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Sarah C Clement, Chantal A Lebbink, Mariëlle S Klein Hesselink, Jop C Teepen, Thera P Links, Cecile M Ronckers, and Hanneke M van Santen

Objective

Childhood cancer survivors (CCS) are at increased risk to develop differentiated thyroid cancer predominantly after radiotherapy (subsequent DTC). It is insufficiently known whether subsequent DTC in CCS has a different presentation or outcome than sporadic DTC.

Methods

Patients with subsequent DTC (n = 31) were matched to patients with sporadic DTC (n = 93) on gender, age and year of diagnosis to compare presentation and DTC outcomes. Clinical data were collected retrospectively.

Results

Among the CCS with subsequent DTC, all but one had received chemotherapy for their childhood cancer, 19 (61.3%) had received radiotherapy including the thyroid region, 3 (9.7%) 131I-MIBG and 8 (25.8%) had received treatment with chemotherapy only. Subsequent DTC was detected by surveillance through neck palpation (46.2%), as a self-identified mass (34.6%), or by chance. Among sporadic DTC patients, self detection predominated (68.8%). CCS with subsequent DTC tended to have on average smaller tumors (1.9 vs 2.4 cm, respectively, (P = 0.051), and more often bilateral (5/25 (60.0%) vs 28/92 (30.4%), P = 0.024). There were no significant differences in the occurrence of surgical complications, recurrence rate or disease-related death.

Conclusion

When compared to patients with sporadic DTC, CCS with subsequent DTC seem to present with smaller tumors and more frequent bilateral tumors. Treatment outcome seems to be similar. The finding that one-third of subsequent DTC cases had been treated with chemotherapy only needs further investigation. These results are important for the development of surveillance programs for CCS at risk for DTC and for treatment guidelines of subsequent DTC.

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Charlotte Michaela Fries, Yoon Ju Bae, Nada Rayes, Benjamin Sandner, Berend Isermann, Michael Stumvoll, Valentina Fagotto, Martin Reincke, Martin Bidlingmaier, Vogel Mandy, Jürgen Kratzsch, and Wiebke Kristin Fenske

Objective

Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has become state of the art for the quantitative analysis of steroid hormones. Although method comparisons show that aldosterone measurement using LC-MS/MS yields considerably lower levels than immunoassays (IAs), method-specific cutoff values for primary aldosteronism (PA) are largely missing. Objective of this study was to analyze the diagnostic accuracy of proposed LC-MS/MS-specific cutoff values for the saline infusion test (SIT).

Design and methods

From 2016 to 2019, 104 consecutive patients suspected of PA underwent the SIT and captopril challenge test in the tertiary medical center at the University Hospital of Leipzig, Germany. Patients with positive case confirmation underwent adrenal imaging and adrenal venous sampling for subtype classification.

Results

Overall, proposed assay-specific PACLC-MS/MS cutoff values for the SIT achieved higher diagnostic accuracy than established PACIA values with a sensitivity and specificity of 87.5% (95% CI: 71.0–96.5) and 97% (95% CI: 89.6–99.6) for a cutoff of 120 pmol/L and 93.8% (95% CI: 79.2–99.2) and 92.5% (95% CI: 83.4–97.5) for a cutoff of 94 pmol/L. The most accurate post-SIT PACLC-MS/MS cutoff value in this study was 83 pmol/L, yielding a sensitivity and specificity of 96.9% (95% CI: 83.8–99.9) and 92.5% (95% CI: 83.4–97.5), respectively.

Conclusions

The present data confirm the need for the implication of lower method-specific aldosterone cutoff values for the diagnosis of PA with LC-MS/MS based aldosterone measurement.

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Viivi Saari, Elina Holopainen, Outi Mäkitie, and Saila Laakso

Objective: To determine the natural course of pubertal development, growth during puberty, and development of POI in females with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also called autoimmune polyendocrine syndrome type I.

Design: Longitudinal follow-up study.

Methods: A national cohort of females with APECED aged 12 years were followed during 1965-2018. Attainment of adult height was defined when patients’ height increased less than 1 cm per year. Diagnosis of POI was based on delayed puberty or POI symptoms with amenorrhea, and/or FSH ≥40 IU/l.

Results: Altogether 40 women with APECED were followed up to the average age of 37.3 (range, 14.6–61.9) years; 16 females (40%) were ≥40 years. Pubertal development started spontaneously in 34 patients and 29 had spontaneous menarche. POI developed in 28 patients (70%) at the median age of 16.0 years (range, 11.3–36.5), and in 20 of them (71%) before attaining adult height. In 11 cases puberty was induced or completed by hormonal therapy. Patients with POI were significantly shorter at menarche, but adult heights did not differ from non-POI females. Patients with POI had more often primary adrenocortical insufficiency (93% vs. 58%, p=0.017) and ovarian antibodies (81% vs. 30%, p=0.003) compared to those with normal ovarian function (n=12).

Conclusions: POI developed in the majority of patients with APECED, often before or shortly after menarche. Timely commencement of hormonal replacement therapy is important to ensure optimal pubertal development and growth. The possibility of fertility preservation before development of POI in APECED patients should be further studied.

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Emilia Sbardella, Zoe Maunsell, Christine J H May, Michael Tadman, Tim James, Bahram Jafar-Mohammadi, Andrea M Isidori, Ashley B Grossman, and Brian Shine

Background

In patients with phaeochromocytomas or paragangliomas (PPGLs), 24-h urine collections for metanephrines (uMNs) are cumbersome.

Objective

To evaluate the diagnostic utility of ratios to creatinine of ‘spot’ uMNs.

Methods

Concentrations of uMNs and plasma metanephrines (pMNs) were measured by HPLC-mass-spectrometry. We retrospectively compared correlations of 24-h-urine output and ratio to creatinine in historical specimens and prospectively assessed 24-h and contemporaneous spot urines and, where possible, pMNs. Using trimmed log-transformed values, we derived reference intervals based on age and sex for spot urines. We used multiples of upper limit of normal (ULNs) to compare areas under curves (AUCs) for receiver-operator characteristic curves of individual, and sum and product of, components.

Results

In 3143 24-h-urine specimens on 2416 patients, the correlation coefficients between the ratios and outputs of metanephrine, normetanephrine and 3-methoxytyramine in 24-h urines were 0.983, 0.905 and 0.875, respectively. In 96 patients, the correlations between plasma concentrations, urine output and ratios in spot specimens were similar to those for raw output or ratios in 24-h specimens. Of the 160 patients with PPGLs, the CIs for AUCs for individual metabolites overlapped for all four types of measurement, as did those for the sum of the multiple ULNs although these were slightly higher (AUC for spot urine: 0.838 (0.529–1), plasma: 0.929 (0.874–0.984) and output: 0.858 (0.764–0.952)).

Conclusions

Ratios of fractionated metanephrines to creatinine in spot urine samples appear to have a similar diagnostic power to other measurements. The ease of spot urine collection may facilitate diagnosis and follow-up of PPGLs through improved patient compliance.

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Stephanie Burger-Stritt, Annemarie Eff, Marcus Quinkler, Tina Kienitz, Bettina Stamm, Holger S Willenberg, Gesine Meyer, Johannes Klein, Nicole Reisch, Michael Droste, and Stefanie Hahner

Objective

Patients with adrenal insufficiency (AI) suffer from impaired quality of life and are at risk of adrenal crisis (AC) despite established replacement therapy. Patient education is regarded an important measure for prevention of AC and improvement of AI management. A standardized education programme was elaborated for patients with chronic AI in Germany.

Design

Longitudinal, prospective, questionnaire-based, multi-centre study.

Methods

During 2-h sessions, patients (n = 526) were provided with basic knowledge on AI, equipped with emergency cards and sets and trained in self-injection of hydrocortisone. To evaluate the education programme, patients from eight certified centres completed questionnaires before, immediately after and 6–9 months after training.

Results

399 completed data sets were available for analysis. Questionnaire score-values were significantly higher after patient education, indicating successful knowledge transfer (baseline: 17 ± 7.1 of a maximum score of 29; after training: 23 ± 4.2; P < 0.001), and remained stable over 6–9 months. Female sex, younger age and primary cause of AI were associated with higher baseline scores; after education, age, cause of AI and previous adrenal crisis had a significant main effect on scores. 91% of patients would dare performing self-injection after training, compared to 68% at baseline. An improvement of subjective well-being through participation in the education programme was indicated by 95% of the patients 6–9 months after participation.

Conclusion

Patient group education in chronic AI represents a helpful tool for the guidance of patients, their self-assurance and their knowledge on prevention of adrenal crises. Repeated training and adaptation to specific needs, for example, of older patients is needed.

Free access

Sonia Moretti, Elisa Menicali, Nicole Nucci, Martina Guzzetti, Silvia Morelli, and Efisio Puxeddu

Immunotherapy has arisen in use in the field of oncology with seven immune checkpoint inhibitors approved for the treatment of a variety of cancer histologies. Depending on the cancer type, the success rate might be different, but in average it is about 20%, with some cases showing a durable response, lasting also after the interruption of the treatment, with a clear benefit on OS. The development of an efficacious cure for advanced thyroid carcinomas is still an unmet need and immunotherapy represents an interesting alternative option also for this cancer. However, very few clinical trials have been accomplished and very few studies exploring a way to overcome resistance have been performed. In this review, we will summarize the mechanisms of immune escape, with a special reference to follicular-derived thyroid carcinoma. Furthermore, we will try to speculate on the use of immune checkpoint inhibitors for the treatment of follicular-derived advanced thyroid carcinoma. Finally, we will summarize the ongoing clinical trials and the future directions of the field.

Open access

Susanne Thiele, Ralf Werner, Annika Stubbe, Olaf Hiort, and Wolfgang Hoeppner

Background: Hypophosphataemic rickets (HR) comprise a clinically and genetically heterogeneous group of conditions, defined by renal-tubular phosphate wasting and consecutive loss of bone mineralisation. X-linked hypophosphataemia (XLH) is the most common form, caused by inactivating dominant mutations in PHEX, a gene encompassing 22 exons located at Xp22.1. XLH is treatable by anti-Fibroblast Growth Factor 23 antibody, while for other forms of HR such a therapy may not be indicated. Therefore, a genetic differentiation of HR is recommended.

Objective: To develop and validate a next generation sequencing panel for HR with special focus on PHEX.

Design and Methods: We designed an AmpliSeq gene panel for the IonTorrent PGM next generation platform for PHEX and ten other HR-related genes. For validation of PHEX sequencing 50 DNA-samples from XLH-patients, in whom 42 different mutations in PHEX and one structural variation have been proven before, were blinded, anonymised and investigated with the NGS panel. In addition, we analyzed one known homozygous DMP1 mutation and two samples of HR-patients, where no pathogenic PHEX mutation had been detected by conventional sequencing.

Results:

The panel detected all 42 pathogenic missense/nonsense/splice-site/indel PHEX-mutations and in one the known homozygous DMP1 mutation. In the remaining two patients, we revealed a somatic mosaicism of a PHEX mutation in one; as well as two variations in DMP1 and a very rare compound heterozygous variation in ENPP1 in the second patient.

Conclusions: This NGS panel is a reliable tool with high sensitivity and specificity for diagnosis of XLH and related forms of HR.

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Daan M Van Velzen, Nienke M Nota, Suat Simsek, Elfi B Conemans, Guy T'Sjoen, and Martin Den Heijer

Objective

Transgender individuals sometimes report a lack of physical change during hormone treatment, such as alterations in muscle tone or fat distribution. Identifying characteristics of this subgroup could be a step towards individualizing hormone therapy in transgender individuals. Therefore, we study the variation of changes in body composition and characteristics associated with a lack of change.

Design and methods:

Body composition measures were recorded in 323 transmen and 288 transwomen at every visit from start of hormone therapy to a maximum of 24 months follow-up. Absence of change was defined as transmen with a decrease in lean body mass or transwomen with a decrease in fat percentage.

Results

A lack of change at 24 months was observed in 19 of 94 (20.2%) transmen and in 9 of 96 (9.4%) transwomen. The risk of not achieving change in body composition was related to lower testosterone levels and less suppression of LH in transmen (OR 0.67, 95% CI: 0.48-0.94 per SD increase in testosterone and OR 1.36, 95% CI 1.01-1.83 per SD increase in LH).

Conclusion

There is a large variation in body composition changes during hormone therapy, with a substantial proportion of individuals with no measurable effects. In transmen, serum testosterone and LH were associated with a lack of change, but serum hormone levels were not associated with body composition changes in transwomen. The results provide a rationale for individualizing hormone therapy in transmen, by considering individuals effects rather than solely relying on a standardized dosages of hormone therapy.

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Rudolf Hoermann, John E M Midgley, Rolf Larisch, and Johannes W Dietrich

Free access

Cesar Luiz Boguszewski

Acromegaly is a debilitating and disfiguring chronic disease, which occurs in both sexes at any age, associated with multiple comorbidities and increased mortality. It is typically caused by a GH-secreting pituitary adenoma that promotes exposure of body tissues to increased concentrations of GH and IGF-I. The diagnosis of acromegaly is still made very late in a substantial number of patients when the disease is already in advanced stages. An epidemiological study from Sweden has elegantly demonstrated that the longer the diagnostic delay in acromegaly, the higher the number of comorbidities. Moreover, about 25% of the Swedish patients had 10 years or more of diagnostic delay and in this group mortality rate was significantly increased. These results reinforce the importance of shortening the latency period between disease onset, diagnosis and treatment to improve patient outcomes. This commentary article discusses strategies to be embraced by the endocrine community to allow early identification of acromegaly among public and health professionals, as internists, primary care clinicians, different specialists and dentists are the first point of contact for most of the patients. We emphasize that acromegaly should be presented as a sporadic, rather than rare, insidious disease, meaning that there is a considerable chance for health professionals to see a patient with acromegaly throughout their careers. The motto ‘you must know it to think of it’ is advocated in awareness efforts to reduce time to diagnosis, which results in lower rates of morbidity and mortality and might positively impact healthcare costs.