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Open access

Benjamin J. Worrall, Alexander Papachristos, Ahmad Aniss, Anthony Glover, Stan B Sidhu, Roderick J. Clifton-Bligh, Diana Learoyd, Venessa Hm Tsang, Matti Gild, Bruce G Robinson, and Mark Sywak

Background: The 2015 American Thyroid Association Guidelines(Guidelines) permit thyroid lobectomy(TL) or total thyroidectomy(TT) in the management of low-risk papillary thyroid cancer(PTC). As definitive risk-stratification is only possible post-operatively, some patients may require completion thyroidectomy(CT) after final histopathological analysis.

Methods: A retrospective cohort study of patients undergoing surgery for low-risk PTC in a tertiary referral centre was undertaken. Consecutive adult patients treated from January 2013–March 2021 were divided into two groups (pre- and post-publication of Guidelines on 01/01/2016). Only those eligible for lobectomy under rule 35(B) of the Guidelines were included: Bethesda V/VI cytology, 1–4cm post-operative size, and without pre-operative evidence of extrathyroidal extension or nodal metastases. We examined rates of TL, CT, local recurrence and surgical complications.

Results: There were 1488 primary surgical procedures performed for PTC on consecutive adult patients during the study period, of which 461 were eligible for TL. Mean tumour size (p=0.20) and mean age(p=0.78) were similar between time-periods. The TL rate increased significantly from 4.5% to 18% in the post-publication period(p<0.001). The proportion of TL patients requiring CT(43% vs 38%) was similar between groups. The overall proportion of patients requiring CT increased significantly from 1.9% to 6.9% in the post-publication period(p=0.023). There was no significant change in complications(p=0.55) or local recurrence rates(p=0.24).

Conclusion: The introduction of the 2015 ATA guidelines resulted in a modest but significant increase in the rate of lobectomy for eligible PTC patients. In the post-publication period, 38% of patients who underwent TL ultimately required CT after complete pathological analysis.

Open access

Gido Snaterse, Johannes Hofland, and Bruno Lapauw

11-oxygenated androgens are a class of steroids capable of activating the androgen receptor (AR) at physiologically relevant concentrations. In view of the AR as a key driver of prostate cancer (PC), these steroids are potential drivers of disease and progression. The 11-oxygenated androgens are adrenal-derived, and persist after androgen deprivation therapy (ADT), the mainstay treatment for advanced PC. Consequently, these steroids are of particular interest in the castration-resistant prostate cancer (CRPC) setting.

The principal androgen of the pathway, 11-ketotestosterone (11KT), is a potent AR agonist and the predominant circulating active androgen in CRPC patients. Additionally, several precursor steroids are present in the circulation which can be converted into active androgens by steroidogenic enzymes present in PC cells. In vitro evidence suggests that adaptations frequently observed in CRPC favour the intratumoral accumulation of 11-oxygenated androgens in particular. Still, apparent gaps in our understanding of the physiology and role of the 11-oxygenated androgens remain.

In particular, in vivo and clinical evidence supporting these in vitro findings is limited. Despite recent advances, a comprehensive assessment of intratumoral concentrations has not yet been performed. The exact contribution of the 11-oxygenated androgens to CRPC progression therefore remains unclear. This review will focus on the current evidence linking the 11-oxygenated androgens to PC, will highlight current gaps in our knowledge, and will provide insight into the potential clinical importance of the 11-oxygenated androgens in the CRPC setting based on the current evidence.

Open access

Lucinda Gruber, Steven Hart, and Louis James Maher

Mutations that predispose to familial pheochromocytoma and paraganglioma (PPGL) include inherited variants in the four genes (SDHA, SDHB, SDHC, SDHD) encoding subunits of succinate dehydrogenase (SDH), an enzyme of the mitochondrial tricarboxylic acid cycle and Complex II of the electron transport chain. In heterozygous variant carriers, somatic loss of heterozygosity is thought to result in tumorigenic accumulation of succinate and reactive oxygen species (ROS). Inexplicably, variants affecting the SDHB subunit predict worse clinical outcomes. Why? Here we consider two hypotheses. First, relative to SDH A, C and D subunits, the small SDHB subunit might be more intrinsically “fragile” to missense mutations because of its relatively large fraction of amino acids contacting prosthetic groups and other SDH subunits. We show evidence that supports this hypothesis. Second, the natural pool of human SDHB variants might, by chance, be biased toward severe truncating variants and missense variants causing more disruptive amino acid substitutions. We tested this hypothesis by creating a database of known SDH variants and predicting their biochemical severities. Our data suggest that natural SDHB variants are more pathogenic. It is unclear if this bias is sufficient to explain clinical data. Other explanations include the possibility that SDH subcomplexes remaining after SDHB loss have unique tumorigenic gain-of-function characteristics, and/or that SDHB may have additional unknown tumor suppressor functions.

Open access

Annabelle G Hayes, Masoumeh G Shirazi, Anand Thiyagarajah, David J Torpy, and Sunita M C De Sousa


Cabergoline-associated valvulopathy (CAV) is defined by the echocardiographic triad of moderate or severe regurgitation, valvular thickening and restricted valvular motion. While it is a well-described complication of dopamine agonist therapy in Parkinson’s disease, only three convincing cases of CAV have previously been described in the treatment of prolactinoma, with none involving the tricuspid valve. We describe a case of CAV affecting the tricuspid valve, ultimately resulting in the patient’s death. The novel finding of CAV affecting the tricuspid valve suggests a possible link between confirmed cases of CAV and the echocardiographic surveillance studies of cabergoline-treated prolactinoma patients which have mostly demonstrated subclinical tricuspid valve changes. The risk of CAV, although small, prompts a mindful prescription of dopamine agonist therapy for prolactinomas and consideration of measures to minimise cabergoline exposure. The cumulative cabergoline doses and duration of therapy associated with CAV in published cases exceed what has been evaluated in case series and surveillance studies, underscoring the importance of case reports in understanding CAV.

Open access

Sofia Maria Lider Burciulescu, Caren Randon, Frederic Duprez, Wouter Huvenne, David Creytens, Kathleen B M Claes, Robin de Putter, Guy T’Sjoen, Corin Badiu, and Bruno Lapauw

Pheochromocytomas (PHEO) and paragangliomas (PGL) can occur sporadic or within genetic predisposition syndromes. Despite shared embryology, there are important differences between PHEO and PGL. The aim of this study was to describe the clinical presentation and disease characteristics of PHEO/PGL. A retrospective analysis of consecutively registered patients diagnosed with or treated for PHEO/PGL in a tertiary care centre was performed. Patients were compared according to anatomic location (PHEO vs PGL) and genetic status (sporadic vs hereditary). In total, we identified 38 women and 29 men, aged 50 ± 19 years. Of these, 42 (63%) had PHEO, and 25 (37%) had PGL. Patients with PHEO presented more frequently with sporadic than hereditary disease (45 years vs 27 (77%) vs 8 (23%)) than patients with PGL (9 (36%) vs 16 (64%), respectively) and were older at diagnosis (55 ± 17 vs 40 ± 18 years, P = 0.001), respectively). About half of the cases in both PHEO and PGL were diagnosed due to disease-related symptoms. In patients with PHEO, tumour diameter was larger (P = 0.001), metanephrine levels higher (P = 0.02), and there was more frequently a history of cardiovascular events than in patients with PGL. In conclusion, we found that patients with PGL more frequently have a hereditary predisposition than those with PHEO, contributing to the fact that diagnosis is generally made earlier in PGL. Although diagnosis in both PHEO and PGL was mostly due to related symptoms, patients with PHEO more often presented with cardiovascular comorbidities than those with PGL which might relate to a higher number of functionally active tumours in the former.

Open access

Trinidad Raices, María Luisa Varela, Adriana María Belén Abiuso, Elba N Pereyra, Carolina Mondillo, Omar P Pignataro, and María Fernanda Riera

Curcumin has been ascribed with countless therapeutic effects, but its impact on testicular function has been scarcely researched. Leydig cells comprise the androgen-secreting population of the testis and may give rise to Leydig cell tumours (LCTs). Due to their steroid-secreting nature, LCTs entail endocrine, reproductive, and psychological disorders. Approximately 10% are malignant and do not respond to chemotherapy and radiotherapy. The aim of this study was to assess curcumin’s impact on Leydig cells’ functions and its potential effect on LCT growth. In vitro assays on MA-10 Leydig cells showed that curcumin (20–80 µmol/L) stimulates acute steroidogenesis, both in the presence and absence of db-cAMP. This effect is accompanied by an increase in StAR expression. Regarding curcumin’s in vitro cytostatic capacity, we show that 40–80 µmol/L curcumin reduces MA-10 Leydig cells’ proliferative capacity, which could be explained by the arrest in G2/M and the reduced viability due to the activation of the apoptotic pathway. Finally, CB6F1 mice were inoculated with MA-10 cells to generate ectopic LCT in both flanks. They received i.p. injections of 20 mg/kg curcumin or vehicle every other day for 15 days. We unveiled curcumin’s capacity to inhibit LCT growth as evidenced by reduced tumour volume, weight, and area under the growth curves. No detrimental effects on general health parameters or testicular integrity were observed. These results provide novel evidence of curcumin’s effects on the endocrine cell population of the testis and propose this natural compound as a therapeutic agent for LCT.

Open access

Vineeth Sukrithan, Prachi Jain, Manisha H Shah, and Bhavana Konda


The treatment landscape for thyroid cancers has changed rapidly with the availability of kinase inhibitors against VEGFR, BRAF, MEK, NTRK, and RET. We provide an up-to-date review of the role of kinase inhibitors in thyroid cancer and discuss upcoming trials.

Design & Methods

A comprehensive review of the available literature describing kinase inhibitors in thyroid cancer was performed.

Results and Conclusions

Kinase inhibitors have become the standard of care for patients with metastatic radioactive iodine-refractory thyroid cancer. Short-term treatment can re-sensitize differentiated thyroid cancer to radioactive iodine, thereby potentially improving outcomes and sparing toxicities associated with the long-term use of kinase inhibitors. The approval of cabozantinib as salvage therapy for progressive radioactive iodine-refractory differentiated thyroid cancer following failure with sorafenib or lenvatinib adds to the available armamentarium of active agents. Vandetanib and cabozantinib have become mainstay treatments for metastatic medullary thyroid cancer regardless of RET mutation status. Selpercatinib and pralsetinib, potent and selective receptor kinase inhibitors with activity against RET, have revolutionized the treatment paradigm for medullary thyroid cancers and other cancers with driver mutations in RET. Dabrafenib plus trametinib for BRAF mutated anaplastic thyroid cancer provides an effective treatment option for this aggressive cancer with a dismal prognosis. In order to design the next generation of agents for thyroid cancer, future efforts will need to focus on developing a better understanding of the mechanisms of resistance to kinase inhibition including bypass signaling and escape mutations.

Open access

Macarena Contreras Angulo, Belén García Izquierdo, Laura Armengod Grao, and Nuria Palacios García


Systemic thrombotic microangiopathy (TMA) is a serious condition whose early treatment is essential to reduce morbidity and mortality. TMA with only renal involvement has been associated with tyrosine kinase inhibitors, including lenvatinib, a drug used for certain advanced neoplasms. To date, TMA with systemic involvement associated with this drug has not been described. We present the case of a patient with progressive metastatic thyroid cancer who developed this complication after starting treatment with lenvatinib. We describe the signs and symptoms that led to the diagnosis and the treatment required for her recovery.

Learning points

  • Thrombotic microangiopathy (TMA) is a group of disorders characterized by thrombosis in capillaries and arterioles due to an endothelial injury. Both, localized and systemic forms have been described.

  • TMA with systemic involvement is characterized by hemolytic anemia, low platelets, and organ damage.

  • Vascular endothelial growth factor signaling inhibitors have been associated with TMA, either restricted to the kidney or with systemic involvement.

  • Lenvatinib has been rarely associated with TMA. Although only forms with isolated or predominantly renal involvement had been described so far, a predominantly systemic form can occur.

  • Lenvatinib-induced systemic TMA must be distinguished from primary forms by measuring ADAMTS-13. Treatment includes discontinuation of the drug and supportive measures.

  • When anemia and thrombocytopenia coexist in a patient receiving treatment with lenvatinib, a peripheral blood smear to exclude TMA is recommended

Open access

Nathan J Graham, Joshua D Smith, Tobias Else, and Gregory J Basura

Head and neck paragangliomas (HNPGLs) are slow-growing, vascular, typically benign tumors whose growth may induce significant lower cranial nerve deficits. While most tumors arise sporadically, a significant portion is associated with defined genetic syndromes. While surgical resection has historically been the gold standard, management strategies have evolved with acknowledgement of high surgical morbidity, slow tumor growth rates, and technological advances. Conservative management approaches via observation and newer radiation therapy techniques have become more common. This review seeks to provide an update on contemporary management strategies for HNPGLs and future directions.