The association between treatment and systemic inflammation in acromegaly.

OBJECTIVE: Acromegaly is characterized by an excess of growth hormone (GH) and insulin like growth-factor 1 (IGF1), and it is strongly associated with cardiovascular diseases (CVD). Both acute and long-lasting pro-inflammatory effects have been attributed to IGF1. Previous results suggest the presence of systemic inflammation in treated patients. Here we assessed the association between treatment of acromegaly, systemic inflammation and vascular function. DESIGN: Ex vivo cytokine production and circulating inflammatory markers were assessed in peripheral blood from treated and untreated acromegaly patients (N = 120), and compared them with healthy controls. A more comprehensive prospective inflammatory and vascular assessment was conducted in a subgroup of six treatment-naive patients with follow-up during treatment. RESULTS: Circulating concentrations of VCAM1, E-selectin and MMP2 were higher in patients with uncontrolled disease, whereas the concentrations of IL18 were lower. In stimulated whole blood, cytokine production was skewed towards a more pro-inflammatory profile in patients, especially those with untreated disease. Prospective vascular measurements in untreated patients showed improvement of endothelial function during treatment. CONCLUSIONS: Acromegaly patients are characterized by a pro-inflammatory phenotype, most pronounced in those with uncontrolled disease. Treatment only partially reverses this pro-inflammatory bias. These findings suggest that systemic inflammation could contribute to the increased risk of CVD in acromegaly patients.

The effect of treatment on quality of life in patients with acromegaly: a prospective study.

OBJECTIVE: Acromegaly has a negative influence on health-related quality of life (HRQoL). Previous studies provide limited information on the course of HRQoL during treatment. This study aims to assess the effect of treatment on the course of HRQoL at six predefined time points. DESIGN: This prospective study examines HRQoL in treatment-naive patients before and during the first 2.5 years of acromegaly treatment. METHODS: Therapy-naive acromegaly patients completed three validated questionnaires (RAND-36, AcroQoL, and the Appearance Self-Esteem (ASE)) at six predetermined time points before, during, and after treatment. Outcomes were correlated to IGF1 levels and disease control status. RESULTS: Twenty-seven acromegaly patients completed the questionnaires at all time points. After treatment, all patients had controlled acromegaly. Scores of RAND-36 domains General health, Vitality and Health change, and all AcroQoL dimensions (except for Relations) improved during treatment (P ≤ 0.003); the largest changes were detected during the first year. Gender influenced HRQoL scores, since AcroQoL scores significantly improved in males but not in females. Over time, IGF1 levels were negatively correlated with HRQoL. After 2.5 years of follow-up, HRQoL of controlled patients was still lower than in the general population. CONCLUSION: HRQoL of acromegaly patients was considerably reduced at diagnosis. Disease control was associated with an improvement of HRQoL scores. Males showed a more pronounced improvement than females. The largest changes were detected in the first year of treatment. However, HRQoL during and after treatment remained impaired in acromegaly patients, emphasizing the need of additional support.

Targetable gene fusions identified in radioactive iodine refractory advanced thyroid carcinoma.

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.

Long-term effects of radioiodine treatment on salivary gland function in adult survivors of pediatric differentiated thyroid carcinoma.

Pediatric differentiated thyroid cancer (DTC) is a rare disease. Initial treatment of DTC consists of a (near) total thyroidectomy and radioactive iodine (131I) therapy. Previous studies in adults showed that 131I treatment may result in a reduced salivary gland function. Studies regarding salivary gland function in children treated for DTC are sparse. Our aim was to assess long-term effects of 131I treatment on salivary gland function in survivors of pediatric DTC. Methods: In a nationwide cross-sectional study, salivary gland function of patients treated for pediatric DTC between 1970 and 2013 (>5 years after diagnosis, ≥18 years old at time of evaluation) was studied. Salivary gland function was assessed by sialometry, sialochemistry and a xerostomia inventory. Salivary gland dysfunction was defined as unstimulated whole saliva flow ≤0.2mL/min and/or a stimulated whole saliva flow ≤0.7 mL/min. Results: Sixty-five patients (median age at evaluation 33 [IQR, 25-40] years, 86.2% female, median follow-up period 11 [IQR, 6-22] years) underwent 131I treatment. Median cumulative 131I activity was 5.88 [IQR, 2.92-12.95] GBq, 47.7% underwent multiple 131I administrations. Salivary gland dysfunction was present in 30 (47.6%) patients. Levels of amylase and total protein in saliva were reduced. Moderate to severe xerostomia was present in 22 (35.5%) patients. Stimulated salivary secretion was lower and severity of xerostomia complaints higher in patients treated with higher cumulative 131I activity. Conclusion: In survivors of pediatric DTC, clinically significant salivary gland dysfunction was found in 35.5% and was related to the cumulative 131I activity of the treatment.

Study protocol: a randomised controlled trial on the clinical effects of levothyroxine treatment for subclinical hypothyroidism in people aged 80 years and over.

BACKGROUND: Subclinical hypothyroidism is common in older people and its contribution to health and disease needs to be elucidated further. Observational and clinical trial data on the clinical effects of subclinical hypothyroidism in persons aged 80 years and over is inconclusive, with some studies suggesting harm and some suggesting benefits, translating into equipoise whether levothyroxine therapy provides clinical benefits. This manuscript describes the study protocol for the Institute for Evidence-Based Medicine in Old Age (IEMO) 80-plus thyroid trial to generate the necessary evidence base. METHODS: The IEMO 80-plus thyroid trial was explicitly designed as an ancillary experiment to the Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism randomised placebo controlled Trial (TRUST) with a near identical protocol and shared research infrastructure. Outcomes will be presented separately for the IEMO and TRUST 80-plus groups, as well as a pre-planned combined analysis of the 145 participants included in the IEMO trial and the 146 participants from the TRUST thyroid trial aged 80 years and over. The IEMO 80-plus thyroid trial is a multi-centre randomised double-blind placebo-controlled parallel group trial of levothyroxine treatment in community-dwelling participants aged 80 years and over with persistent subclinical hypothyroidism (TSH ≥4.6 and ≤ 19.9 mU/L and fT4 within laboratory reference ranges). Participants are randomised to levothyroxine 25 or 50 micrograms daily or matching placebo with dose titrations according to TSH levels, for a minimum follow-up of one and a maximum of three years. Primary study endpoints: hypothyroid physical symptoms and tiredness on the thyroid-related quality of life patient-reported outcome (ThyPRO) at one year. Secondary endpoints: generic quality of life, executive cognitive function, handgrip strength, functional ability, blood pressure, weight, body mass index, and mortality. Adverse events will be recorded with specific interest on cardiovascular endpoints such as atrial fibrillation and heart failure. DISCUSSION: The combined analysis of participants in the IEMO 80-plus thyroid trial with the participants aged over 80 in the TRUST trial will provide the largest experimental evidence base on multimodal effects of levothyroxine treatment in 80-plus persons to date. TRIAL REGISTRATION: Nederlands (Dutch) Trial Register: NTR3851 (12-02-2013), EudraCT: 2012-004160-22 (17-02-2013), ABR-41259.058.13 (12-02-2013).

Effect of anthelmintic treatment on leptin, adiponectin and leptin to adiponectin ratio: a randomized-controlled trial.

Emerging evidence suggests that helminths might confer protection against the development of type 2 diabetes. We aimed to assess the role of adipokines in mediating the effect of helminths on insulin resistance. Serum samples were obtained from a randomized-controlled trial of anthelmintic treatment in an area endemic for soil-transmitted helminths (STH), Flores Island, Indonesia. In STH-infected subjects, anthelmintic treatment significantly increased the ratio of leptin to adiponectin (treatment effect factor (95% confidence interval (CI)), P-value for interaction: 1.20 (1.06-1.35), P=0.010), which largely stemmed from a significant reduction in adiponectin (0.91 (0.85-0.98), P=0.020) and a trend for an increase in leptin level (1.10 (1.00-1.21), P=0.119). No significant effect on resistin level was observed. This increase in leptin to adiponectin ratio seemed to contribute to the observed effect of deworming on increased insulin resistance (IR) as adjustment for leptin to adiponectin ratio attenuated the effect on IR from 1.07 (1.01-1.14, P=0.023) to 1.05 (0.99-1.11, P=0.075). Anthelmintic treatment in STH-infected subjects increases leptin to adiponectin ratio which may in small part contribute to the modest increase in IR. Further studies will be needed to assess the effect of the changes in adipokine levels on the host immune response and metabolism.

The effect of three-monthly albendazole treatment on Th2 responses: Differential effects on IgE and IL-5.

Helminth parasites induce a strong Th2 response, characterized by high levels of IgE and elevated signature cytokines such as IL-5. As many global deworming programmes are underway, there is concern that this might lead to emergence of Th1-mediated pathologies when the counterbalancing helminth-induced Th2 response is absent. Therefore, we assessed the effect of deworming on Th2-mediated responses in a household-clustered randomized controlled trial in Indonesia. Total plasma IgE and whole-blood IL-5 responses to mitogen phytohaemagglutinin (PHA) were measured in 1494 and 682 subjects, respectively, at baseline, 9 and 21 months after three-monthly single-dose treatment with albendazole or placebo. Anthelmintic treatment did not result in complete removal of helminth infections in the community. However, treatment significantly decreased IgE levels in albendazole- compared to placebo-treated subjects. IL-5 responses to PHA were not significantly affected by anthelmintic treatment and tended to increase in albendazole-treated subjects, indicating that intensive treatment of helminth parasites has different outcomes on B-cell (IgE levels) and T-cell (IL-5) responses. The data shows that 2 years of deworming can have differential effects on responses typified as Th2-mediated, which needs to be taken into account when examining the impact of helminths on noncommunicable diseases.

Serum microRNA-1 and microRNA-133a levels reflect myocardial steatosis in uncomplicated type 2 diabetes.

Using in vitro, in vivo and patient-based approaches, we investigated the potential of circulating microRNAs (miRNAs) as surrogate biomarkers of myocardial steatosis, a hallmark of diabetic cardiomyopathy. We analysed the cardiomyocyte-enriched miRNA signature in serum from patients with well-controlled type 2 diabetes and with verified absence of structural heart disease or inducible ischemia, and control volunteers of the same age range and BMI (N = 86), in serum from a high-fat diet-fed murine model, and in exosomes from lipid-loaded HL-1 cardiomyocytes. Circulating miR-1 and miR-133a levels were robustly associated with myocardial steatosis in type 2 diabetes patients, independently of confounding factors in both linear and logistic regression analyses (P < 0.050 for all models). Similar to myocardial steatosis, miR-133a levels were increased in type 2 diabetes patients as compared with healthy subjects (P < 0.050). Circulating miR-1 and miR-133a levels were significantly elevated in high-fat diet-fed mice (P < 0.050), which showed higher myocardial steatosis, as compared with control animals. miR-1 and miR-133a levels were higher in exosomes released from lipid-loaded HL-1 cardiomyocytes (P < 0.050). Circulating miR-1 and miR-133a are independent predictors of myocardial steatosis. Our results highlight the value of circulating miRNAs as diagnostic tools for subclinical diabetic cardiomyopathy.

Helminths, hygiene hypothesis and type 2 diabetes.

Worldwide, there is little overlap between the prevalence of soil-transmitted helminths and type 2 diabetes (T2D). Helminth-induced type 2 immune responses and immune regulatory network might modulate the obesity-induced activation of inflammatory pathways that are associated with the development of insulin resistance, a strong predictor of the development of T2D. However, other factors such as helminth-associated changes in adiposity and gut microbiome might also contribute to improved metabolic outcomes. In this review, we summarize epidemiological evidence for the link between helminths and T2D and discuss the potential mechanisms, based on findings from experimental studies as well as the limited number of studies in humans.

Glucocorticoid receptor polymorphisms modulate cardiometabolic risk factors in patients in long-term remission of Cushing's syndrome.

CONTEXT: Glucocorticoid receptor (GR) polymorphisms modulate glucocorticoid (GC) sensitivity and are associated with altered metabolic profiles. OBJECTIVE: To evaluate the presence of GR polymorphisms (BclI (rs41423247), N363S (rs56149945), ER22/23EK (rs6189/rs6190), and 9ß (rs6198) and investigate their associations with metabolic alterations in patients in long-term remission of Cushing's syndrome (CS). DESIGN AND SETTING: Cross-sectional case-control study. PATIENTS AND METHODS: Sixty patients in long-term remission of CS were genotyped. Associations between GR polymorphisms and multiple vascular, body composition and metabolic parameters were investigated. MAIN OUTCOME MEASURES: Allelic frequencies of the polymorphisms and their associations with several cardiometabolic risk factors. RESULTS: This study shows that carriers of the 9ß polymorphism have a higher systolic blood pressure and lower resistin levels. The GC sensitizing BclI polymorphism is associated with an adverse cardiometabolic risk factor profile: higher fat percentages of extremities and legs, higher serum leptin and E-selectin levels, and higher intima media thickness in carriers versus non-carriers. CONCLUSIONS: The 9ß and BclI polymorphisms of the GR adversely affect the cardiometabolic profile in patients who are in remission after the treatment of CS. This suggests that genetically altered GC sensitivity modulates the long-term adverse cardiometabolic effects resulting from (endogenous) hypercortisolism.

Cardiovascular flexibility in middle-aged overweight South Asians vs. white Caucasians: response to short-term caloric restriction.

BACKGROUND AND AIMS: South Asians have a higher risk of developing cardiovascular disease than white Caucasians. The underlying cause is unknown, but might be related to higher cardiac susceptibility to metabolic disorders. Short-term caloric restriction (CR) can be used as a metabolic stress test to study cardiac flexibility. We assessed whether metabolic and functional cardiovascular flexibility to CR differs between South Asians and white Caucasians. METHODS AND RESULTS: Cardiovascular function and myocardial triglycerides were assessed using a 1.5T-MRI/S-scanner in 12 middle-aged overweight male South Asians and 12 matched white Caucasians before and after an 8-day very low calorie diet (VLCD). At baseline South Asians were more insulin resistant than Caucasians. Cardiac dimensions were smaller, despite correction for body surface area, and pulse wave velocity (PWV) in the distal aorta was higher in South Asians. Systolic and diastolic function, myocardial triglycerides and pericardial fat did not differ significantly between groups. After the VLCD body weight reduced on average by 4.0 ± 0.2 kg. Myocardial triglycerides increased in both ethnicities by 69 ± 18%, and diastolic function decreased although this was not significant in South Asians. However, pericardial fat and PWV in the proximal and total aorta were reduced in Caucasians only. CONCLUSION: Myocardial triglyceride stores in middle-aged overweight and insulin resistant South Asians are as flexible and amenable to therapeutic intervention by CR as age-, sex- and BMI-matched but less insulin resistant white Caucasians. However, paracardial fat volume and PWV showed a differential effect in response to an 8-day VLCD in favor of Caucasians. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=2473).

Three-dimensional facial analysis in acromegaly: a novel tool to quantify craniofacial characteristics after long-term remission.

PURPOSE: The exact quantification of craniofacial characteristics in patients with acromegaly is important because it provides insight in the pathophysiology of the disease and offers a tool to evaluate the effects of treatment on tissue specific endpoints. However, until recently this was not feasible due to limitations of available cephalometric methods. The new technique of three-dimensional (3D) cephalometry enables the accurate quantification of facial anatomical characteristics of both soft tissue and bone. This is the first study that uses 3D cephalometry to analyze craniofacial disproportions in patients in long-term remission of acromegaly. METHODS: Sixteen patients in remission of acromegaly for over 24 months (50% male, mean age 56.0 ± 10.7 years, mean body mass index 29.3 ± 5.5 kg/m(2)) were compared to 16 matched control subjects. A 3D cone beam computed tomography scan and 3D stereophotograph of each individual were acquired and analyzed using 3D cephalometry. RESULTS: In addition to an accurate quantification of the classical craniofacial characteristics, 3D cephalometry, shows that many typical soft tissue deformities persist, even after long-term remission. Furthermore, we found that, compared to controls, the patients in remission of acromegaly have a wider face at the level of the zygoma and longer maxilla (p < 0.05). CONCLUSIONS: 3D cephalometry is an attractive novel imaging modality to accurately investigate craniofacial disproportions of both soft tissue and bony parts of the face in patients with acromegaly, which makes it a promising technique for future research purposes and clinical practice.

Thyroglobulin autoantibodies as surrogate biomarkers in the management of patients with differentiated thyroid carcinoma.

Differentiated thyroid cancer is a rare malignancy, but leaves numerous survivors for life-long follow-up. The cornerstone in current guidelines for follow-up is by measuring the thyroid specific tumour marker, thyroglobulin in serum. Most patients can be followed by this method, but some thyroid cancer patients have antithyroglobulin antibodies in serum, both at diagnosis and after treatment, where follow-up is commenced. These antibodies interfere technically in the immunological methods for measuring thyroglobulin, and the antithyroglobulin antibody positive patients are thus eliminated from following current guidelines. In recent years studies have indicated that following the concentration of antithyroglobulin antibodies in serum may be a surrogate marker for recurrence of the thyroid carcinoma. This has recently resulted in publication of an expert position paper, providing a flow scheme for these particular patients. The current review summarises the literature which is the basis for the paper.

RP105 deficiency aggravates cardiac dysfunction after myocardial infarction in mice.

BACKGROUND: Toll-like receptor-4 (TLR4), a receptor of the innate immune system, is suggested to have detrimental effects on cardiac function after myocardial infarction (MI). RP105 (CD180) is a TLR4 homolog lacking the intracellular signaling domain that competitively inhibits TLR4-signaling. Thus, we hypothesized that RP105 deficiency, by amplifying TLR4 signaling, would lead to aggravated cardiac dysfunction after MI. METHODS AND RESULTS: First, whole blood from RP105-/- and wild-type (WT) male C57Bl/6N mice was stimulated with LPS, which induced a strong inflammatory TNFα response in RP105-/- mice. Then, baseline heart function was assessed by left ventricular pressure-volume relationships which were not different between RP105-/- and WT mice. Permanent ligation of the left anterior descending coronary artery was performed to induce MI. Infarct sizes were analyzed by (immuno)histology and did not differ. Fifteen days post MI heart function was assessed and RP105-/- mice had significantly higher heart rate (+21%, P<0.01), end systolic volume index (+57%, P<0.05), end systolic pressure (+22%, P<0.05) and lower relaxation time constant tau (-12%, P<0.05), and a tendency for increased end diastolic volume index (+42%, P<0.06), compared to WT mice. In the area adjacent to the infarct zone, compared to the healthy myocardium, levels of RP105, TLR4 and the endogenous TLR4 ligand fibronectin-EDA were increased as well as the number of macrophages, however this was not different between both groups. CONCLUSION: Deficiency of the endogenous TLR4 inhibitor RP105 leads to an enhanced inflammatory status and more pronounced cardiac dilatation after induction of MI, underscoring the role of the TLR4 pathway in post-infarction remodeling.

Cost-effectiveness of FDG-PET/CT for cytologically indeterminate thyroid nodules: a decision analytic approach.

CONTEXT: Patients with thyroid nodules of indeterminate cytology undergo diagnostic surgery according to current guidelines. In 75% of patients, the nodule is benign. In these patients, surgery was unnecessary and unbeneficial because complications may occur. Preoperative fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) was found to have a very high negative predictive value (96%) and might therefore avoid futile surgery, complications, and costs. In the United States, two molecular tests of cytology material are routinely used for this purpose. OBJECTIVE: Five-year cost-effectiveness for routine implementation of FDG-PET/CT was evaluated in adult patients with indeterminate fine-needle aspiration cytology and compared with surgery in all patients and both molecular tests. DESIGN: A Markov decision model was developed to synthesize the evidence on cost-effectiveness about the four alternative strategies. The model was probabilistically analyzed. One-way sensitivity analyses of deterministic input variables likely to influence outcome were performed. SETTING AND SUBJECTS: The model was representative for adult patients with cytologically indeterminate thyroid nodules. MAIN OUTCOME MEASURES: The discounted incremental net monetary benefit (iNMB), the efficiency decision rule containing outcomes as quality-adjusted life-years and (direct) medical cost, of implementation of FDG-PET/CT is displayed. RESULTS: Full implementation of FDG-PET/CT resulted in 40% surgery for benign nodules, compared with 75% in the conventional approach, without a difference in recurrence free and overall survival. The FDG-PET/CT modality is the more efficient technology, with a mean iNMB of €3684 compared with surgery in all. Also, compared with a gene expression classifier test and a molecular marker panel, the mean iNMB of FDG-PET/CT was €1030 and €3851, respectively, and consequently the more efficient alternative. CONCLUSION: Full implementation of preoperative FDG-PET/CT in patients with indeterminate thyroid nodules could prevent up to 47% of current unnecessary surgery leading to lower costs and a modest increase of health-related quality of life. Compared with an approach with diagnostic surgery in all patients and both molecular tests, it is the least expensive alternative with similar effectiveness as the gene-expression classifier.

The thyroid axis 'setpoints' are significantly altered after long-term suppressive LT4 therapy.

The aim of the study was to investigate the changes in the thyroid axis setpoint after long-term suppressive levothyroxine therapy for differentiated thyroid carcinoma and the resulting changes in levothyroxine requirement. Ninety-nine differentiated thyroid cancer patients were reviewed. All patients had at least one known TSH-level≥0.01 mU/l (lower detection limit) and <1.0 mU/l within 2 years of initial treatment (time 1) and had at least one TSH-value≥0.01 mU/l and <1.0 mU/l after continuous LT4 therapy for a minimum of 5 years (time 2).At time 2 the mean LT4 dosage/kg body weight, TSH, FT3, and FT4 levels were significantly lower than at time 1, while body weight was higher. At time 2, the FT3/FT4 ratio rate had dropped significantly (p<0.001). At time 1, patients would require 2.96 µg/kg body weight to reach total TSH suppression. The dose of levothyroxine/kg required for suppression can be lowered by about 0.05 µg/kg body weight for each year of suppressive therapy. After a median of 12.7 years of continuous suppressive levothyroxine therapy, patients would require 2.25 µg/kg body weight (-23.5%) to reach total TSH-suppression. At least part of this reduction was independent of aging. As a result of changes in thyroid hormone metabolism and thyroid axis setpoint, long-term TSH-suppressive therapy contributes to a reduction in the dosage of levothyroxine per kilogram body weight required for full TSH suppression over time.

High levels of procoagulant factors mediate the association between free thyroxine and the risk of venous thrombosis: the MEGA study.

BACKGROUND: Thyroid hormone affects the coagulation system, but its effect on clinical disease is not clear. We determined the associations of levels of free thyroxine (FT4), thyroid-stimulating hormone (TSH) and anti-thyroid peroxidase antibodies (antiTPO) with levels of coagulation factors and the risk of venous thrombosis. METHODS: In a large population based case-control study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study) on the etiology of venous thrombosis, we determined the levels of FT4, TSH, antiTPO, factor FII, FVII, FVIII, FIX, FX, von Willebrand factor (VWF), antithrombin, protein C, protein S and fibrinogen in 2177 cases and 2826 controls. RESULTS: High levels of FT4 were associated with increased concentrations of procoagulant factors, and not with levels of anticoagulant factors. High levels of FT4 were also associated with the risk of venous thrombosis, up to an odds ratio (OR) of 2.2 (95% confidence interval [CI] 1.0-4.6) for levels above 24.4 pm relative to FT4 levels between 15.5 and 18.9 pm. In 11 cases and one control, clinical hyperthyroidism had been diagnosed within a year of the thrombotic event, leading to an OR of 17.0 (95% CI 2.2-133.0) for thrombosis. The ORs approached unity after adjustment for FVIII and VWF, which suggests that the effect was mediated by these factors. Low TSH levels were also, but less evidently, associated with thrombosis, whereas there was no association between antiTPO and venous thrombosis risk. CONCLUSIONS: High levels of FT4 increase the concentrations of the procoagulant proteins FVIII, FIX, fibrinogen, and VWF, and by this mechanism increase the risk of venous thrombosis.

Unmet information needs and impact of cancer in (long-term) thyroid cancer survivors: results of the PROFILES registry.

OBJECTIVE: The objective of this study was to provide insight into the following: (a) the perceived level of, satisfaction with, and helpfulness of received information and unmet information needs among thyroid cancer (TC) survivors and (b) the relation between unmet information needs and impact of cancer (IOC). METHODS: All patients diagnosed with TC between 1990 and 2008, as registered in the Eindhoven Cancer Registry, received a survey on information provision (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Information module) and IOC. RESULTS: Thyroid cancer survivors (n = 306; response rate = 86%) indicated to receive no or only a little information about different aspects of their disease (27-86%), medical tests (20-27%), treatment (21-90%), and aftercare (86-91%). Almost half of the survivors (47%) were not at all or a little satisfied with the amount of information received; 31% found the received information not or a little helpful; a third of the patients (34%) indicated that they wanted to receive more information (defined as unmet needs). TC survivors with unmet informational needs scored significantly higher on both the positive (mean 3.2 vs. 2.9) and negative IOC scale (mean 2.5 vs. 2.2) compared with survivors without unmet needs (p < 0.01). In multivariate linear regression analyses, unmet information needs were positively associated with all positive IOC scales except positive self-evaluation (betas ranging from 0.16 to 0.24; p < 0.05), and all negative IOC scales except for appearance concerns (betas ranging from 0.12 to 0.19; p < 0.05). CONCLUSION: Thyroid cancer survivors experienced several areas of information provision as insufficient, suggesting room for improvement. Unmet information needs among TC survivors are associated with both positive and negative impacts of cancer.

Illness perceptions, risk perception and worry in SDH mutation carriers.

Succinate dehydrogenase (SDH) mutation carriers are predisposed for developing paragangliomas. This study aimed to explore illness perceptions, risk perception and disease-related worry in these individuals. All consecutive SDHB and SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center (LUMC), a tertiary referral center, were eligible for inclusion. Illness perceptions were assessed using the validated Illness Perception Questionnaire-Revised and compared to reference populations. Risk perception and worry were measured by two items each and associations with illness perceptions explored. Twenty SDHB and 118 SDHD mutation carriers responded. Compared with various reference groups, SDH mutation carriers perceived less controllability of their condition. SDHB mutation carriers considered their condition to be less chronic in nature (p = 0.005) and perceived more personal (p = 0.018) and treatment control (p = 0.001) than SDHD mutation carriers. Mutation carriers with manifest disease reported more negative illness perceptions and a higher risk perception of developing subsequent tumors than asymptomatic mutation carriers. Illness perceptions, risk perception and disease-related worry were strongly correlated. Risk perception and disease-related worry may be assessed through illness perceptions. The development of interventions targeting illness perceptions may provide tools for genetic counseling.