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Elena Valassi, Antoine Tabarin, Thierry Brue, Richard A Feelders, Martin Reincke, Romana Netea-Maier, Miklos Toth, Sabina Zacharieva, Susan M Webb, Stylianos Tsagarakis, Philippe Chanson, Marija Pfeifer, Michael Droste, Irina Komerdus, Darko Kastelan, Dominique Maiter, Olivier Chabre, Holger Franz, Alicia Santos, Christian J Strasburger, Peter J Trainer, John Newell-Price and Oskar Ragnarsson

Objective

Patients with Cushing’s syndrome (CS) have increased mortality. The aim of this study was to evaluate causes and time of death in a large cohort of patients with CS, and to establish factors associated with increased mortality.

Methods

In this cohort-study, we analysed 1564 patients included in the European Registry of CS (ERCUSYN); 1045 (67%) had pituitary-dependent CS, 385 (25%) adrenal-dependent CS, 89 (5%) had an ectopic source and 45 (3%) other causes. The median (IQR) follow-up time in ERCUSYN was 2.7 (1.2-5.5) years.

Results

Forty-nine patients had died at the time of the analysis; 23 (47%) with pituitary- dependent CS, 6 (12%) with adrenal-dependent CS, 18 (37%) with ectopic CS and two (4%) with CS due to other causes. Of 42 patients whose cause of death was known, 15 (36%) died due to progression of the underlying disease, 13 (31%) due to infections, 7 (17%) due to cardiovascular or cerebrovascular disease and two due to pulmonary embolism. The commonest cause of death in patients with pituitary-dependent CS and adrenal-dependent CS were infectious diseases (n=8), and progression of the underlying tumour (n=10) in patients with ectopic CS. Patients who had died were older and more often males, and had more frequently muscle weakness, diabetes mellitus and ectopic CS, compared to survivors. Of 49 deceased patients, 22 (45%) died within 90 days from start of treatment and 5 (10%) before any treatment was given. The commonest cause of these deaths were infections (n=10; 37%). Age, ectopic CS and active disease were associated with overall death before and within 90 days from start of treatment.

Conclusion

Mortality rate was highest in patients with ectopic CS. Infectious diseases were the commonest cause of death soon after diagnosis, emphasizing the need for clinical vigilance at that time, especially in patients with diabetes mellitus.

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Jessica Boyd, Alexander A Leung, Hossein SM Sadrzadeh, Christina Pamporaki, Karel Pacak, Timo Deutschbein, Stephanie Fliedner and Gregory A Kline

Objective

Determine rate of high plasma normetanephrine or metanephrine (PNM-PMN) in a large sample of patients according to PNM-PMN posture and age-adjusted references.

Design

Retrospective re-analysis of PNM-PMN from a Canadian reference laboratory (n = 5452), 2011–2015; most were in seated position (n = 5112) rather than supine (n = 340). An international PPGL database demonstrated expected distribution of supine PNM-PMN in PPGL patients.

Methods

All PNM-PMN from a tertiary referral laboratory were reviewed. Any PNM-PMN result greater than 2× upper reference limit (URL) was considered likely true PPGL. Results 1–2× URL were uncertain, requiring additional testing/follow-up despite most being false positive given the rarity of PPGL. The rate of results in the 1–2× URL category were calculated for each group according to collection posture and differing published URL: seated, supine or supine age adjusted.

Results

When collected and interpreted by seated URL, 19.6% of PNM required additional testing; only 4.6% being >2× URL. For patients over age 50 years, the abnormal rate was 24.9%. When collected supine, interpreted by supine age-adjusted URL, only 5.3% of PNM were mildly elevated. Possible false positives may be even lower when considering PMN or plasma methoxytyramine which were commonly high in true PPGL despite mild PNM elevations.

Conclusions

In a general medical population, seated PNM has a high rate of abnormal results, far exceeding expected prevalence. Supine measurement with supine, age-adjusted interpretation is strongly preferred prior to costly or invasive PPGL investigations.

Summary

Review of 5452 plasma normetanephrine measurements showed 20% to be high, likely false positives for most. Supine, age-adjusted measures were half as likely to be elevated.

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Ana C. Keselman, Ayelen Martin, Paula Alejandra Scaglia, Nora Sanguineti, Romina Armando, Mariana Gutiérrez, Debora Braslavsky, María G Ballerini, María G Ropelato, Laura Ramirez, Elizabeta Landi, Sabina Domené, Julia Fernanda Castro, Hamilton Cassinelli, Barbara Casali, Graciela del Rey, Angel Campos-Barros, Julián Nevado, Horacio Mario Domené, Hector G Jasper, Claudia Arberas, Rodolfo A Rey, Pablo Lapunzina, Ignacio Bergadá and Patricia Pennisi

Background: IGF1 is a key factor in fetal and postnatal growth. To date, only three homozygous IGF1 gene defects leading to complete or partial loss of IGF1 activity have been reported in three short patients born small for gestational age. We describe the fourth patient with severe short stature presenting a novel homozygous IGF1 gene mutation

Results: We report a boy born from consanguineous parents at 40 weeks of gestational age with intrauterine growth restriction and severe post-natal growth failure. Physical examination revealed proportionate short stature, microcephaly, facial dysmorphism, bilateral sensorineural deafness and mild global developmental delay. Basal GH fluctuated from 0.2 to 29 ng/ml, while IGF1 levels ranged from -1.15 to 2.95 SDS. IGFBP3 was normal-high. SNP array delimited chromosomal regions of homozygosity, including 12q23.2 where IGF1 is located. IGF1 screening by HRM revealed a homozygous missense variant NM_000618.4(IGF1):c.322T>C, p.(Tyr108His). The change of the highly conserved Tyr60 in the mature IGF1 peptide was consistently predicted as pathogenic by multiple bioinformatic tools. Tyr60 has been described to be critical for IGF1 interaction with type 1 IGF receptor (IGF1R). In vitro, HEK293T cells showed a marked reduction of IGF1R phosphorylation after stimulation with serum from the patient as compared to sera from age-matched controls. Mutant IGF1 was also less efficient in inducing cell growth. Conclusion: The present report broadens the spectrum of clinical and biochemical presentation of homozygous IGF1 defects and underscores the variability these patients may present depending on the IGF/IGF1R pathway activity.

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Alexander Faje, Kerry Reynolds, Leyre Zubiri, Donald Lawrence, Justine V Cohen, Ryan J Sullivan, Lisa Nachtigall and Nicholas Tritos

Objective

Little has been published describing hypophysitis after nivolumab or pembrolizumab treatment. We aimed to (i) assess the risk of hypophysitis following nivolumab or pembrolizumab treatment, (ii) characterize the clinical presentation and outcomes in these patients and (iii) compare these patients to hypophysitis following ipilimumab and ipilimumab plus nivolumab (combo). We hypothesized that headaches, pituitary enlargement on MRI and multiple anterior pituitary hormone deficiencies would occur less often in the nivolumab/pembrolizumab group versus ipilimumab or combo hypophysitis patients.

Design and methods

We conducted a multi-center retrospective review utilizing the Research Patient Database registry to evaluate individuals diagnosed with hypophysitis following treatment with nivolumab/pembrolizumab (n = 22), ipilimumab (n = 64) and combo (n = 20). Encounter notes, radiologic imaging and laboratory results for these patients were comprehensively reviewed.

Results

Hypophysitis was rare following treatment with nivolumab/pembrolizumab (0.5%, 17/3522) compared to ipilimumab (13.6%, 34/250), P < 0.0001. Hypophysitis was diagnosed later in nivolumab/pembrolizumab (median: 25.8 weeks, interquartile range (IR): 18.4–44.0) compared to ipilimumab (9.3, IR: 7.2–11.1) or combo patients (12.5, IR: 7.4–18.6), P < 0.0001 for both. Headache and pituitary enlargement occurred less commonly in nivolumab/pemrolizumab patients (23% and 5/18, respectively) compared to ipilimumab (75%, 60/61) and combo (75%, 16/17) treatment groups (P < 0.0001 versus ipilimumab and P = 0.001 versus combo for headache and P < 0.0001 for both for enlargement).

Conclusions

This study represents the first comprehensive cohort analysis of nivolumab or pembrolizumab-associated hypophysitis in a large patient group. Hypophysitis occurs rarely with these medications, and these patients have a distinct phenotype compared to hypophysitis after treatment with ipilimumab or ipilimumab plus nivolumab.

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Snjezana Kos, Christa Cobbaert, Martijn T. Kuijper, Wilma Oostdijk, Sabine E. Hannema, Jan M Wit, N R Biermasz and Bart E Ballieux

Three recent publications in this journal have reported that the differences in IGF-1 normative data significantly impact the classification of patients with growth hormone (GH)- excess and deficiency disorders in such a way that clinical performance is severely flawed. This concerns not only pediatric but also adult patients. With this letter, we aim to address additional issues, not previously addressed, which add to the complexity of the interpretation of IGF-1 results. Specifically, the relation between analytical performance of IGF-1 assays and acceptable clinical performance is discussed.

Open access

Jeroen M K de Filette, Joeri J Pen, Lore Decoster, Thomas Vissers, Bert Bravenboer, Bart J Van der Auwera, Frans K Gorus, Bart O Roep, Sandrine Aspeslagh, Bart Neyns, Brigitte Velkeniers and Aan V Kharagjitsingh

Objective

To better define the rare adverse event (AE) of diabetes mellitus associated with immune checkpoint inhibitors (ICIs).

Design and methods

We report the case of a lung cancer patient with diabetic ketoacidosis (DKA) and autoimmune thyroiditis during pembrolizumab treatment. We provide a systematic review of all published cases (PubMed/Web of Science/Cochrane, through November 2018) of autoimmune diabetes mellitus related to blockade of the cytotoxic T-lymphocyte antigen 4 (CTLA-4)-, programmed cell death 1 (PD-1) receptor or its ligand (PD-L1) or combination (ICI) therapy.

Results

Our literature search identified 90 patient cases (our case excluded). Most patients were treated with anti-PD-1 or anti-PD-L1 as monotherapy (79%) or in combination with CTLA-4 blockade (15%). On average, diabetes mellitus was diagnosed after 4.5 cycles; earlier for combination ICI at 2.7 cycles. Early-onset diabetes mellitus (after one or two cycles) was observed during all treatment regimens. Diabetic ketoacidosis was present in 71%, while elevated lipase levels were detected in 52% (13/25). Islet autoantibodies were positive in 53% of patients with a predominance of glutamic acid decarboxylase antibodies. Susceptible HLA genotypes were present in 65% (mostly DR4). Thyroid dysfunction was the most frequent other endocrine AE at 24% incidence in this patient population.

Conclusion

ICI-related diabetes mellitus is a rare but often life-threatening metabolic urgency of which health-care professionals and patients should be aware. Close monitoring of blood glucose and prompt endocrine investigation in case of hyperglycemia is advisable. Predisposing factors such as HLA genotype might explain why some individuals are at risk.

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Seung-Hyun Ko, Kyungdo Han, Jae Seung Yun, Sungjin Chung and Eun Sil Koh

Objective: Obesity and type 2 diabetes are becoming increasingly prevalent worldwide and are both associated with the increased incidence of kidney and bladder cancers. However, previous reports have provided conflicting results. We investigated the impact of body mass index (BMI) and diabetes on the incidence of both cancers in the general population.

Methods: Using nationally representative data from the Korean National Health Insurance System, 9,777,133 subjects without any malignancy who underwent health examinations in 2009 were followed to the end of 2017.

Results: After a median follow-up period of 8.32 years, 12,544 incidents of kidney cancer and 15,137 incidents of bladder cancer were identified. The hazard ratio (HR) for kidney cancer was the lowest in people with a BMI <18.5 kg/m2 (HR 0.82, 95% confidence interval [CI] 0.72–0.94) and the highest in those with a BMI 30 kg/m2 (HR 1.71, 95% CI 1.57–1.87) compared to a reference BMI group (18.5–23 kg/m2). In subjects with diabetes, obesity was associated with increased risk of kidney cancer although the HRs were lower than observed in those without diabetes. Otherwise, there was a reduction in risk of bladder cancer with obesity in men and the HR for bladder cancer was not affected by BMI increase in women. There was a strongly positive association between diabetes and bladder cancer in the total study population.

Conclusions: Obesity was a strong risk factors for kidney cancer, whereas the association between obesity and bladder cancer differed by gender. The subjects with diabetes had a higher risk for both cancers than those without diabetes.

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Lee S. Nguyen, Nathalie Rouas-Freiss, Christian Funck-Brentano, Monique Leban, Edgardo Carosella, Philippe Touraine, Shaida Varnous, Anne Bachelot and Joe-Elie Salem

Background. HLA-G is an immune checkpoint molecule, naturally expressed during pregnancy, playing a critical role in the tolerance of the fetal semi-allograft from the maternal immune system. While HLA-G expression levels are associated with progesterone, the influence of other hormones is still unclear. Congenital adrenal hyperplasia (CAH) represents an adequate model to study the hormonal influence on biomarkers as it leads to impaired cortisol biosynthesis and increased progesterone and androgens production due to 21-hydroxylase enzyme deficiency.

Methods. In a cross-sectional study of CAH patients matched on sex and age with healthy control, the association between circulating levels of soluble HLA-G and hormones was assessed by use of non-parametric analyses tests. Multivariable linear regressions were performed on normalized data.

Results. Overall, 83 CAH patients and 69 healthy controls were included. Among CAH patients, all were under glucocorticoid and 52 (62.6%) were under mineralocorticoid supplementation. Compared to controls, CAH patients had increased HLA-G levels (15 vs 8 ng/mL, p=0.02). In controls, HLA-G level was independently associated with progesterone and estradiol (β= 0.44 (0.35;1.27) and -0.44 (-0.94;-0.26) respectively, both p-values = 0.001). In CAH patients, HLA-G level was independently associated with mineralocorticoid supplementation dosage (β= 0.25 (0.04;0.41), p=0.001) and estradiol (β= -0.22 (-0.57;-0.02), p<0.001).

Conclusion. CAH patients had higher HLA-G levels than healthy controls. HLA-G level was positively associated with progesterone and corticosteroid supplementation, and negatively with estradiol. The association between mineralocorticoid, renin and HLA-G levels may suggest a role of the renin-angiotensin system in the expression of soluble HLA-G.

Free access

Frédérique Albarel, Frédéric Castinetti and Thierry Brue

In recent years, the development of immunotherapy has constituted a revolution in the therapy for many cancers, with a specific toxicity profile including endocrine immune-related adverse events. Immune check point inhibitors (ICI)-induced hypophysitis is a common endocrine side effect, particularly with CTLA-4 antibodies and combination therapy, with frequent hormonal deficiencies at diagnosis. It can be difficult to evoke such diagnosis as the initial clinical symptoms are not specific (headache, asthenia…); thus, patients receiving such immunomodulatory therapies should be closely monitored by systematic hormone measurements, especially in the first weeks of treatment. Usually, hormonal deficiencies improve, except for corticotroph function. Despite a lack of large prospective studies on ICI-induced hypophysitis, some detailed longitudinal cohort studies have focused on such cases of hypophysitis and allow for optimal monitoring, follow-up and management of patients with this immune-related adverse event. In the case of ICI-induced hypophysitis, patients need long-term multidisciplinary follow-up, with specific education for those patients with corticotropin deficiency to allow them to be autonomous with their treatment. In this review, based on a clinical case, we detail the most relevant and novel aspects related to the incidence, diagnosis, treatment, evolution and management of hypophysitis induced by immunotherapy, with a focus on possible mechanisms and current recommendations and guidelines. Lastly, we emphasize several key points, such as the absence of indication to systematically treat with high-dose glucocorticoid and the pursuit of immunotherapy in such hypophysitis. These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

Free access

Grigoris Effraimidis

Prediction models are of a great assistance for predicting the development of a disease, detecting or screening undiagnosed patients, predicting the effectiveness of a treatment and helping toward better decision-making. Recently, three predictive scores in the field of autoimmune thyroid disease (AITD) have been introduced: The Thyroid Hormones Event Amsterdam (THEA) score: a predictive score of the development of overt AITD, the Graves’ Events After Therapy (GREAT) score: a prediction score for the risk of recurrence after antithyroid drugs withdrawal and the Prediction Graves’ Orbitopathy (PREDIGO) score: a prediction score for the development of Graves’ orbitopathy in newly diagnosed patients with Graves’ hyperthyroidism. Their construction, clinical applicability, the possible preventative measurements which can be taken to diminish the risks and the potential future developments which can improve the accuracy of the predictive scores are discussed in this review.