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Open access

Mark J C van Treijen, Catharina M Korse, Wieke H Verbeek, Margot E T Tesselaar, and Gerlof D Valk


Up to now, serial NETest measurements in individuals assessing the disease course of gastroenteropancreatic neuroendocrine tumors (GEPNETs) at long-term follow-up and treatment response were not studied.


The study was a longitudinal validation study of serial NETest measurements – a blood-based gene expression signature – in 132 patients with GEPNETs on therapy or watch-and-wait strategy.


Serial samples were collected during 46 (range: 6–71) months of follow-up. NETest scores were compared with Response Evaluation Criteria in Solid Tumors version 1.1-defined treatment response (e.g. no evidence of disease (NED), stable disease (SD) or progressive disease (PD)).


Consecutive NETest scores fluctuated substantially (range: 0–100) over time in individuals with SD (n = 28) and NED (n = 30). Follow-up samples were significantly higher in SD (samples 3–5) and NED subgroups (samples 2–5) compared with baseline results, without changes in imaging. In 82% of untreated patients with PD, consecutive NETest scores consistently remained high. In patients undergoing systemic treatment, the median pre-treatment NETest score in treatment-responders was 76.5 (n = 22) vs 33 (n = 12) in non-responders (P = 0.001). Patients with low pre-treatment scores had 21 months reduced progression-free survival (10 vs 31 months; P = 0.01). The accuracy of the NETest for treatment response prediction was 0.73 (P = 0.009).


In patients not undergoing treatment, consecutive low NETest scores are associated with indolent behavior. Patients who develop PD exhibit elevated scores. Elevated results have important predictive value for treatment responsiveness and could be used for individualizing decisions on systemic therapy. The clinical value of follow-up NETest scores for patients who choose to watch and wait requires further study.

Open access

Małgorzata Więcek, Jakub Gawlik, Zuzanna Nowak, and Aneta Gawlik

Loss of fertility is one of the most important concerns facing Turner Syndrome (TS) patients as they transition into adult healthcare. Due to the limited and rapidly decreasing ovarian reserve many TS patients require fertility preservation (FP) techniques to preserve their reproductive potential until they are ready to pursue procreation. One has to also remember about the additional risks connected with pregnancy in TS patients. In order to determine the optimal time for introducing FP techniques and decrease the chance of an unnecessary intervention, markers and procedures assessing ovarian reserve have been developed. The exposure to potential cardiovascular complications should be determined before FP to avoid unnecessary procedures in patients with potential contraindications to pregnancy. The aim of the present review is to answer the following three questions important for successful preservation of fertility and safe pregnancy in TS. Which markers of ovarian reserve should be used as selection criteria for FP? Which methods of FP are the safest and most effective? If are there any cardiovascular contraindications to fertility preservation? For each of those questions separate literature searches have been conducted. A total of 86 articles have been included in this review, 34 for the first question, 35 for the second and 17 for the third. Ovarian reserve markers and cardiovascular contraindications to pregnancy should be established before FP, hoverer there are no unambiguous indicators which patients should be disqualified from the FP and more evidence is needed in this subject.

Open access

Rafaella Sales de Freitas, Thiago F A França, and Sabine Pompeia

Kisspeptins play a crucial role during pubertal development, but little is known about how their peripheral concentrations relate to sexual maturation. This is partly due to the lack of non-invasive, quick, and reliable peripheral kisspeptin measures, which limit widespread testing. Here, we investigated the relationship between kisspeptin concentrations measured from midstream urine samples with 2-h retention periods and developmental markers (age, self-reported pubertal status, and saliva concentrations of testosterone and DHEA sulphate ) in 209 typically developing 9- to 15-year-old males and females. As a result of the study, we found marked sex differences. Kisspeptin concentrations were similar between sexes until around 12 years of age, but, thereafter, kisspeptin concentrations in females did not change significantly, whereas, in males, there was a clear positive correlation with developmental measures. Our results replicate previous findings regarding kisspeptin concentration changes across the pubertal transition obtained from blood samples, suggesting that measuring these peptides in urine has the potential for exploring kisspeptins’ peripheral effects and their associations with pubertal status.

Open access

Marcela Moraes Mendes, Patricia Borges Botelho, and Helena Ribeiro

Vitamin D enhances calcium absorption and bone mineralisation, promotes maintenance of muscle function, and is crucial for musculoskeletal health. Low vitamin D status triggers secondary hyperparathyroidism, increases bone loss, and leads to muscle weakness. The primary physiologic function of vitamin D and its metabolites is maintaining calcium homeostasis for metabolic functioning, signal transduction, and neuromuscular activity. A considerable amount of human evidence supports the well-recognised contribution of adequate serum 25-hydroxyvitamin D concentrations for bone homeostasis maintenance and prevention and treatment strategies for osteoporosis when combined with adequate calcium intake. This paper aimed to review the literature published, mainly in the last 20 years, on the effect of vitamin D and its supplementation for musculoskeletal health in order to identify the aspects that remain unclear or controversial and therefore require further investigation and debate. There is a clear need for consistent data to establish realistic and meaningful recommendations of vitamin D status that consider different population groups and locations. Moreover, there is still a lack of consensus on thresholds for vitamin D deficiency and optimal status as well as toxicity, optimal intake of vitamin D, vitamin D supplement alone as a strategy to prevent fractures and falls, recommended sun exposure at different latitudes and for different skin pigmentations, and the extra skeletal effects of vitamin D.

Open access

Agnieszka Adamska, Vitalii Ulychnyi, Katarzyna Siewko, Anna Popławska-Kita, Małgorzata Szelachowska, Marcin Adamski, Angelika Buczyńska, and Adam Jacek Krętowski

Cardiovascular risk factors could be present in mild adrenal autonomous cortisol secretion (MACS). However, the most frequent cardiovascular risk factors in MACS have not been established. The aim of the presseent study was to analyse the difference in cardiovascular risk factors in patients with MACS in comparison to those with non-functioning adrenal tumour (NFAT). A total of 295 patients with adrenal incidentaloma were included in this retrospective study. We divided our group into those who showed suppression in 1 mg overnight dexamethasone suppression test (DST) (NFAT) (serum cortisol level ≤1.8 μg/dL) and those who did not show suppression in the DST (MACS) (serum concentration of cortisol > 1.8 μg/dL and ≤5 μg/dL). In the studied groups, we analysed the presence of cardiovascular risk factors, such as obesity, prediabetes, type 2 diabetes mellitus (T2DM), hypertension, hyperlipidaemia, chronic kidney disease and cardiovascular events. In our study, 18.9% of patients were defined as MACS. Importantly, T2DM was diagnosed in 41% of MACS vs 23% of NFAT (P < 0.01) and higher frequency of occurrence of hyperlipidaemia in NFAT (72.4%) vs MACS (53.6%) (P = 0.01) was observed. We did not observed differences in the frequency of obesity, hypertension, chronic kidney disease, prediabetes, atrial fibrillation, stroke, ST and non-ST elevation myocardial infarction and coronary angioplasty between patients with MACS and NFAT (all P > 0.05; respectively). In MACS, T2DM is more prevalent than in NFAT; hyperlipidaemia is more prevalent in NFAT. Accordingly, no differences were found in the incidence of obesity, hypertension, prediabetes, chronic kidney disease between studied groups as well as cardiovascular events.

Open access

J Gebauer, R Skinner, R Haupt, L Kremer, H van der Pal, G Michel, G T Armstrong, M M Hudson, L Hjorth, H Lehnert, and T Langer

Many long-term childhood cancer survivors suffer from treatment-related late effects, which may occur in any organ and include a wide spectrum of conditions. Long-term follow-up (LTFU) is recommended to facilitate early diagnosis and to ensure better health outcomes. Due to the heterogeneity of these sequelae, different specialists work together in the diagnosis and treatment of these conditions. Experts from both pediatric and internal medicine are involved in age-appropriate care by providing a transition process. Hence, LTFU of childhood cancer survivors is a prototypic example of multidisciplinary care for patients with complex needs treated in a specialized setting. International collaborations of healthcare professionals and scientists involved in LTFU of childhood cancer survivors, such as the International Guideline Harmonization Group, compile surveillance recommendations that can be clinically adopted all over the world. These global networks of clinicians and researchers make a joint effort to address gaps in knowledge, increase visibility and awareness of cancer survivorship and provide an excellent example of how progress in clinical care and scientific research may be achieved by international and multidisciplinary collaboration.

Open access

Liang Xue, Jianwu Wu, Jie Chen, and Yongkai Yang

Purpose: We aimed to assess the factors influencing the development of diabetes insipidus after transsphenoidal surgery for pituitary adenomas.

Methods: A retrospective analysis was conducted on the clinical data of patients with pituitary adenomas who underwent transsphenoidal surgery. The predictors of postoperative diabetes insipidus were determined using statistical analysis.

Results: Of the 415 patients who underwent microscopic transsphenoidal surgery for pituitary adenomas, 196 experienced postoperative diabetes insipidus. The sinking depth of the diaphragma sellae and the difference between the preoperative and postoperative pituitary stalk deviation angles in the diabetes insipidus group were greater than those in the non-diabetes insipidus group. Logistic regression analysis showed that the risk of diabetes insipidus after transsphenoidal surgery was higher in patients with a larger difference in their pituitary stalk deviation angles (odds ratio [OR] = 2.407, 95% confidence interval [CI] = 1.335–4.342; P = 0.004).

Conclusion: The difference in the pituitary stalk deviation angle could predict the onset of diabetes insipidus after transsphenoidal surgery for pituitary adenomas.

Open access

Xiaowen Zhang, Chen Han, Hongwei Wang, Xinghong Sun, Xin Dou, Xueying He, Di Wu, Shanmei Shen, Dalong Zhu, Xin-Lin Zhang, and Yan Bi

Thyroid eye disease (TED) is the major extrathyroidal manifestation of Graves’ disease (GD). Treatment choice is based on clinical activity and severity of TED, as evaluated with clinical activity score (CAS) and magnetic resonance (MR) imaging. We aimed to determine the relationship between neutrophil to lymphocyte ratio (NLR), a readily available indicator of systemic inflammation, and clinical and MR imaging parameters in TED patients. 87 consecutive TED patients were included. The average signal intensity ratio (SIR), average extraocular muscle (EOM) diameter, and proptosis of the study eye were extracted from MR images. A baseline NLR ≥2.0 was recorded in 37 (42.5%) patients and NLR <2.0 in 50 (57.5%) patients. TED patients with NLR ≥2.0 were older, had a higher CAS, average SIR, average EOM diameter and proptosis, and a lower serum TRAb level than patients with NLR <2.0 (all p<0.05). All MR parameters showed significant correlation with CAS (p<0.05). NLR correlated significantly with CAS (p=0.001), average SIR (p=0.004), average EOM diameter (p=0.007) and proptosis (p=0.007). Multiple regression revealed a significant correlation between NLR and CAS (P=0.001), average SIR (p=0.029) and proptosis (p=0.037). Cox regression analysis showed that a high NLR at baseline was associated with a worse clinical outcome of TED (hazard ratio 3.7, 95% CI 1.22-11.2, p=0.02), at a median follow-up of 25 months. In conclusion, NLR was correlated with CAS and MR imaging parameters, and was associated with a worse clinical outcome of TED at follow-up in TED patients. Additional prospective studies are needed to validate our findings.

Open access

E. K White, I V Wagner, C van Beuzekom, V Iotova, S. F Ahmed, O Hiort, and A.m Pereira

In 2017, the European Commission installed 24 European Reference Networks (ERN) for different categories of rare and complex conditions to facilitate cross-border health care via virtual case consultations in a secure clinical patient management system (CPMS). The ERN for rare endocrine conditions (Endo-ERN) previously reviewed the CPMS, in which they detailed difficulties physicians encountered with the system and proposed solutions to these that should enable the system to be used to a greater extent. This paper will further the endeavor of the first by performing a critical evaluation of the CPMS, assessing how these suggested improvements have been implemented, and if these have affected the usage of the system. The evaluation involves an assessment of CPMS usage statistics since it’s conception that takes into consideration the technical updates and the external factors that may have affected these, including data from a review survey following a training workshop for our new HCPs added in January 2022. It appears that the improvements made to the system since the first review, in particular the implementation of the Operational Helpdesk (OH), have had a positive effect in increasing CPMS membership, however the regular usage of the system continues to fluctuate. Several suggestions are made on how to further facilitate the use of CPMS by our members both individually and network wide, by integrating CPMS activities with other network initiatives and further integration of these into national healthcare systems as well as looking for ways to measure patient satisfaction from the CPMS discussions outcomes.

Open access

Ziting Liang, Mengge Yang, Changjuan Xu, Rong Zeng, and Liang Dong


This study aimed to investigate the effects and safety of metformin in patients with concurrent diabetes mellitus (DM) and chronic obstructive pulmonary disease (COPD).


PubMed, Embase, Web of Science, the China National Knowledge, and Cochrane Database were searched to find studies that examined the effects and safety of metformin in patients with concurrent DM and COPD. We conducted a meta-analysis with a risk ratio (RR) and assessed the quality of included studies and pooled evidence.


Eight studies were involved. Metformin was associated with lower risk of COPD-related hospitalizations (RR: 0.72, 95% CI: 0.53–0.98; I2= 89%) and all-cause mortality (RR: 0.60, 95% CI: 0.36–1.01, I2= 69%) in patients with concurrent DM and COPD, but did not increase the risk of hyperlactatemia (RR: 1.14, 95% CI: 0.92–1.41, I2 = 8%).


Metformin use is associated with lower risk of COPD-related hospitalizations and risk of all-cause mortality without increasing the risk of hyperlactatemia. Considerations should be given to conduct more high-quality randomized trials involving larger samples.