Search Results

You are looking at 1 - 10 of 27 items for

  • Author: Johannes W A Smit x
Clear All Modify Search
Full access

Herman Verloop, Johannes W A Smit and Olaf M Dekkers

Objective

Thyroid function abnormalities are common during treatment with tyrosine kinase inhibitors such as sorafenib. Suggested causes are direct effects on thyroid tissue and increased extrathyroidal metabolism of serum thyroxine and 3,5,3-triiodothyronine. We postulated that tyrosine kinase inhibitors may affect the peripheral metabolism of TSH as well. The effect of sorafenib on TSH clearance was studied.

Design

In a study of athyreotic patients on TSH suppression therapy, TSH concentrations were measured after recombinant human TSH (rhTSH) injections before and after 26 weeks of sorafenib therapy.

Methods

Before and after the last week of sorafenib therapy, 20 patients with progressive differentiated thyroid carcinoma received a standard dose regimen of two injections 0.9 mg rhTSH on two consecutive days. TSH concentrations were measured 48 h (TSH48 h) and 96 h (TSH96 h) after the first rhTSH injection. The area under the curve (TSH-AUC), reflecting TSH content between 48 and 96 h following rhTSH administration, was calculated.

Results

TSH48 h levels (120.5 mU/l before vs 146.3 mU/l after; P=0.029), TSH96 h levels (22.0 mU/l before vs 35.5 mU/l after; P=0.001), and TSH-AUC (142.7 vs 186.8 mU/l; P=0.001) were significantly higher after sorafenib treatment. Higher sorafenib doses were associated with increased changes in TSH96 h and TSH-AUC. In two patients, TSH levels after sorafenib therapy exceeded 200 mU/l.

Conclusions

Sorafenib therapy is accompanied by higher rhTSH levels, probably due to a decreased TSH clearance. Further studies are recommended to clarify whether a decreased clearance of TSH is sorafenib specific.

Full access

Ying Y Liu, Hans Morreau, Job Kievit, Johannes A Romijn, Nancy Carrasco and Johannes W Smit

Objectives

The microscopic distinction between benign and malignant thyroid lesions in clinical practice is still largely based on conventional histology. This study was performed to evaluate the diagnostic value of galectin-3 (Gal-3), Hector Battifora mesothelial-1 (HBME-1), cytokeratin (CK)-19, CBP P300-interacting transactivator with glutamic acid E- and aspartic acid D-rich C-terminal domain (CITED-1), fibronectin (FN)-1, peroxisome proliferator-activated receptor (PPAR)-γ, and intracellular sodium/iodide symporter (iNIS) immunostaining in a large panel of thyroid neoplasms. Our study differed from earlier ones with regard to the identification of optimal semiquantitative cut-off levels using receiver operator curve (ROC) analysis and hierarchical cluster analysis.

Methods

We used tissue arrays containing 177 thyroid tissues: 100 benign tissues (including normal thyroid, Graves disease, multinodular goiter, and follicular adenoma (FA)) and 77 thyroid carcinomas (including papillary thyroid carcinoma (PTC), follicular thyroid carcinoma, and follicular variant of PTC (FVPTC)). Antibody staining was scored semiquantitatively based on the ROC analyses and with hierarchical cluster analysis.

Results

In general, we found overexpression of FN-1, CITED-1, Gal-3, CK-19, HBME-1, and iNIS in malignant thyroid lesions. Gal-3, FN-1, and iNIS had the highest accuracy in the differential diagnosis of follicular lesions. A panel of Gal-3, FN-1, and iNIS, identified by hierarchical cluster analysis, had a 98% accuracy to differentiate between FA and malignant thyroid lesions. In addition, HBME-1 was found to be useful in the differentiation between FA and FVPTC (accuracy 88%).

Conclusion

We conclude that identifying optimal antibody panels with cluster analysis increases the diagnostic value in the differential diagnosis of thyroid neoplasms, the combination of FN-1, Gal-3, and iNIS having the best accuracy (98%).

Full access

Jitske Tiemensma, Adrian A Kaptein, Alberto M Pereira, Johannes W A Smit, Johannes A Romijn and Nienke R Biermasz

Objective

Illness perceptions pertain to the pattern of beliefs patients develop about their illness. Illness perceptions are determinants of quality of life (QoL). Factors contributing to persisting impaired QoL after Cushing's syndrome (CS) remain largely unknown. Therefore, the objective of this study was to explore illness perceptions, as potentially modifiable psychological factors, in relation to QoL in patients with long-term remission of CS.

Design

Cross-sectional study.

Methods

We included patients with long-term remission of CS (n=52). Illness perceptions were evaluated using the Illness Perception Questionnaire (IPQ)-Revised, and QoL was measured using the physical symptom checklist, EuroQoL-5D (EQ-5D), and the CushingQoL. Reference data were derived from recent studies and included patients with vestibular schwannoma (n=80), acute (n=35) or chronic (n=63) pain, and chronic obstructive pulmonary disease (COPD; n=171).

Results

Illness perceptions showed a strong correlation with QoL. Patients with CS scored distinctively more negative on the IPQ compared with patients with vestibular schwannoma and patients with acute pain, and also reported more illness-related complaints (all P<0.01). There were also some differences in illness perceptions between patients with CS and patients with chronic pain and patients with COPD, but there was no distinct pattern.

Conclusions

Patients after long-term remission of CS report more negative illness perceptions compared with patients with other acute or chronic conditions. Further research is needed to assess whether QoL in CS can be improved by addressing these illness perceptions, for example, by a self-management intervention program.

Full access

Alberto M Pereira, Victoria Delgado, Johannes A Romijn, Johannes W A Smit, Jeroen J Bax and Richard A Feelders

Objective

In patients with active Cushing's syndrome (CS), cardiac structural and functional changes have been described in a limited number of patients. It is unknown whether these changes reverse after successful treatment. We therefore evaluated the changes in cardiac structure and dysfunction after successful treatment of CS, using more sensitive echocardiographic parameters (based on two-dimensional strain imaging) to detect subtle changes in cardiac structure and function.

Methods

In a prospective study design, we studied 15 consecutive CS patients and 30 controls (matched for age, sex, body surface area, hypertension, and left ventricular (LV) systolic function). Multidirectional LV strain was evaluated by two-dimensional speckle tracking strain imaging. Systolic (radial thickening, and circumferential and longitudinal shortening) and diastolic (longitudinal strain rate at the isovolumetric relaxation time (SRIVRT)) parameters were measured.

Results

At baseline, CS patients had similar LV diameters but had significantly more LV hypertrophy and impaired LV diastolic function, compared to controls. In addition, CS patients showed impaired LV shortening in the circumferential (−16.5±3.5 vs −19.7±3.4%, P=0.013) and longitudinal (−15.9±1.9 vs −20.1±2.3%, P<0.001) directions and decreased SRIVRT (0.3±0.15 vs 0.4±0.2/ s, P=0.012) compared to controls. After normalization of corticosteroid excess, LV structural abnormalities reversed, LV circumferential and longitudinal shortening occurred, and SRIVRT normalized.

Conclusion

CS induces not only LV hypertrophy and diastolic dysfunction but also subclinical LV systolic dysfunction, which reverses upon normalization of corticosteroid excess.

Full access

Herman Verloop, Olaf M Dekkers, Robin P Peeters, Jan W Schoones and Johannes W A Smit

Iodothyronine deiodinases represent a family of selenoproteins involved in peripheral and local homeostasis of thyroid hormone action. Deiodinases are expressed in multiple organs and thyroid hormone affects numerous biological systems, thus genetic variation in deiodinases may affect multiple clinical endpoints. Interest in clinical effects of genetic variation in deiodinases has clearly increased. We aimed to provide an overview for the role of deiodinase polymorphisms in human physiology and morbidity. In this systematic review, studies evaluating the relationship between deiodinase polymorphisms and clinical parameters in humans were eligible. No restrictions on publication date were imposed. The following databases were searched up to August 2013: Pubmed, EMBASE (OVID-version), Web of Science, COCHRANE Library, CINAHL (EbscoHOST-version), Academic Search Premier (EbscoHOST-version), and ScienceDirect. Deiodinase physiology at molecular and tissue level is described, and finally the role of these polymorphisms in pathophysiological conditions is reviewed. Deiodinase type 1 (D1) polymorphisms particularly show moderate-to-strong relationships with thyroid hormone parameters, IGF1 production, and risk for depression. D2 variants correlate with thyroid hormone levels, insulin resistance, bipolar mood disorder, psychological well-being, mental retardation, hypertension, and risk for osteoarthritis. D3 polymorphisms showed no relationship with inter-individual variation in serum thyroid hormone parameters. One D3 polymorphism was associated with risk for osteoarthritis. Genetic deiodinase profiles only explain a small proportion of inter-individual variations in serum thyroid hormone levels. Evidence suggests a role of genetic deiodinase variants in certain pathophysiological conditions. The value for determination of deiodinase polymorphism in clinical practice needs further investigation.

Full access

Nieke E Kokshoorn, Nienke R Biermasz, Ferdinand Roelfsema, Johannes W A Smit, Alberto M Pereira and Johannes A Romijn

Context

Recombinant human GH (rhGH) is prescribed for the treatment of adults with GH deficiency (GHD). However, conflicting data are available on the efficacy of rhGH treatment in elderly GHD patients.

Objective

To assess the efficacy of rhGH treatment in elderly GHD subjects.

Methods

We searched the available literature in PubMed, Cochrane Library, Web of Science and EMBASE.

Study selection

Studies on GHD patients, aged >60 years, treated with rhGH were eligible for inclusion. Data extraction was performed by two reviewers independently.

Results

We found 11 eligible studies with a total of 534 patients. Only two studies had prospective, randomized, placebo-controlled study designs of rhGH treatment with a duration of 6 (n=15) and 12 months (n=62), respectively. Treatment with rhGH decreased total and low density lipoprotein (LDL) cholesterol levels by 4–8 and 11–16%, respectively, but did not alter high density lipoprotein or triglyceride levels. RhGH did not affect body mass index, but decreased waist circumference (by ∼3 cm) and waist/hip ratio. RhGh did not consistently affect blood pressure or bone mineral density. RhGH increased lean body mass by 2–5% and decreased total fat mass by 7–10% in four studies, but did not affect body composition in two other studies. RhGH consistently improved quality of life (QoL) parameters reflected in AGHDA-scores. There were no explicit data on elderly GHD patients aged >80 years.

Conclusion

RhGH replacement in elderly subjects with GHD decreases LDL cholesterol levels and improves QoL, but the effects on other parameters are not unequivocal. There were no data on the efficacy and safety of rhGH treatment in octogenarians with GHD.

Full access

Robbert B T Verkooijen, Jan W A Smit, Johannes A Romijn and Marcel P M Stokkel

Objective: The aim of the present study is to assess the prevalence of second primary tumors in patients treated for thyroid cancer. Furthermore, we wanted to assess the standardized risk rates for all second primary tumors, but especially for breast cancer, as data in the literature indicate an excessive risk in differentiated thyroid cancer (DTC) patients for this tumor.

Materials and methods: We included consecutive patients, who received ablation treatment with I-131 at the Leiden University Medical Center between January 1985 and December 1999 (n = 282). The mean period of follow-up was 10.6 ± 4.1 years.

Results: Thirty-five of the 282 patients (12.4%) had a second primary tumor (SPT), either preceding or following the diagnosis of thyroid cancer. Five other patients had three primary tumors, including DTC. As a result, 40 additional tumors were found in this group, revealing an overall prevalence of 14.2%. Twenty tumors (7.1%) preceded the thyroid cancer with a mean interval of 5.7 years (range: 0.5–22.0 years), whereas 20 tumors (7.1%) occurred after this tumor with a mean interval of 6.7 years (range: 1.0–15.0 years). In 13 female patients, breast cancer was found as SPT. The standardized incidence rate (SIR) for all cancers after the diagnosis of DTC in this study population was not increased (1.13; confidence interval (CI): 0.68–1.69). However, we found an increased SIR of 2.26 (CI: 1.60–3.03) for all cancers either following or preceding DTC, which is mainly caused by a SIR of 3.95 (CI: 2.06–6.45) for breast cancer.

Conclusion: Patients with DTC have an overall increased standardized incidence rate for second primary tumors, but not for second primary tumors following I-131 therapy. These findings suggest a common etiologic and/or genetic mechanism instead of a causal relation.

Full access

Robbert B T Verkooijen, Daphne Rietbergen, Jan W Smit, Johannes A Romijn and Marcel P M Stokkel

Background: This study addresses the questions whether patients with a high risk for recurrent thyroid cancer can be identified at initial stage, i.e. at the time of ablation.

Methods: We evaluated tumor recurrence in consecutive patients treated for differentiated thyroid cancer (DTC). Prognostic factors were statistically analyzed. We defined prognostic parameters based on thyroglobulin (Tg) levels, 24-h I-131 uptake rates and TSH values: (a) Tg/TSH, (b) Tg/24-h I-131 uptake value, and (c) Tg/(TSH×24-h I-131 uptake).

Results: We included 190 patients (50 male, 140 female; mean age 47 years) with DTC for analysis, 146 without distant metastases and 44 with M1 tumor stage at initial presentation. The mean period of follow-up was 10.4 years (s.d. ± 3.7 years). In 18 out of the 146 DTC patients with M0 disease (12.4%), tumor recurrence was found during follow-up. Although tumor stage, age, and standard biochemical values significantly differ between patients with and without recurrent disease or between patients with M0 and M1 tumor stage, the newly defined parameter Tg/(TSH×24-h I-131 uptake) was the best independent significant prognostic parameter in the assessment whether patients will develop a tumor recurrence during follow-up or not.

Conclusion: High Tg/(TSH×24-h I-131 uptake) ratios justify an adjustment of the I-131 activity for ablation therapy. To assess the optimal cut-off value for a dose adjustment, however, further studies are required in more patients, but the initial results are encouraging with respect to improving outcome in DTC patients.

Full 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.

Full access

Ying Y Liu, Marcel P Stokkel, Alberto M Pereira, Eleonora P Corssmit, Hans A Morreau, Johannes A Romijn and Johannes W A Smit

Objective: Treatment options for metastases of differentiated thyroid carcinoma (DTC) are limited due to decreased uptake of radioiodide (I-131). Therefore, strategies to improve I-131 uptake are mandatory. It has been suggested that retinoids have beneficial effects on iodide uptake in vitro and in humans. However, to date, only studies with 13-cis-retinoic acid have been performed in humans. We therefore decided to study the effects of 6 weeks of treatment with the retinoid X receptor activator bexarotene on I-131 uptake in patients with metastatic DTC.

Design: Open prospective intervention study.

Methods: Twelve patients with metastases of DTC, with insufficient uptake of I-131, received 6 weeks of treatment with 300 mg bexarotene/day. Prior to, and after this intervention, I-131 uptake was measured by whole-body scintigraphy and single photon emission tomography (SPECT) 3 days after 185 MBq I-131. Diagnostic imaging was preceded by two consecutive injections of recombinant human TSH.

Results: Bexarotene treatment induced I-131 uptake in metastases of 8 out of 11 patients (one patient died for reasons not related to the study). However, uptake was only discernable at SPECT and had incomplete matching with metastases as visualized by CT scanning.

Conclusions: Bexarotene partially restores I-131 uptake in metastases of DTC. The clinical relevance of this observation may be limited due to the differential responses of the different metastases within each patient and the low intensity of I-131 uptake.