Cigarette smoking is associated with higher thyroid hormone and lower TSH levels: the PREVEND study Abstract Purpose The extent to which smoking is associated with thyroid stimulating hormone (TSH), free thyroxine (FT4), and free triiodothyronine (FT3) when taking account of clinical variables including alcohol consumption is unclear. We aimed to determine associations of TSH, FT4, and FT3 levels with current smoking. Methods A cross-sectional study was performed in 5766 euthyroid participants (Prevention of Renal and Vascular End-Stage Disease cohort). Current smoking was determined by self-report, categorized as never, former, and current (≤20 and >20 cigarettes per day). Smoke exposure was determined by urinary cotinine. Results Current smoking of ≤20 and >20 cigarettes per day was associated with lower TSH and higher FT3 levels. FT4 levels were higher in subjects smoking <20 cigarettes per day vs. never and former smokers. Current smokers also consumed more alcohol. Multivariable linear regression analyses adjusted for age, sex, anti-TPO autoantibody positivity, alcohol consumption, and other variables demonstrated that lower TSH, higher FT4 and higher FT3 were associated with smoking ≤20 cigarettes per day vs. subjects who never smoked (P < 0.001, P = 0.018, and P < 0.001, respectively) without a further significant incremental effect of smoking >20 cigarettes per day. In agreement, TSH was inversely, whereas FT4 and FT3 levels were positively associated with urinary cotinine (P < 0.001 for each). In contrast, alcohol consumption >30 g per day conferred higher TSH and lower FT3 levels. Conclusions Cigarette smoking is associated with modestly higher FT4 and FT3, and lower TSH levels, partly opposing effects of alcohol consumption.

Teriparatide (rhPTH 1–34) treatment in the pediatric age: long-term efficacy and safety data in a cohort with genetic hypoparathyroidism Abstract Background Hypoparathyroidism is characterized by the absence or inadequately low circulating concentrations of the parathyroid hormone, resulting in hypocalcemia, hyperphosphatemia, and elevated fractional excretion of calcium in the urine. The use of activated vitamin D analogs and calcium supplements represent conventional therapy. Subcutaneous recombinant human parathormone [rhPTH(1–34)] has been proposed as a substitutive treatment, even to avoid side effects of vitamin D and calcium. Objective To assess the long-term safety and efficacy of rhPTH(1–34) in a pediatric cohort of patients with genetic hypoparathyroidism. Methods The study is a 9.2-year self-controlled study of six pediatric patients (four males and two females, aged 9.4 ± 5.2) with DiGeorge, hypoparathyroidism-deafness-renal dysplasia (HDR) or autoimmune-candidiasis-polyendocrinopathy-ectodermal-dysplasia (APECED) syndrome, associated with autoimmune intestinal malabsorption in a patient. The presence of clinical signs of hypocalcemia and biochemical parameters, such as calcium, phosphate, alkaline phosphatase in the blood and calcium–creatinine ratio in urine, were compared during conventional treatment and rhPTH(1–34) (teriparatide, 12.5 μg twice daily). Results The rhPTH(1–34) treatment allowed a reduction, although not always a complete suspension, of calcium supplementation and a slight reduction of calcitriol therapy. The number of tetanic episodes was reduced in four patients during the rhPTH(1–34) treatment. Mean blood calcium, alkaline phosphatase, and phosphate did not significantly change, while a significant reduction of the urinary calcium-to-creatinine ratio (0.55 ± 0.32 vs 0.16 ± 0.09, p = 0.03) was obtained. Renal ultrasound examination showed a worsening in three patients, while it did not change in the remaining three subjects during the follow-up. Conclusions In children with syndromic hypoparathyroidism presented here, replacement therapy with rhPTH(1–34) allowed to maintain adequate levels of the calcium and phosphate in the blood, normalize urinary calcium excretion, and reduce tetanic episodes. In patients with low compliance to conventional therapy or intestinal malabsorption, the use of rhPTH(1–34) could be considered, also to reduce the side effects of treatment with vitamin D and calcium.

The risk of lymph node metastases and their impact on survival in patients with appendiceal neuroendocrine neoplasms: a systematic review and meta-analysis of adult and paediatric patients Abstract Background There are no clear histopathological parameters determining the risk of lymph node (LN) metastases and appropriateness of completion prophylactic right hemicolectomy (RHC) in patients with appendiceal neuroendocrine neoplasms (ANENs). Materials and methods The PubMed, Cochrane Library, Embase, Web of Science and SCOPUS databases were searched up to November 2018. Quality/risk of bias was assessed using the Newcastle–Ottawa Scale (NOS). Results A total of 526 articles were screened. In 11 adult and 3 paediatric studies, 602 and 77 unique patients, respectively, with ANEN and undergoing RHC, were included. The rate of LN metastases for a cutoff size >10 mm was 48.6% (vs 12.1% for lesions <10 mm) among adult patients, with an odds ratio (OR) of 4.8 (95% CI, 1.5–15.8). For 20 mm size cutoff, these figures were 61% (vs 28.2% for lesions <20 mm) with an OR of 3.2 (95% CI, 1.3–7.8). Vascular-, lymph vessel- and perineural invasions were identified as predictive factors for LN metastases in adult patients. In paediatric patients, there were no strong morphological predictors for LN metastases. The 10-year disease-specific survival (DSS) for adult patients without LN metastases was 99.2% vs 95.6% in patients with LN (OR: 0.2; 95% CI, 0.02–2.4). The complication rate of prophylactic RHC was 11.4%. Conclusions This meta-analysis demonstrates that tumour size >20 mm as well as >10 mm and/or vascular-, lymph vessel- and perineural invasions are associated with increased risk for LN metastases in adult patients with ANEN. The prognostic value of LN positivity remains to be determined in further studies with long-term follow-up.

Acknowledgement of Reviewers 2018

BET bromodomain inhibition suppresses adipogenesis in mice Abstract Purpose We recently reported that inhibition of BET bromodomain suppresses adipogenesis in vitro. In the present study we aimed to address whether BET bromodomain inhibition can suppress adipogenesis in vivo. Methods Brd4fl/fl mice were crossed with B6.Cg-Tg(Fabp4-cre)1Rev/J mice to generate Brd4fl/+/Fabp4-cre mice. We used high fat diet (HFD, 45% fat) mice treated with vehicle (DMSO) or JQ1 (intraperitoneal, IP injection, 50 mg/kg/day), respectively, for 6 weeks. Body weight was measured once a week. Dual-energy X-ray absorptiometry was determined and brown adipose tissue was harvested at the end of the experiment. Results Partial deletion of Brd4 leads to the lower body weight. JQ1 treatment further confirmed that BET bromodomain inhibition suppresses body weight gain and decreases white adipose depots compared with the control mice. In addition, JQ1 treatment reduces the size of brown adipose tissue and impairs its thermogenesis. Conclusions BET bromodomain inhibition suppresses adipogenesis in the mice.

Thermal ablation procedures: the need of careful appraisal

Thyroid profile during the alternative Sunitinib dosing 2/1 schedule in metastatic renal cell carcinoma Abstract Purpose Hypothyroidism is a common side effect of Sunitinib (SUN) treatment in metastatic renal cell carcinoma (mRCC) patients. We aimed to evaluate thyroid profile during the alternative 2/1 SUN treatment schedule and to assess the predictive value of hypothyroidism in terms of survival. Methods We performed a prospective observational study enrolling 42 consecutive mRCC patients starting first-line alternative SUN dosing 2/1 schedule. Thyroid function was assessed at baseline and during the first three SUN cycles (1 cycle = 6 weeks = 2 ON/1 OFF + 2 ON/1 OFF), and then after 6 and 12 months. Thyroid ultrasound was performed at baseline and after 3, 6, and 12 months. Results Subclinical hypothyroidism developed in 24% of patients during the first cycle; in other 24% in the second cycle and in 14% in the third cycle. The highest TSH values were reached during the second cycle, ON phase (6.58 ± 5.74 μI U/l). We observed a reduction in thyroid size, in echogenicity and in parenchymal perfusion in all patients. Progression-free survival (PFS) tended to be longer in patients with TSH ≥ 5 μI U/ml during the second cycle (p = 0.069). TSH level was an independent risk factor for PFS in men (p = 0.009) but not in women (p = 0.285). Conclusions This is the first study investigating functional and morphological effects on thyroid during the alternative 2/1 SUN schedule in mRCC patients. We detected an early onset of subclinical hypothyroidism, observing the association between TSH ≥ 5 μI U/ml and: (i) longer PFS in men; (ii) progressive decrease of thyroid size in absence of significant changes in autoimmune thyroid profile.

Dexmedetomidine alleviates insulin resistance in hepatocytes by reducing endoplasmic reticulum stress Abstract Purpose Dexmedetomidine (DEX) stabilizes intraoperative blood glucose levels and reduces insulin resistance (IR), a common perioperative complication. However, the molecular mechanisms underlying these effects remain unclear. Since endoplasmic reticulum stress (ERS) is a mechanism of IR, this study sought to examine whether DEX can effectively alleviate IR by reducing ERS. Methods HepG2 and LO2 cells were treated with different concentrations of insulin. The glucose content assay and Cell Counting Kit-8 (CCK-8) were then employed to determine the optimal insulin concentration capable of inducing IR without affecting cell viability. Insulin-resistant hepatocytes were cultured with different concentrations of DEX for 24 h, and the glucose concentration in the supernatant was measured. ERS was assessed by qPCR and western blotting. The latter was also used to quantify the expression of phosphorylated protein kinase B (p-AKT), phosphoenolpyruvate carboxykinase (PEPCK), and glucose 6 phosphatase (G6Pase), which are key proteins involved in the action of insulin. Results After 48-h of culturing with 10 μg/mL insulin, glucose consumption in hepatocytes was found to be reduced. IR hepatocytes cultured with 10, 100, or 1000 ng/ml DEX for 24 h showed a concentration-dependent increase in glucose consumption. Elevated mRNA and protein levels of ERS markers binding immunoglobulin protein (BIP) and ER protein 29 (ERp29), were reversed by DEX treatment. Moreover, reduced p-AKT and increased PEPCK and G6Pase protein levels in IR hepatocytes were also restored following DEX treatment. Conclusion DEX may alleviate IR in hepatocytes by reducing ERS serving to restore insulin action via the IRS-1/PI3K/AKT pathway.

Antineoplastic activity of artemisinin in adrenocortical carcinoma

Correction to: Prevalence and risk factors for hypoparathyroidism following total thyroidectomy in Spain: a multicentric and nation-wide retrospective analysis An amendment to this paper has been published and can be accessed via a link at the top of the paper.