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Open access

Xiaoya Zheng, Heng Xiao, Jian Long, Qiang Wei, Liping Liu, Liping Zan, and Wei Ren

Objective: Programmed cell death protein-1 (PD-1) inhibitors are widely used for the treatment of hepatocellular carcinoma (HCC). Thyroid dysfunction is common in patients treated with this therapy, although the dynamic changes in thyroid function and sonographic features remain unclear.

Methods: We analyzed 38 patients with HCC who received anti-PD-1 therapy at our hospital. Demographic, clinical, laboratory and ultrasound data were extracted from electronic medical records. The grading of thyroid nodules was based on the ACR-TIRADS classification. Statistical analyses were performed using GraphPad Prism 5.0.

Results: Fifteen patients (40%) had hypothyroidism, among which 6 had hypothyroidism at baseline while 3 had overt hypothyroidism and 6 had subclinical hypothyroidism after anti-PD1 therapy. The proportion of patients with euthyroid function and thyroid antibody positivity was significantly lower than that of patients with thyroid dysfunction (10% vs. 39%, p<0.05). Nine patients (24%) had irregular echo patterns on sonographic imaging, 6 of whom had irregular echo patterns present during the treatment, but only one had them persist until the end of treatment. At baseline, the classification of most thyroid nodules was grade 3, with a significant increase in grade 4A and 4B classifications during treatment, though most nodules remained grade 3 at the end of treatment. There were no significant differences in survival rates between the euthyroid and thyroid dysfunction groups.

Conclusion: Anti-PD-1 therapy-induced thyroid dysfunction was accompanied by changes in thyroid function, antibodies, and ultrasonography. Therefore, in patients receiving anti-PD-1 therapy, close, dynamic monitoring of thyroid function, antibodies and ultrasonographic characteristics is necessary.

Open access

Panisa Hantrakun, Rattanaporn Sekararithi, Thidarat Jaiwongkam, Sirinart Kumfu, Chatree Chai-adisaksopha, Nipon Chattipakorn, Theera Tongsong, and Phudit Jatavan


To evaluate the effect of metformin in improving platelet dysfunction in women with gestational diabetes mellitus (GDM).

Patients and methods

A randomized controlled trial was conducted on pregnant women diagnosed with GDM. Singleton low-risk pregnancies meeting the inclusion criteria were randomly allocated at 27–31 weeks to receive metformin and placebo through the rest of pregnancy. Thirty-seven and 39 cases were recruited into the metformin group and the placebo group, respectively. MPVs, P-selectin, and 8-isoprostane levels were determined at the time of allocation and 6 weeks after treatment. Obstetric and neonatal outcomes were also assessed.


Most baseline characteristics of the two groups were comparable. The levels of P-selectin after 6 weeks of treatment were significantly higher in the metformin group (68.9 ± 14.4 vs 60.6 ± 11.3; P-value = 0.006), indicating more platelet activation. All of the obstetric and neonatal outcomes were comparable except that birth weight was significantly lower in the metformin group (3018 ± 364 g vs 3204 ± 393 g; P-value = 0.037).


Metformin, in addition to diet and lifestyle modifications, does not improve or worsen oxidative stress and platelet dysfunction in women with GDM. Nevertheless, metformin significantly reduces fetal weight in women with GDM, theoretically preventing macrosomia.

Open access

Brendan J Nolan, Aviva S Frydman, Shalem Y Leemaqz, Meg Carroll, Mathis Grossmann, Jeffrey D Zajac, and Ada S Cheung

Objective: The role of micronised progesterone in hormone regimens for transgender individuals undergoing feminising hormone therapy remains uncertain. We aimed to determine the effect of oral micronised progesterone (progesterone) on sleep quality, psychological distress and breast development in transgender individuals undergoing feminising hormone therapy.

Design: Prospective case-control study. Twenty-three transgender individuals on stable estradiol treatment newly commencing 100mg oral progesterone (n=23) and controls continuing standard care (n=19) were assessed over 3 months.

Methods: Pittsburgh Sleep Quality Index (PSQI), Kessler psychological distress scale (K10), and Tanner stage to assess breast development were assessed at 0 and 3 months. Non-parametric ANCOVA were used to compare differences between groups.

Results: Compared with controls over 3 months, there was no difference in PSQI (P=0.35), K10 (P=0.64) or Tanner stage (P=0.42). There was no significant difference in the proportion of individuals with clinically significant improvement in PSQI (25% vs. 22%, P=0.84). One individual had a significant deterioration in psychological distress that improved following cessation of progesterone.

Conclusions: Low-dose progesterone was not associated with changes in sleep quality, psychological distress, or breast development over three months follow-up, though there was significant inter-individual variability. Larger, placebo-controlled trials are required to further evaluate different doses of progesterone in feminising hormone therapy regimens.

Open access

Katrine M Lauritsen, Jens Hohwü Voigt, Steen Bønløkke Pedersen, Troels K Hansen, Niels Møller, Niels Jessen, Lars C Gormsen, and Esben Søndergaard

SGLT2 inhibition induces an insulin-independent reduction in plasma glucose causing increased lipolysis and subsequent lipid oxidation by energy-consuming tissues. However, it is unknown whether SGLT2 inhibition also affects lipid storage in adipose tissue. Therefore, we aimed to determine the effects of SGLT2 inhibition on lipid storage and lipolysis in adipose tissue. We performed a randomized, double-blinded, placebo-controlled crossover design of 4 weeks of empagliflozin 25 mg and placebo once-daily in 13 individuals with type 2 diabetes treated with metformin. Adipose tissue fatty acid uptake, lipolysis rate and clearance were measured by 11C-palmitate PET/CT. Adipose tissue glucose uptake was measured by 18F-FDG PET/CT. Protein and gene expression of pathways involved in lipid storage and lipolysis were measured in biopsies of abdominal s.c. adipose tissue. Subjects were weight stable, which allowed us to quantify the weight loss-independent effects of SGLT2 inhibition. We found that SGLT2 inhibition did not affect free fatty acids (FFA) uptake in abdominal s.c. adipose tissue but increased FFA uptake in visceral adipose tissue by 27% (P  < 0.05). In addition, SGLT2 inhibition reduced GLUT4 protein (P  = 0.03) and mRNA content (P  = 0.01) in abdominal s.c. adipose tissue but without affecting glucose uptake. In addition, SGLT2 inhibition decreased the expression of genes involved in insulin signaling in adipose tissue. We conclude that SGLT2 inhibition reduces GLUT4 gene and protein expression in abdominal s.c. adipose tissue, which could indicate a rebalancing of substrate utilization away from glucose oxidation and lipid storage capacity through reduced glycerol formation.

Open access

Eng Loon Tng, Yee Sian Tiong, Aye Thida Aung, Nicole Ya Yuan Chong, and Zhemin Wang

Background: Evidence on the efficacy and safety of anticoagulation in preventing stroke and thromboembolic events in people with thyrotoxic atrial fibrillation is scarce.

Objective: We evaluated the efficacy and safety of anticoagulation in people with thyrotoxic atrial fibrillation.

Methods: Our study protocol was published in the International Prospective Register of Systematic Reviews (PROSPERO) (registration number CRD42020222782). Four databases and two systematic review registers were searched through 25 November 2020 for interventional and observational studies comparing anticoagulation therapy with active comparators, placebo, or no treatment in people with thyrotoxic atrial fibrillation. Random-effects meta-analysis and sensitivity analysis were performed. Quality of evidence was described using the GRADE framework.

Results: 23,145 records were retrieved. 1 randomized controlled trial and 8 cohort studies were ultimately included. Effect estimates on the efficacy and safety of anticoagulation were extracted. Meta-analysis using the inverse variance and random-effects methods was conducted on 4 cohort studies with 3443 participants and 277 events. Anticoagulation in people with thyrotoxic atrial fibrillation reduced the risk of ischemic stroke and systemic thromboembolism by 3% (95% confidence interval (CI): 1 – 6%). Warfarin may prevent ischemic stroke in people with thyrotoxic atrial fibrillation if the CHA2DS2-VASc score exceeds 1 and when atrial fibrillation persists beyond 7 days. Direct oral anticoagulants may be associated with fewer bleeding events than warfarin.

Conclusions: Anticoagulation prevents ischemic stroke and systemic thromboembolism in people with thyrotoxic atrial fibrillation. Direct oral anticoagulants may be associated with fewer bleeding events.

Open access

Muhammad Fahad Arshad, Ahmed Iqbal, James Weeks, Ines Fonseca, Alia Munir, and William Bennet

Objective: To evaluate ‘real-world’ safety and efficacy of the European Society of Endocrinology (ESE) guidelines for treatment of severe symptomatic hyponatraemia using hypertonic saline (HTS).

Design: Retrospective, observational, cohort study, examining the use of HTS for severe symptomatic hyponatraemia at Sheffield Teaching Hospitals between 2017-2020.

Methods: Patients were identified from pharmacy records and demographic, clinical, and treatment data extracted.

Results: Out of 112 patients (Females: Males=61:51), the mean age ± SD was 66.3± 16.0 years and mean pre-treatment serum sodium ± SD was 113.8 ± 6.4 mmol/L. Overall, overcorrection rates at 24 and 48 hours (>10mmol/L and >18mmol/L) were 44.9% and 19.6%, respectively while 19.6% of patients were treated for overcorrection. Above-target rise in sodium (>5mmol/L) after first and second boluses was noted in 22.6% and 34.6% of patients. In-hospital and 12-month mortality was 7.1% and 18.7% respectively with no cases of osmotic demyelination (ODS). The mean venous blood gas (VBG) sodium was 1.9 mmol/L lower than paired serum sodium (n=32)(113.6 ± 6.6 vs. 115.7 ± 7.8 mmol/L).

Conclusion: We report real-world data demonstrating that a significant number of patients overcorrected using current guidelines. Also, several patients had above-target rise in sodium after one bolus of HTS, and sodium measurement should be considered before the second bolus unless ongoing severe symptoms persist. A point of care VBG sodium concentration was useful for this purpose. In addition to careful monitoring, a cautious but anticipatory overcorrection prevention strategy should be considered in the first 24 hours.

Open access

Vita Birzniece, Teresa Lam, Mark McLean, Navneeta Reddy, Haleh Shahidipour, Amy Hayden, Howard Gurney, Glenn Stone, Rikke Hjortebjerg, and Jan Frystyk


Androgen deprivation therapy (ADT), a principal therapy in patients with prostate cancer, is associated with the development of obesity, insulin resistance, and hyperinsulinemia. Recent evidence indicates that metformin may slow cancer progression and improves survival in prostate cancer patients, but the mechanism is not well understood. Circulating insulin-like growth factors (IGFs) are bound to high-affinity binding proteins, which not only modulate the bioavailability and signalling of IGFs but also have independent actions on cell growth and survival. The aim of this study was to investigate whether metformin modulates IGFs, IGF-binding proteins (IGFBPs), and the pregnancy-associated plasma protein A (PAPP-A) – stanniocalcin 2 (STC2) axis.

Design and methods

In a blinded, randomised, cross-over design, 15 patients with prostate cancer on stable ADT received metformin and placebo treatment for 6 weeks each. Glucose metabolism along with circulating IGFs and IGFBPs was assessed.


Metformin significantly reduced the homeostasis model assessment as an index of insulin resistance (HOMA IR) and hepatic insulin resistance. Metformin also reduced circulating IGF-2 (P  < 0.05) and IGFBP-3 (P  < 0.01) but increased IGF bioactivity (P  < 0.05). At baseline, IGF-2 correlated significantly with the hepatic insulin resistance (r2= 0.28, P  < 0.05). PAPP-A remained unchanged but STC2 declined significantly (P  < 0.05) following metformin administration. During metformin treatment, change in HOMA IR correlated with the change in STC2 (r2= 0.35, P  < 0.05).


Metformin administration alters many components of the circulating IGF system, either directly or indirectly via improved insulin sensitivity. Reduction in IGF-2 and STC2 may provide a novel mechanism for a potential metformin-induced antineoplastic effect.

Open access

Lian Duan, Han-Yu Zhang, Min Lv, Han Zhang, Yao Chen, Ting Wang, Yan Li, Yan Wu, Junfeng Li, and Kefeng Li

Background and objective: Radioiodine therapy (RAI) is one of the most common treatment solutions for Graves' disease (GD). However, many patients will develop hypothyroidism as early as 6 months after RAI. This study aimed to implement machine learning (ML) algorithms for early prediction of post-RAI hypothyroidism.

Methods: 471 GD patients who underwent RAI between January 2016 and June 2019 were retrospectively recruited and randomly split into the training set (310 patients) and the validation set (161 patients). These patients were followed for 6 months after RAI. A set of 138 clinical and lab test features from the electronic medical record (EMR) were extracted, and multiple ML algorithms were conducted to identify the features associated with the occurrence of hypothyroidism at 6 months after RAI.

Results: An integrated multivariate model containing patients’ age, thyroid mass, 24 h radioactive iodine uptake, serum concentrations of aspartate aminotransferase (AST), thyrotropin-receptor antibodies (TRAb), thyroid microsomal antibodies (TMA), and blood neutrophil count demonstrated an area under the ROC (AUROC) of 0.72 (95% CI: 0.61 - 0.85), an F1 score of 0.74, and an MCC score of 0.63 in the training set. The model also performed well in the validation set with an AUROC of 0.74 (95% CI: 0.65 - 0.83), an F1 score of 0.74, and a MCC of 0.63. A user-friendly nomogram was then established to facilitate the clinical utility.

Conclusion: The developed multivariate model based on EMR data could be a valuable tool for predicting post-RAI hypothyroidism, allowing them to be treated differently before the therapy. Further study is needed to validate the developed prognostic model at independent sites.

Open access

Carole Morin, Keo-Morakort Benedetto, Agathe Deville, Laurent Milot, Aurélie Theillaumas, Valerie Hervieu, Mathieu Pioche, Gilles Poncet, Julien Forestier, Laurent François, Francoise Borson-Chazot, Mustapha Adham, Catherine Lombard-Bohas, and Thomas Walter

Purpose: To improve neuroendocrine neoplasm (NEN) management, the European Neuroendocrine Tumor Society (ENETS) recognised 62 Centers of Excellence (CoE). This retrospective study compares conformity of patients’ initial management within vs outside an ENETS CoE with clinical practice guidelines (CPGs).

Methods: Patients diagnosed with a NEN between August 2018 and July 2020 and presented in the Lyon-CoE Multidisciplinary Tumour Board (MDT) were included. Factors potentially associated with conformity of initial management (work-up and first treatment) to CPG underwent univariate and multivariate analyses.

Results: Among the 615 included patients, 170 (27.6%) were initially managed in the CoE and 445 (72.4%) were only presented at the CoE-MDT. Patients in the CoE group more often had intestinal or pancreatic primaries, metastatic disease (61.8% vs 33%), hereditary syndrome and a functioning tumour. Work-up conformity was 37.1% in the CoE (vs 29.9%, p=0.09); this was 95.8% for the first treatment (vs 88.7%, p=0.01). After multivariate analysis, CPG conformity was significantly higher for patients managed in the CoE, for younger patients, for those having a grade 1-2 tumour, and a genetic syndrome. Pancreatic and small intestinal (SI) NET surgeries performed in the CoE had higher splenic preservation rate during left pancreatectomy, better detection of multiple tumours in SI surgeries, and higher number of resected lymph nodes.

Conclusions: Given the widespread observance of CPG, not all patients require management in the CoE. Referral should be considered for more complex cases such as metastatic diseases, G2 tumours or carcinoid syndromes. Finally, we should encourage centralization of NET surgery.

Open access

Panagiotis Anagnostis, Irene Lambrinoudaki, John C Stevenson, and Dimitrios G Goulis

Cardiovascular disease (CVD) is of major concern in women entering menopause. The changing hormonal milieu predisposes them to increased CVD risk, due to a constellation of risk factors, such as visceral obesity, atherogenic dyslipidemia, dysregulation in glucose homeostasis, non-alcoholic fatty liver disease and arterial hypertension. However, an independent association of menopause per se with increased risk of CVD events has only been proven for early menopause (<45 years). Menopausal hormone therapy (MHT) ameliorates most of the CVD risk factors mentioned above. Transdermal estrogens are the preferable regimen, since they do not increase triglyceride concentrations and they are not associated with increased risk of venous thromboembolic events (VTE). Although administration of MHT should be considered on an individual basis, MHT may reduce CVD morbidity and mortality, if commenced during the early postmenopausal period (<60 years or within ten years since the last menstrual period). In women with premature ovarian insufficiency (POI), MHT should be administered at least until the average age of menopause (50–52 years). MHT is contraindicated in women with a history of VTE and is not currently recommended for the sole purpose of CVD prevention. The risk of breast cancer associated with MHT is generally low and is mainly conferred by the progestogen. Micronized progesterone and dydrogesterone are associated with lower risk compared to other progestogens.