroid Association (ATA) and the European Thyroid Association (ETA) have recently published guidelines on the diagnosis and management of hypothyroidism. These guidelines have been based on extensive reviews of the medical literature and include sections on the role of combination therapy with L-T4 and liothyronine (L-T3) in individuals who are persistently dissatisfied with L-T4 therapy. This position statement by the British Thyroid Association (BTA) summarises the key points in these guidelines and makes recommendations on the management of primary hypothyroidism based on the current literature, review of the published positions of the ETA and ATA, and in line with best principles of good medical practice. The statement is endorsed by the Association of Clinical Biochemistry, (ACB), British Thyroid Foundation, (BTF), Royal College of Physicians (RCP) and Society for Endocrinology (SFE).

Lateral cervical lymph node metastases in papillary thyroid cancer: a systematic review of imaging-guided and prophylactic removal of the lateral compartment.

BACKGROUND: Papillary thyroid cancer (PTC) is a common endocrine cancer and frequently presents with lymph node (LN) metastases. The frequency of LN metastases in the lateral compartment and their surgical removal are poorly defined. There are no prospective randomised controlled trials addressing an eventual outcome difference relating to the extent of the initial surgical approach. The aim of this study was to define the extent of lateral LN involvement and the role of imaging in identification of these metastatic LN. DESIGN AND METHODS: A systematic review of studies of patients with PTC undergoing either prophylactic or therapeutic lymphadenectomy of the lateral cervical compartment. Studies involving imaging modalities in the detection of lateral cervical LNs in PTC were also analysed. RESULTS: Systematic review on the frequency of lateral LN metastases and their detection using various imaging tools identified 19 studies containing data on 5587 patients undergoing prophylactic or imaging-guided removal of the lateral compartment. Imaging-guided surgery retrieved cancerous lateral LNs in 446/3178 or 14% of eligible patients, whilst prophylactic lateral neck dissection yielded histopathological proof of cancer in 1177/204 or 57·5% of patients. The frequency of lateral compartment metastases increased with T stage. The sensitivity of ultrasound and CT was poor as low as 27% when accurately calculated. CONCLUSION: Metastatic cervical LNs were found in more than half of patients when prophylactic lateral LN dissection was performed. Use of conventional imaging for the selection of the surgical approach to the lateral cervical compartment may commonly identify stage N1a instead of N1b and thus lead to false stage assignment as stage III rather than stage IV, concealing the severe prognostic implications of this stage progression in individual patients.

Thyroid cancer and renal transplantation: a meta-analysis.

Kidney transplantation and the associated immune suppression are associated with a significantly increased risk of developing cancer during long-term follow-up. Thyroid cancer has been recognised as a potential post-transplant risk but has not yet been subject of a focused review. We therefore performed a meta-analysis on data of 50,861 patients with a total follow-up of 198 595 patient-years and identified a 6.9-fold higher standardised incidence ratio (95% confidence interval 5.6-8.7, P<0.001) of thyroid cancer post renal transplantation as compared with a non-transplant group. All such cancers were of papillary type as far as histopathology was known. The mean time to discovery was 6.0 years post transplantation. This puts thyroid cancer into the group of high cancer risk following solid organ transplantation which already includes cervical cancer, non-melanoma skin cancer, oral and lip cancer and haematological malignancies. It is unclear what causes the increased cancer incidence. Inclusion of thyroid ultrasound in long-term post-transplant evaluation may help to ensure timely recognition of this condition.