Hürthle cell carcinoma of the thyroid (HCC) is a form of thyroid cancer recalcitrant to radioiodine therapy that exhibits an accumulation of mitochondria. We performed whole-exome sequencing on a cohort of primary, recurrent, and metastatic tumors, and identified recurrent mutations in DAXX, TP53, NRAS, NF1, CDKN1A, ARHGAP35, and the TERT promoter. Parallel analysis of mtDNA revealed recurrent homoplasmic mutations in subunits of complex I of the electron transport chain. Analysis of DNA copy-number alterations uncovered widespread loss of chromosomes culminating in near-haploid chromosomal content in a large fraction of HCC, which was maintained during metastatic spread. This work uncovers a distinct molecular origin of HCC compared with other thyroid malignancies.

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Microenvironmental signals can determine hematopoietic stem cell (HSC) fate choices both directly and through stimulation of niche cells. In the bone marrow, prostaglandin E 2 (PGE 2 ) is known to affect both osteoblasts and osteoclasts, whereas in vitro it expands HSCs and affects differentiation of hematopoietic progenitors. We hypothesized that in vivo

Background Surgery for catecholamine‐producing tumours can be complicated by intraoperative and postoperative haemodynamic instability. Several perioperative management strategies have emerged but none has been evaluated in randomized trials. To assess this issue, contemporary perioperative management and outcome data from 21 centres were collected. Methods Twenty‐one centres contributed outcome data from patients who had surgery for phaeochromocytoma and paraganglioma between 2000 and 2017. The data included the number of patients with and without α‐receptor blockade, surgical and anaesthetic techniques, complications and perioperative mortality. Results Across all centres, data were reported on 1860 patients with phaeochromocytoma or paraganglioma, of whom 343 underwent surgery without α‐receptor blockade. The majority of operations (78·9 per cent) were performed using minimally invasive techniques, including 16·1 per cent adrenal cortex‐sparing procedures. The cardiovascular complication rate was 5·0 per cent overall: 5·9 per cent (90 of 1517) in patients with preoperative α‐receptor blockade and 0·9 per cent (3 of 343) among patients without α‐receptor blockade. The mortality rate was 0·5 per cent overall (9 of 1860): 0·5 per cent (8 of 517) in pretreated and 0·3 per cent (1 of 343) in non‐pretreated patients. Conclusion There is substantial variability in the perioperative management of catecholamine‐producing tumours, yet the overall complication rate is low. Further studies are needed to better define the optimal management approach, and reappraisal of international perioperative guidelines appears desirable.

Patients with anaplastic thyroid cancer (ATC) have an extremely poor prognosis despite multimodal therapy with surgery and chemoradiation. Lenvatinib, a multi-targeted tyrosine kinase inhibitor, as well as checkpoint inhibitors targeting the programmed cell death pathway, have proven effective in some patients with advanced thyroid cancer. Combination of these therapies is a potential means to boost effectiveness and minimize treatment resistance in ATC. We utilized our novel immunocompetent murine model of orthotopic ATC to demonstrate that lenvatinib led to significant tumor shrinkage and increased survival, while combination therapy led to dramatic improvements in both. Lenvatinib monotherapy increased tumorinfiltrating macrophages, CD8 + T-cells, regulatory T-cells, and most notably, polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs). While both combination therapies led to further increases in CD8 + T-cells, only the lenvatinib and anti-PD-1 combination decreased PMN-MDSCs. PMN-MDSC expansion was also seen in the blood of mice and one patient receiving lenvatinib therapy for ATC. RNA-Seq of the ATC cell line used in our mouse model demonstrated that lenvatinib has multifaceted effects on angiogenesis, response to hypoxia, the epithelial-to-mesenchymal transition, and on multiple pathways implicated in inflammation and host immunity. Combination of lenvatinib with anti-Gr-1 antibody ameliorated lenvatinib's expansion of MDSCs and significantly improved lenvatinib's anti-tumor effect. These data suggest that MDSCs play a negative role in ATC's response to lenvatinib and support future study of their role as a potential biomarker and treatment target.