Department of Pediatric Endocrinology, Wilhelmina Children’s Hospital/ University Medical Center Utrecht, Utrecht, The Netherlands
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Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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Developmental Endocrinology Research Group, Royal Hospital for Children, University of Glasgow, Glasgow, UK
Office for Rare Conditions, University of Glasgow, Glasgow, UK
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Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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Background
Although differentiated thyroid carcinoma (DTC) is the most frequent endocrine pediatric cancer, it is rare in childhood and adolescence. While tumor persistence and recurrence are not uncommon, mortality remains extremely low. Complications of treatment are however reported in up to 48% of the survivors. Due to the rarity of the disease, current treatment guidelines are predominantly based on the results of small observational retrospective studies and extrapolations from results in adult patients. In order to develop more personalized treatment and follow-up strategies (aiming to reduce complication rates), there is an unmet need for uniform international prospective data collection and clinical trials.
Methods and analysis
The European pediatric thyroid carcinoma registry aims to collect clinical data for all patients ≤18 years of age with a confirmed diagnosis of DTC who have been diagnosed, assessed, or treated at a participating site. This registry will be a component of the wider European Registries for Rare Endocrine Conditions project which has close links to Endo-ERN, the European Reference Network for Rare Endocrine Conditions. A multidisciplinary expert working group was formed to develop a minimal dataset comprising information regarding demographic data, diagnosis, treatment, and outcome. We constructed an umbrella-type registry, with a detailed basic dataset. In the future, this may provide the opportunity for research teams to integrate clinical research questions.
Ethics and dissemination
Written informed consent will be obtained from all participants and/or their parents/guardians. Summaries and descriptive analyses of the registry will be disseminated via conference presentations and peer-reviewed publications.
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Objective
Neutropenia is a complication of Graves' disease (GD), but there is currently no means by which to predict its occurrence. This study aimed to investigate the risk factors for the development of neutropenia in untreated GD.
Methods
This was a retrospective cohort study. Between January 1, 2010, and July 31, 2020, 1000 patients with new-onset or relapsing GD without treatment were enrolled in the study and divided into two groups: neutropenia group (neutrophil count < 2 × 109/L) and non-neutropenia group (neutrophil count ≥ 2 × 109/L). Clinical characteristics of subjects were compared between the two groups, and logistic regression analysis was applied to determine risk factors for neutropenia. To further explore the correlation of radioactive iodine uptake (RAIU) with neutropenia, subjects were first classified according to quartile of 3 h RAIU and 24 h RAIU prior to logistic regression analysis.
Results
Of all patients recruited, 293 (29.6%) were diagnosed with neutropenia. Compared with non-neutropenic patients, those with neutropenia had a higher level of free thyroxine (FT4) (56.64 ± 31.80 vs 47.64 ± 39.64, P = 0.001), 3 h RAIU (55.64 ± 17.04 vs 49.80 ± 17.21, P < 0.001) and 24 h RAIU (67.38 ± 12.54 vs 64.38 ± 13.58, P < 0.001). Univariate logistic regression analysis revealed that FT4, 3 h RAIU, 24 h RAIU, creatinine, and low-density lipoprotein were risk factors for development of neutropenia in GD. After adjusting for confounding factors of age, BMI, and sex, we determined that 3 h RAIU and 24 h RAIU (Model 1: OR = 1.021, 95% CI: 1.008–1.033, P = 0.001; Model 2: OR = 1.023, 95% CI: 1.007–1.039, P = 0.004), but not FT4, were associated with the development of neutropenia.
Conclusions
RAIU is associated with neutropenia in patients with untreated GD.
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Objective
Thyroid-stimulating hormone (TSH) is influenced by genetic and environmental factors such as socioeconomic position (SEP). However, interactions between TSH-related genetic factors and indicators of SEP have not been investigated to date. The aim of the study was to determine whether education and income as SEP indicators may interact with TSH-related genetic effect allele sum scores (GESTSH_2013 and GESTSH_2020) based on two different GWAS meta-analyses that affect TSH values in a population-based study.
Methods
In 4085 participants of the Heinz Nixdorf Recall Study associations between SEP indicators, GESTSH and TSH were quantified using sex- and age-adjusted linear regression models. Interactions between SEP indicators and GESTSH were assessed by GESTSH × SEP interaction terms, single reference joint effects and calculating genetic effects stratified by SEP group.
Results
Participants within the highest education group showed the strongest genetic effect with on average 1.109-fold (95% CI: 1.067–1.155) higher TSH values per GESTSH_2013 SD, while in the lowest education group, the genetic effect was less strong (1.061-fold (95% CI: 1.022–1.103)). In linear regression models including interaction terms, some weak indication for a positive GESTSH_2013 by education interaction was observed showing an interaction effect size estimate of 1.005 (95% CI: 1.000–1.010) per year of education and GESTSH_2013 SD. No indication for interaction was observed for using income as SEP indicator. Using the GESTSH_2020, similar results were observed.
Conclusion
Our results gave some indication that education may affect the expression of TSH-related genetic effects. Stronger genetic effects in high-education groups may be explained by environmental factors that have an impact on gene expression and are more prevalent in high SEP groups.
Department of Ultrasound, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China
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Background
Papillary thyroid carcinoma is the most common thyroid carcinoma worldwide. Papillary thyroid carcinoma metastasis to the cervical region increases the probability of local or regional recurrence and the requirement for further surgery. Contrast-enhanced ultrasound has been suggested as a possible adjunct diagnostic technique for evaluating papillary thyroid carcinoma metastatic lymph nodes in several studies. This meta-analysis aims to evaluate the diagnostic accuracy of contrast-enhanced ultrasound for cervical lymph nodes metastatic in papillary thyroid carcinoma patients.
Methods
A search for studies evaluating the role of contrast-enhanced ultrasound for assessing cervical lymph nodes metastatic in papillary thyroid carcinoma patients from January 2000 to May 2022 was performed in PubMed, Embase, OVID, and Web of Science databases. The Quality Assessment of Diagnostic Accuracy Studies 2 evaluated the quality of the studies. All analyses were performed using Review Manager 5.3 and Stata 17.0.
Results
A total of seven articles were finally included in this study. Perfusion type, enhancement homogeneous, hilum absent, and perfusion defect were involved in the meta-analysis as the standard of contrast-enhanced ultrasound, among which, perfusion type showed the best diagnostic performance. The pooled estimated sensitivity, specificity, positive likelihood, negative likelihood ratio, and diagnostic odds ratio of perfusion type in contrast-enhanced ultrasound for detecting lymph node metastasis were 0.95 (0.91, 0.97), 0.87 (0.69, 0.96), 7.51 (2.80, 20.14), 0.06 (0.03, 0.10), and 124.17 (42.78, 360.46), respectively. Heterogeneity was moderate.
Conclusion
The perfusion type in contrast-enhanced ultrasound has good diagnostic performance for cervical lymph nodes metastasis in papillary thyroid carcinoma patients.
German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
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German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
Department of Nuclear Medicine, University Hospital Münster, Münster, Germany
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German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
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German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
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German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
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German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
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Institute of Pathology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
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German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
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Objective
Recurrence of differentiated thyroid cancer (DTC) is associated with reduced quality of life, and therefore, early identification of patients at risk is urgently needed.Here we investigated the predictive power of various cut-off values of single stimulated thyroglobulin (s-Tg) and single highly sensitive measured, unstimulated thyroglobulin (u-hsTg) measurements close to the end of primary therapy for recurrence-free survival (RFS) in long-term follow-up (>10 years) of patients with DTC.
Methods
In DTC patients with adjuvant radioiodine therapy, we assessed retrospectively u-hsTg (6 ± 3 months before s-Tg measurement) and s-Tg measurements (≤24 months after last radioiodine therapy). Positive predictive (PPV)/negative predictive values (NPV) of various cut-off values (s-Tg: 0.5/1.0 ng/mL; u-hsTg: 0.09/0.2 ng/mL) for patient outcomes as well as additional factors associated with disease development were analyzed.
Results
In total, 175 patients were retrospectively reviewed (tumor recurrence: n = 14/complete remission: n = 161). Examined cut-off values for s-Tg and u-hsTg showed significant predictive power for RFS (log-rank: all P < 0.001). NPV/PPV for s-Tg were 98.6%/36.4%, respectively (0.5 ng/mL cut-off) and 96.7%/42.9%, respectively (1.0 ng/mL cut-off); those for u-hsTg were 97.3%/35.7%, respectively (0.09 ng/mL cut-off) and 95.2%/85.7%, respectively (0.2 ng/mL cut-off). U-hsTg (P < 0.001) and patient age (P < 0.05) were significantly associated with tumor recurrence. One-third of patients with tumor recurrence in the course initially showed undetectable u-hsTg after completion of primary therapy.
Conclusion
With >10 years of follow-up, both s-Tg and u-hsTg have a comparably high predictive power for RFS, while only u-hsTg was significantly associated with a recurrence event.Serial u-hsTg measurements seem warranted since patients with tumor recurrence during follow-up may have an undetectable tumor marker at baseline.
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Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
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Emma Children’s Hospital, Amsterdam UMC, Department of Pediatrics, Amsterdam, The Netherlands
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University Hospital Würzburg, Department of Nuclear Medicine, Würzburg, Germany
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Background
Childhood cancer survivors (CCS) who received radiation therapy exposing the thyroid gland are at increased risk of developing differentiated thyroid cancer (DTC). Therefore, the International Guideline Harmonization Group (IGHG) on late effects of childhood cancer therefore recommends surveillance. It is unclear whether surveillance reduces mortality.
Aim
The aim of this study was to compare four strategies for DTC surveillance in CCS with the aim of reducing mortality: Strategy-1, no surveillance; Strategy-2, ultrasound alone; Strategy-3, ultrasound followed by fine-needle biopsy (FNB); Strategy-4, palpation followed by ultrasound and FNB.
Materials and methods
A decision tree was formulated with 10-year thyroid cancer-specific survival as the endpoint, based on data extracted from literature.
Results
It was calculated that 12.6% of CCS will develop DTC. Using Strategy-1, all CCS with DTC would erroneously not be operated upon, but no CCS would have unnecessary surgery. With Strategy-2, all CCS with and 55.6% of CCS without DTC would be operated. Using Strategy-3, 11.1% of CCS with DTC would be correctly operated upon, 11.2% without DTC would be operated upon and 1.5% with DTC would not be operated upon. With Strategy-4, these percentages would be 6.8, 3.9 and 5.8%, respectively. Median 10-year survival rates would be equal across strategies (0.997).
Conclusion
Different surveillance strategies for DTC in CCS all result in the same high DTC survival. Therefore, the indication for surveillance may lie in a reduction of surgery-related morbidity rather than DTC-related mortality. In accordance with the IGHG guidelines, the precise strategy should be decided upon in a process of shared decision-making.
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Objective
The central neck lymph node (LN) status is important for the treatment strategy of papillary thyroid cancer (PTC), while the diagnosis is difficult. This study aims to evaluate the diagnostic value of fine-needle aspiration (FNA) and its washout thyroglobulin (FNA-Tg) detection in central neck LN metastasis.
Methods
Central neck LNs with FNA cytology (FNA-C) and FNA-Tg measurements from a tertiary hospital were included. Tg levels were correlated with histopathological or follow-up results. The diagnostic performance of FNA-C, FNA-Tg, and combining FNA-C and FNA-Tg for detecting LN metastasis was assessed.
Results
A total of 132 LNs in the central neck from 129 patients were studied. The median FNA-Tg concentration of 74 metastatic LNs was 552.5 ng/mL, whereas, in 58 benign LNs, the median Tg concentration was 0.1 ng/mL (P < 0.001). Receiver operating characteristic analysis (area under the curve, 0.861) was used, and a cutoff value of 14.6 ng/mL was obtained. There was no significant increase in the diagnostic accuracy when FNA-Tg was used or combined with FNA-C, compared with FNA-C alone. The size, location of LNs, the presence of the ipsilateral thyroid gland, and Hashimoto's thyroiditis did not affect the incidence of misdiagnosis.
Conclusions
FNA-C is the gold standard for evaluating central neck metastasis in PTC patients. Measurement of Tg levels in FNA washout does not improve the diagnostic accuracy any further.
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Purpose
The levothyroxine absorption test (LT4AT) is an important tool for distinguishing hypothyroidism due to malabsorption from ‘pseudomalabsorption’ conditions. Our aim was to review our institution’s LT4AT results and assess its role in the management of patients with refractory hypothyroidism.
Methods
We performed a retrospective study of all patients evaluated for refractory hypothyroidism who underwent LT4AT in our tertiary center between 2014 and 2020. Its results and the impact on thyroid function management during follow-up were assessed.
Results
Ten female patients were included with a mean age of 40 years (min-max: 26–62). Mean weight was 72 kg (min–max: 43–88) and baseline LT4 dosage ranged from 2.5 to 5.3 µg/kg/day. The most common causes of hypothyroidism were postsurgical in 50% (n = 5) and autoimmune in 20% (n = 2). During LT4AT, normal LT4 absorption was found in all but one individual (mean FT4 increase of 231%, min–max: 85–668). The only patient with objective LT4 absorption impairment (maximal increase of 48% by hour 5) presented also Helicobacter pylori gastritis and prior history of ‘intestinal surgery’ during childhood. No adverse events were reported during any of the LT4ATs. During follow-up (median 11.5 months (IQR 23)), three patients obtained euthyroidism and six had improved their hypothyroidism state.
Conclusions
The LT4AT is an effective and safe way to assess refractory hypothyroidism and provides valuable information to distinguish LT4 malabsorption from ‘pseudomalabsorption’. Our data suggest that most patients with suspicious LT4 malabsorption perform normally during LT4AT. This test provides relevant information for better management of patients with refractory hypothyroidism.
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Clinical Research Centre, Medical University of Bialystok, Bialystok, Poland
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Graves’ orbitopathy (GO) is a potentially sight-threatening and disfiguring, extrathyroidal manifestation of Graves’ disease. It often impairs patients’ quality of life, causing severe social and psychological sequelae. Intravenous glucocorticosteroids is currently the mainstay of therapy, but the efficacy is often underwhelming and recurrence rate is high. For many years, clinicians have been searching for new methods of treatment. Rituximab (RTX) is a chimeric monoclonal antibody targeted against CD20 which is a surface antigen present on B cells. It is frequently used to treat non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, or various types of vasculitis. Numerous clinical trials employing RTX in the treatment of GO have shown promising results. RTX is currently considered to be a valid second-line treatment option in patients unresponsive to previous interventions or in disease reactivation. This review summarizes the available literature on this topic, including two largest, randomized, controlled studies. Potential benefits, as well as the limitations of RTX therapy, are discussed.
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Background
Graves’ disease is a common autoimmune disease. Cytokines and their signalling pathways play a major part in the pathogenesis of Graves’ disease; however, the underlying mechanism needs to be clarified.
Aims
The aim of this study was to explore whether circular RNAs participate in the immunological pathology of Graves’ disease via cytokine-related signalling pathways.
Methods
Bioinformatics analysis was performed to identify differentially expressed circular RNAs and their targets and associated pathways. A total of three patients with Graves’ disease and three sex- and age-matched healthy controls were enrolled for validation with microarray analysis and real-time quantitative PCR (qPCR). An additional 24 patients with Graves’ disease and 24 gender- and age-matched controls were included for validation by real-time fluorescent qPCR. Flow cytometry and CCK8 assays were used to detect the apoptotic and proliferative levels of Jurkat cells (T lymphocytes) with the silenced expression of circRNA. ELISA was performed to detect the growth and apoptosis-related proteins. The competition mechanism of endogenous RNA was explored by real-time fluorescence qPCR.
Results
A total of 366 significantly differentially expressed circular RNAs were identified in the Graves’ disease group compared to healthy controls. The level of hsa_circ_0090364 was elevated in Graves’ disease patients and positively correlated with thyroid-stimulating hormone receptor antibodies. Further analyses suggested that hsa_circ_0090364 may regulate the JAK-STAT pathway via the hsa-miR-378a-3p/IL-6ST/IL21R axis to promote cell growth.
Conclusions
These results provide novel clues into the pathophysiological mechanisms of Graves’ disease and potential targets for drug treatment.
