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T C Schneider, R M Abdulrahman, E P Corssmit, H Morreau, J W A Smit and E Kapiteijn

Objective

We conducted a prospective phase II clinical trial to determine the efficacy of sorafenib in patients with advanced radio-iodine refractory differentiated thyroid cancer. In this article, the long-term results are presented.

Patients and methods

Thirty-one patients with progressive metastatic or locally advanced radioactive iodine refractory differentiated thyroid cancer received sorafenib 400 mg orally twice daily. The study end points included response rate, progression-free survival (PFS), overall survival (OS), best response by Response Evaluation Criteria in Solid Tumors criteria 1.0, and toxicity.

Results

Median PFS was 18 months (95% confidence interval (95% CI): 7–29 months) and median OS was 34.5 months (95% CI: 19–50 months). Eight patients (31%) achieved a partial response and 11 patients (42%) showed stable disease after a median follow-up of 25 months (range 3.5–39 months). Toxicity mostly included hand foot syndrome, weight loss, diarrhea, and rash.

Conclusion

Sorafenib has clinically relevant antitumor activity in patients with progressive metastatic or locally advanced radio-iodine refractory differentiated thyroid cancer. Sorafenib can nowadays be considered as the standard option in these patients.

Free access

N van Duinen, E P M Corssmit, W H A de Jong, D Brookman, I P Kema and J A Romijn

Context

A substantial number of patients with head and neck paragangliomas (HNPGLs) have biochemically active tumors, evidenced by increased urinary excretion of catecholamines and metabolites, including 3-methoxytyramine (3MT). It is unclear whether plasma levels of these parameters are more sensitive to detect biochemical activity in HNPGL patients than urinary excretion rates.

Objective

To compare plasma free levels vs urinary excretion rates of deconjugated 3MT and combined metanephrines (MNs) in patients with HNPGL.

Patients and methods

We included 124 consecutive patients with HNPGL for screening of catecholamine excess by measurement of 24-h urinary excretion rates of deconjugated (nor)metanephrine, (nor)epinephrine, dopamine, vanillylmandelic acid, 3MT, and plasma free levels of (nor)metanephrine and 3MT.

Results

Plasma free 3MT levels were increased in 35 of the 124 patients (28%), whereas 24-h urinary excretion of deconjugated 3MT was increased in 30 patients (24%) (P=0.13). Plasma free MN levels were increased in seven patients (6%) and urinary deconjugated MN levels in six patients (5%) (P=1.00). Plasma free normetanephrine (NMN) levels were increased in seven patients (6%), and five patients had increased urinary excretion of deconjugated NMN (4%) (P=0.69). Plasma free combined MN levels (NMN, MN, and 3MT) were increased in 41 patients (33%), whereas 24-h urinary excretion rates of deconjugated combined MNs were increased in 33 patients (27%, P<0.05).

Conclusions

The combined levels of free MNs and free 3MT in plasma indicate a higher number of biochemically active HNPGLs than the 24-h urinary excretion rates of these markers.

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C Nederstigt, B S Uitbeijerse, L G M Janssen, E P M Corssmit, E J P de Koning and O M Dekkers

Introduction

The association between type 1 diabetes (T1D) and other auto-immune diseases is well known. However, a quantitative overview of all associated auto-immune diseases and their prevalence in T1D is lacking.

Methods

We searched PubMed, Web of Science, EMBASE and Cochrane library in September 2018 to identify relevant articles about the prevalence of the following associated auto-immune diseases in T1D cohorts: auto-immune thyroid disease, celiac disease, gastric autoimmunity including pernicious anemia, vitiligo and adrenal gland insufficiency. A meta-analysis was performed to estimate pooled prevalence using a random-effects model. Furthermore, random-effects meta-regression analysis was performed to assess the association between prevalence and mean age or diabetes duration.

Results

One hundred eighty articles were eligible including a total of 293 889 type 1 diabetes patients. Hypothyroidism (65 studies) was prevalent in 9.8% (95% CI: 7.5–12.3) of patients. Meta-regression showed that for every 10-year age increase, hypothyroidism prevalence increased 4.6% (95% CI: 2.6–6.6, P < 0.000, 54 studies). Weighted prevalence of celiac disease was 4.5% (95% CI: 4.0–5.5, 87 studies). Gastric autoimmunity was found in 4.3% of patients (95% CI: 1.6–8.2, 8 studies) and vitiligo in 2.4% (95% CI: 1.2–3.9, 14 studies) of patients. The prevalence of adrenal insufficiency was 0.2% (95% CI: 0.0–0.4, 14 studies) and hyperthyroidism was found in 1.3 percent (95% CI: 0.9–1.8, 45 studies) of type 1 diabetes patients. For all analyses, statistical heterogeneity between studies was moderate to high.

Conclusions

The prevalence of antibody-mediated auto-immune disease is high among type 1 diabetes patients. Especially hypothyroidism and celiac disease are frequently found.

Free access

E N Klein Hesselink, D Steenvoorden, E Kapiteijn, E P Corssmit, A N A van der Horst-Schrivers, J D Lefrandt, T P Links and O M Dekkers

Context

Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients.

Methods

All major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand–foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported.

Results

In total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33–64)%, and was 17 (95% CI 12–24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14–77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34–46)% and 27 (95% CI 22–32)% respectively. Clinical benefit was found in 53 (95% CI 48–59)% of DTC patients on sorafenib, and in 84 (95% CI 79–88)% and 55 (95% CI 49–61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity.

Conclusion

The currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity.

Restricted access

K van der Tuin, M Ventayol Garcia, W E Corver, M N Khalifa, D Ruano Neto, E P M Corssmit, F J Hes, T P Links, J W A Smit, T S Plantinga, E Kapiteijn, T van Wezel and H Morreau

Objective

Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas.

Design

Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hürthle cell- and 14 anaplastic thyroid carcinoma).

Methods

Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants.

Results

Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET (PTC1), PRKAR1A/RET (PTC2) and ETV6/NTRK3 , and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hürthle cell carcinomas are rare (2/35).

Conclusion

Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants and can be effectively identified in formalin-fixed tissue. These gene fusions might provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.

Free access

Karen A Heemstra, Rene E Toes, Jan Sepers, Alberto M Pereira, Eleonora P Corssmit, Tom W J Huizinga, Johannes A Romijn and Johannes W Smit

Objective

Conventional therapies for Graves' disease, consisting of medical therapy or radioiodine are unsatisfactory, because of limited efficacy and adverse events. Interventions aimed at the underlying autoimmune pathogenesis of Graves' disease may be worthwhile to explore. We therefore performed a prospective, 26-week phase II study with open-ended observational extension to assess the efficacy of rituximab in patients with recurrent Graves' disease.

Design

We performed a prospective, 26-week phase II study with open-ended observations.

Methods

Thirteen patients with relapsing Graves' disease (9 females and 4 males, age 39.5±9.5 years) received 2 dosages of rituximab 1000 mg i.v. with a 2-week interval. Before administration and on several periods after the administration of TSH, free thyroxine (FT4), thyrotropin binding inhibitory immunoglobulins (TBII) and the proportion of CD19 and MS4A1 positive peripheral blood mononuclear cells were measured.

Results

The proportion of MS4A1 positive lymphocytes decreased in all patients from 5.8% at baseline to 1.4% at 26 weeks (P=0.007). Four patients with high initial FT4 levels did not respond to treatment. All remaining patients had a decrease in FT4 levels at 26 weeks (P=0.001) and an increase in TSH levels (P=0.011). TBII decreased in all remaining patients (P=0.003). At a follow-up time of 14–27 months, nine of these patients were still euthyroid with normal FT4 (P<0.001) and TSH levels (P=0.008).

Conclusions

The present study results suggest a beneficial role of rituximab in mild relapsing Graves' disease. A subsequent randomized controlled trial with rituximab is recommended.

Free access

L T van Hulsteijn, A Louisse, B Havekes, A A Kaptein, J C Jansen, F J Hes, J W A Smit and E P M Corssmit

Context

Germline mutations in succinate dehydrogenase (SDH) genes predispose carriers for developing paragangliomas, and studies on their quality of life (QoL) are scarce.

Objectives

The objectives of this study were to assess QoL in patients with paragangliomas (PGL), to evaluate long-term QoL, and to explore potential differences in QoL between SDH mutation carriers and paraganglioma patients without an SDH mutation.

Design

Cross-sectional, case–control study.

Setting

Tertiary referral center.

Subjects

One hundred and seventy four paraganglioma patients were included: 25 SDHB, two SDHC, and 122 SDHD mutation carriers and 25 patients without an SDH mutation. They provided 100 peers as control persons. Furthermore, patients were compared with age-adjusted reference populations.

Main outcome measures

QoL was assessed using three validated health-related QoL questionnaires: the Hospital Anxiety and Depression Scale, the Multidimensional Fatigue Index 20, and the Short Form 36.

Results

Patients reported a significantly impaired QoL compared with their own controls, mainly on fatigue and physical condition subscales. Compared with age-adjusted literature values, patients had significantly impaired scores on physical, psychological, and social subscales. A decreased QoL was mainly related to paraganglioma-associated complaints.

There was no difference in QoL between the various SDH mutation carriers or paraganglioma patients without an SDH mutation. QoL in asymptomatic mutation carriers, i.e. without manifest disease, did not differ from QoL of the general population. Long-term results in 41 patients showed no alteration in QoL besides a reduced level of activity.

Conclusion

QoL is decreased in paraganglioma patients but stable when measured over time.

Free access

N van Duinen, D Steenvoorden, B A Bonsing, J Vuyk, A H J T Vriends, J C Jansen, J A Romijn and E P M Corssmit

Context

Sporadic pheochromocytomas are detected by clinical signs and symptoms, whereas pheochromocytomas in patients with a known hereditary predisposition for these tumors are detected by repetitive screening for catecholamine excess.

Objective

To document the clinical, biochemical, and pathological differences between patients with sporadic pheochromocytomas, detected by signs and symptoms and patients with pheochromocytomas, detected by biochemical screening in established hereditary syndromes.

Design

Retrospective follow-up study.

Patients and methods

We included 60 consecutive patients diagnosed with pheochromocytoma (pheochromocytomas detected by signs and symptoms: n=28 and pheochromocytomas detected by screening: n=32) in our center.

Results

Patients with pheochromocytomas detected by screening presented with less complaints of diaphoresis (P<0.01), palpitations (P=0.01), paleness (P=0.01), nausea (P<0.01), and vomiting (P=0.01) compared with patients with symptomatic pheochromocytomas. Patients with pheochromocytomas detected by screening tended to be younger at the time of diagnosis (41±2 vs 47±3 years, P=0.07). In addition, patients with pheochromocytomas detected by screening had significantly lower rates of 24-h urinary catecholamine excretion, and considerably smaller tumors (3.7±0.5 vs 7.3±0.7 cm, P<0.01).

Conclusions

Pheochromocytomas detected by screening of patients with a hereditary predisposition have a much lower prevalence of signs and symptoms, lower catecholamine excess, and smaller tumors, compared with sporadic pheochromocytomas, detected by signs and symptoms. These data support the benefits of screening for pheochromocytomas in patients with hereditary syndromes predisposing for these tumors.

Free access

A A van der Klaauw, A M Pereira, S W van Thiel, J W A Smit, E P M Corssmit, N R Biermasz, M Frolich, A Iranmanesh, J D Veldhuis, F Roelfsema and J A Romijn

Background: Radiotherapy for pituitary adenomas frequently leads to GH deficiency (GHD). The characteristics of GH secretion in GHD induced by postoperative radiotherapy for acromegaly are not known.

Hypothesis: In the long term, stimulated and spontaneous GH release is not different between patients with GHD treated by postoperative radiotherapy for acromegaly or for other pituitary adenomas.

Design/subjects: We compared the characteristics of basal and stimulated GH secretion in patients with GHD, who had previously received adjunct radiotherapy after surgery for GH-producing adenomas (n=10) vs for other pituitary adenomas (n=10). All patients had a maximal GH concentration by insulin tolerance test (ITT) of 3 μg/l or less, compatible with severe GHD. Mean time after radiation was 17 and 18.7 years, respectively. Stimulated GH release was also evaluated by infusion of growth hormone-releasing hormone (GHRH), GHRH–arginine and arginine, and spontaneous GH by 10 min blood sampling for 24 h. Pulse analyses were performed by Cluster and approximate entropy.

Outcomes: There were no differences between both patient groups in stimulated GH concentrations in any test. Spontaneous GH secretion was not different between both patient groups, including basal GH release, pulsatility and regularity. Pulsatile secretion was lost in two acromegalic and three non-acromegalic patients. Insulin-like growth factor-I (IGF-I) was below −2 s.d. score in nine patients in each group.

Conclusion: Acromegalic patients treated by surgery and postoperative radiotherapy with an impaired response to the ITT do not differ, in the long term, in GH secretory characteristics from patients treated similarly for other pituitary tumors with an impaired response to the ITT. The ITT (or the GHRH–arginine test) is therefore reliable in establishing the diagnosis of GHD in patients treated for acromegaly by surgery and radiotherapy.

Free access

W H van Houtum, E P M Corssmit, P B Douwes Dekker, J C Jansen, A G L van der Mey, A H J T Bröcker-Vriends, P E M Taschner, M Losekoot, M Frölich, M P M Stokkel, C J Cornelisse and J A Romijn

Objective: The aim of this study was to identify the prevalence of catecholamine excess and phaeochromocytomas in a well-defined population of people with hereditary head and neck paragangliomas.

Methods: We studied in a prospective follow-up protocol all consecutive patients referred to the Department of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands with documented head and neck paragangliomas and either a positive family history for paragangliomas or a proven SDHD gene mutation. Initial analysis included medical history, physical examination and the measurement of excretion of catecholamines in two 24-h urine collections. In the case of documented catecholamine excess iodinated meta-iodobenzylguanidine (123I-MIBG) scintigraphy and magnetic resonance imaging were done.

Results: Between 1988 and 2003, 40 consecutive patients (20 male and 20 female) with documented head and neck paragangliomas were screened. Biochemical screening revealed urinary catechol-amine excess in 15 patients (37.5%). In nine of these 15 patients a lesion was found by 123I-MIBG scintigraphy. Exact localization by magnetic resonance imaging revealed phaeochromocytomas in seven of the 15 patients. One of the nine patients had an extra-adrenal paraganglioma. Histopathological examination in a subset of tumors displayed loss of heterozygosity of the wild-type SDHD allele in all cases.

Conclusions: The prevalence of catecholamine excess (37.5%) and phaeochromocytomas (20.0%) is high in patients with familial head and neck paragangliomas. Therefore, patients with hereditary head and neck paragangliomas require lifelong follow up by biochemical testing for catecholamine excess.