Objective: This study assessed the health-related quality of life (HRQoL) in patients undergoing 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT for an indeterminate (Bethesda III/IV) thyroid nodule.... Show moreObjective: This study assessed the health-related quality of life (HRQoL) in patients undergoing 2-[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT for an indeterminate (Bethesda III/IV) thyroid nodule. FDG-PET/CT accurately rules out malignancy and prevents 40% of futile diagnostic surgeries in these nodules. Design: Secondary analyses of HRQoL data from a randomised controlled multicentre trial (NCT02208544) in 126 patients from 15 hospitals in the Netherlands were done. Methods: Longitudinal HRQoL assessment was performed using the EuroQol 5-dimension 5-level (EQ-5D-5L), the RAND 36-item Health Survey v2.0 (RAND-36), and the Thyroid Patient-Reported Outcome (ThyPRO) questionnaire on baseline, 3, 6, and 12 months, relative to the date of the FOG-PET/CT scan. Results: Patients who were randomised to active surveillance following an FDG-negative nodule instead of diagnostic surgery reported stable HRQoL scores throughout the year. Univariate analysis indicated better HRQoL for patients undergoing surveillance than surgical patients with benign histopathology on multiple physical and psychosocial domains. Univariate within-group analysis suggested both temporary and continued HRQoL deteriorations in patients with benign histopathology over time. Multivariate within-group analysis demonstrated no significant longitudinal HRQoL changes in patients undergoing active surveillance. In contrast, in patients with benign histopathology, worse HRQoL was observed with regard to ThyPRO cognitive impairment (P = 0.01) and cosmetic complaints (P = 0.02), whereas goitre symptoms (P < 0.001) and anxiety (P = 0.04) improved over time. In patients with malignant histopathology, anxiety also decreased (P = 0.05). Conclusions: The reassurance of a negative FDG-PET/CT resulted in sustained HRQoL throughout the first year of active surveillance. Diagnostic surgery for a nodule with benign histopathology resulted in more cognitive impairment and physical problems including cosmetic complaints, but improved goitre symptoms and anxiety. Anxiety was also reduced in patients with malignant histopathology. Show less
Purpose To assess the impact of an [F-18]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with... Show morePurpose To assess the impact of an [F-18]FDG-PET/CT-driven diagnostic workup to rule out malignancy, avoid futile diagnostic surgeries, and improve patient outcomes in thyroid nodules with indeterminate cytology.Methods In this double-blinded, randomised controlled multicentre trial, 132 adult euthyroid patients with scheduled diagnostic surgery for a Bethesda III or IV thyroid nodule underwent [F-18]FDG-PET/CT and were randomised to an [F-18] FDG-PET/CT-driven or diagnostic surgery group. In the [F-18]FDG-PET/CT-driven group, management was based on the [F-18]FDG-PET/CT result: when the index nodule was visually [F-18]FDG-positive, diagnostic surgery was advised; when [F-18]FDG-negative, active surveillance was recommended. The nodule was presumed benign when it remained unchanged on ultrasound surveillance. In the diagnostic surgery group, all patients were advised to proceed to the scheduled surgery, according to current guidelines. The primary outcome was the fraction of unbeneficial patient management in one year, i.e., diagnostic surgery for benign nodules and active surveillance for malignant/borderline nodules. Intention-to-treat analysis was performed. Subgroup analyses were performed for non-Hurthle cell and Hurthle cell nodules.Results Patient management was unbeneficial in 42% (38/91 [95% confidence interval [CI], 32-53%]) of patients in the [F-18] FDG-PET/CT-driven group, as compared to 83% (34/41 [95% CI, 68-93%]) in the diagnostic surgery group (p < 0.001). [F-18]FDG-PET/CT-driven management avoided 40% (25/63 [95% CI, 28-53%]) diagnostic surgeries for benign nodules: 48% (23/48 [95% CI, 33-63%]) in non-Hurthle cell and 13% (2/15 [95% CI, 2-40%]) in I-Liable cell nodules (p = 0.02). No malignant or borderline tumours were observed in patients under surveillance. Sensitivity, specificity, negative and positive predictive value, and benign call rate (95% CI) of [F-18]FDG-PET/CT were 94.1% (80.3-99.3%), 39.8% (30.0-50.2%), 95.1% (83.5-99.4%), 35.2% (25.4-45.9%), and 31.1% (23.3-39.7%), respectively.Conclusion An [F-18]FDG-PET/CT-driven diagnostic workup of indeterminate thyroid nodules leads to practice changing management, accurately and oncologically safely reducing futile surgeries by 40%. For optimal therapeutic yield, application should be limited to non-Hurthle cell nodules. Show less
Hybrid e-health support was given to 11 insulin-dependent type 2 diabetes mellitus (DM2) patients, with electronic support plus a multi-disciplinary health support team. Challenges were low ICT and... Show moreHybrid e-health support was given to 11 insulin-dependent type 2 diabetes mellitus (DM2) patients, with electronic support plus a multi-disciplinary health support team. Challenges were low ICT and health literacy. After 50 weeks, attractiveness and feasibility of the intervention were perceived as high: recommendation 9.5 out of 10 and satisfaction 9.6 out of 10. Technology acceptance model (TAM) surveys showed high usefulness and feasibility. Acceptance and health behaviours were reinforced by the prolonged health results: aerobic and strength capacity levels were improved at 50 weeks, plus health related quality of life (plus biometric benefits and medication reductions, reported elsewhere). Regarding e-health theory, we conclude that iterative skill growth cycles are beneficial for long-term adoption and e-relationships. Next, the design analysis shows opportunities for additional affective and social support, on top of the strong benefits already apparent from the direct progress feedback loops used within the health coach processes. Show less
Aydemirli, M.D.; Snel, M.; Wezel, T.; Ruano, D.; Obbink, C.M.H.; Hout, W.B.; ... ; Morreau, H. 2021
Objective To evaluate our institutional experience with molecular diagnostics (MD) on thyroid cytology smears, evaluate the costs and describe MD guided clinical management of indeterminate... Show moreObjective To evaluate our institutional experience with molecular diagnostics (MD) on thyroid cytology smears, evaluate the costs and describe MD guided clinical management of indeterminate Bethesda III/V thyroid nodules. Methods We performed a retrospective review of 164 Bethesda III or V thyroid cytopathology reports subjected to MD from 2013 to 2020, that altered Bethesda classification or management. MD consisted of mutation and gene fusion analysis by next-generation sequencing (NGS) of morphologically analysed and selected cytological slides. Findings were modelled to nationwide data on Bethesda incidences from 'the Dutch Pathology Registry' PALGA, and costs were estimated. Results 82 of 164 cases received an upgrade in Bethesda class. Twenty cases changed from Bethesda III to IV/V, 62 from Bethesda III or V to VI, and 72 remained unaltered. We estimate net savings with implementing MD, by preventing 454 repeat cytology and 326 (diagnostic) hemithyroidectomies, to be at least 2 million Euro annually in the Netherlands. Per Bethesda III and V patient, net savings would be about 100 Euro and 4100 Euro, respectively. Conclusion NGS-based MD on nucleic acids extracted directly from cytology slides is a feasible and cost saving tool for personalized management in indeterminate Bethesda III/V thyroid cytology. Based on the interpretation of our retrospective data, we assume that this approach results in less disease burden for the patient, reduced surgical interventions and complication risks, reduced sick leave, among others. Further evaluation of structural implementation of the presented approach in routine thyroid Bethesda III/V cytology in a prospective setting is warranted. Show less
Schoeb, M.; Winter, E.M.; Sleddering, M.A.; Lips, M.A.; Schepers, A.; Snel, M.; Appelman-Dijkstra, N.M. 2021
Context: In primary hyperparathyroidism (PHPT) bone mineral density (BMD) is typically decreased in cortical bone and relatively preserved in trabecular bone. An increased fracture rate is observed... Show moreContext: In primary hyperparathyroidism (PHPT) bone mineral density (BMD) is typically decreased in cortical bone and relatively preserved in trabecular bone. An increased fracture rate is observed however not only at peripheral sites but also at the spine, and fractures occur at higher BMD values than expected. We hypothesized that components of bone quality other than BMD are affected in PHPT as well.Objective: To evaluate bone material properties using impact microindentation (IMI) in PHPT patients.Methods: In this cross-sectional study, the Bone Material Strength index (BMSi) was measured by IMI at the midshaft of the tibia in 37 patients with PHPT (28 women), 11 of whom had prevalent fragility fractures, and 37 euparathyroid controls (28 women) matched for age, gender, and fragility fracture status.Results: Mean age of PHPT patients and controls was 61.813.3 and 61.0 +/- 11.8 years, respectively, P = .77. Calcium and PTH levels were significantly higher in PHPT patients but BMD at the lumbar spine (0.92 +/- 0.15 vs 0.89 +/- 0.11, P = .37) and the femoral neck (0.70 +/- 0.11 vs 0.67 +/- 0.07, P = .15) were comparable between groups. BMSi however was significantly lower in PHPT patients than in controls (78.2 +/- 5.7 vs 82.8 +/- 4.5, P < .001). In addition, BMSi was significantly lower in 11 PHPT patients with fragility fractures than in the 26 PHPT patients without fragility fractures (74.7 +/- 6.0 vs 79.6 +/- 5.0, P = .015).Conclusion: Our data indicate that bone material properties are altered in PHPT patients and most affected in those with prevalent fractures. IMI might be a valuable additional tool in the evaluation of bone fragility in patients with PHPT. Show less
Sternocostoclavicular hyperostosis (SCCH) is a rare autoinflammatory bone disorder caused by chronic nonbacterial osteomyelitis (CNO), which is associated with sclerosis and hyperostosis primarily... Show moreSternocostoclavicular hyperostosis (SCCH) is a rare autoinflammatory bone disorder caused by chronic nonbacterial osteomyelitis (CNO), which is associated with sclerosis and hyperostosis primarily affecting the sternum, the medial end of the clavicles, and the first ribs. Other areas of the axial skeleton may also be affected. The more severe synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is additionally associated with dermatoses and joint manifestations. This Dutch retrospective cross-sectional single-center cohort study characterizes the spectrum of clinical features in adult CNO/SCCH patients at the time of diagnosis. The only inclusion criteria was the availability of complete sets of clinical and imaging data systematically collected over three decades using in-house protocols. Data from 213 predominantly female patients (88%) with a median age of 36 years at presentation were studied. The mean diagnostic delay was 5 +/- 5 years. The main symptoms were chronic pain (92%), bony swelling (61%), and restricted shoulder girdle function (46%); 32% had palmoplantar pustulosis and 22% had autoimmune disease. The majority (73%) had isolated SCCH; 59 (27%) had additional localizations in vertebrae (19%), the mandible (9%), or both (2%); 4 had SAPHO. The prevalence of current or past smoking was high (58%), particularly for patients with palmoplantar pustulosis (76%). There was a significant relationship between delay in diagnosis and both the extent of affected skeletal sites (p = 0.036) and erythrocyte sedimentation rate levels (p = 0.023). Adult-onset CNO is characterized by distinctive clinical and radiological features, but diverse aspects of its spectrum are currently not fully captured by a comprehensive classification. Delayed diagnosis is still common and potentially associated with irreversible structural changes and debilitating chronic symptoms, increasing the burden of illness and negatively impacting on quality of life. It is hoped that findings from this study will dispel confusion about nomenclature and classification of adult-onset CNO and increase awareness of its distinctive clinical and radiological features, and thus facilitate early diagnosis and referral for treatment, which should positively impact prognosis by preventing disease progression, although this remains to be established. (c) 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research. Show less
Meijs, A.C.; Schroijen, M.A.; Snel, M.; Corssmit, E.P.M. 2021
Introduction In addition to catecholamines, pheochromocytomas and paragangliomas (PPGL) may secrete interleukin-6 (IL-6). IL-6 contributes to the development of unusual symptoms, which may hinder... Show moreIntroduction In addition to catecholamines, pheochromocytomas and paragangliomas (PPGL) may secrete interleukin-6 (IL-6). IL-6 contributes to the development of unusual symptoms, which may hinder the diagnosis. Patients and methods We report the clinical course and subsequent treatment of IL-6 producing PPGL in three patients from a single tertiary referral centre for PPGL patients in the Netherlands. Conclusion PPGL combined with persistent elevated inflammatory markers, either in the presence or absence of pyrexia, raised suspicion of IL-6 overproduction in these three patients. Although surgical resection of the tumour is the only curative treatment option, our case series adds to the accumulating evidence that alpha-blockers might be effective in these patients. Show less
Koster, E.J. de; Sulaiman, T.; Hamming, J.F.; Schepers, A.; Snel, M.; Velden, F.H.P. van; ... ; Vriens, D. 2021
Changing insights regarding radioiodine (I-131) administration in differentiated thyroid carcinoma (DTC) stir up discussions on the utility of pre-ablation diagnostic scintigraphy (DxWBS). Our... Show moreChanging insights regarding radioiodine (I-131) administration in differentiated thyroid carcinoma (DTC) stir up discussions on the utility of pre-ablation diagnostic scintigraphy (DxWBS). Our retrospective study qualitatively and semi-quantitatively assessed posttherapy I-131 whole-body scintigraphy (TxWBS) data for thyroid remnant size and metastasis. Findings were associated with initial treatment success after nine months, as well as clinical, histopathological, and surgical parameters. Possible management changes were addressed. A thyroid remnant was reported in 89 of 97 (92%) patients, suspicion of lymph node metastasis in 26 (27%) and distant metastasis in 6 (6%). Surgery with oncological intent and surgery by two dedicated thyroid surgeons were independently associated with a smaller remnant. Surgery at a community hospital, aggressive tumor histopathology, histopathological lymph node metastasis (pN1) and suspicion of new lymph node metastasis on TxWBS were independently associated with an unsuccessful treatment. Thyroid remnant size was unrelated to treatment success. All 13 pN1 patients with suspected in situ lymph node metastases on TxWBS had an unsuccessful treatment, opposite 19/31 (61%) pN1 patients without (p = 0.009). Pre-ablative knowledge of these TxWBS findings had likely influenced management in 48 (50%) patients. Additional pre-ablative diagnostics could optimize patient-tailored I-131 administration. DxWBS should be considered, especially in patients with pN1 stage or suspected in situ lymph node metastasis. Dependent on local surgical expertise, DxWBS is not recommended to evaluate thyroid remnant size. Show less
Pheochromocytoma/paraganglioma (PPGL)-induced catecholamine crisis is a rare endocrine emergency leading to life-threatening hemodynamic instability causing end-organ damage or dysfunction. As it... Show morePheochromocytoma/paraganglioma (PPGL)-induced catecholamine crisis is a rare endocrine emergency leading to life-threatening hemodynamic instability causing end-organ damage or dysfunction. As it is associated with a significant mortality rate of approximately 15%, recognizing the signs and symptoms and making the appropriate diagnosis are critical. For this purpose, we report the clinical course of the crisis in four out of a total of six patients with a PPGL crisis from a cohort of 199 PPGL patients of a single tertiary referral center for PPGL patients in the Netherlands diagnosed between 2002 and 2020. Successful treatment of a PPGL crisis demands prompt diagnosis, vigorous pharmacological therapy, and emergency tumor removal if the patient continues to deteriorate. Show less
Purpose of review Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The... Show morePurpose of review Although the majority of pheochromocytoma and paraganglioma are benign, 15-17% develop metastatic disease, being present at the initial diagnosis in about 11-31% of cases. The natural course of metastasized disease is highly heterogeneous, with an overall 5-year survival rate varying between 40% and 85%. For individual patients, overall survival, progression-free survival, and clinical outcome are difficult to predict. Management of metastasized pheochromocytoma and paraganglioma is challenging. Currently available therapeutic options are surgical debulking, treatment with radiopharmaceuticals (I-131-MIBG, Y-90 and Lu-177-DOTATATE), chemotherapy and targeted therapy. Recent findings The pathogenesis of pheochromocytoma and paraganglioma (PPGL) is largely driven by genomic alterations in PPGL susceptibility genes related to three different clusters: altered pseudo-hypoxic signaling (cluster-1), altered MAP-kinase signaling (cluster-2) and altered Wnt signaling (cluster-3). Novel targeted therapies (tyrosine kinase inhibitors) and potential future therapeutic options, guided by improved knowledge about the oncogenic cluster 1-3 signaling pathways, will be discussed. Treatment of metastasized pheochromocytoma and paraganglioma remains challenging. Profiling of gene expression and methylation can serve as a powerful tool for characterizing disease clusters and for guiding targeted therapy to improve selectivity and efficacy. Current knowledge of signatures involved in molecular signaling, metabolism, and resistance mechanisms of PPGLs suggests that therapeutic regimens can be optimized to each molecular subtype. Show less
Puy, R.S. du; Poortvliet, R.K.E.; Snel, M.; Elzen, W.P.J. den; Ballieux, B.E.P.B.; Dekkers, O.M.; ... ; Gussekloo, J. 2019
Clinical question What are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised... Show moreClinical question What are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised controlled trials, which could alter practice. Current practice Current guidelines tend to recommend thyroid hormones for adults with thyroid stimulating hormone (TSH) levels >10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing.Recommendation The guideline panel issues a strong recommendation against thyroid hormones in adults with SCH (elevated TSH levels and normal free T4 (thyroxine) levels). It does not apply to women who are trying to become pregnant or patients with TSH >20 mIU/L. It may not apply to patients with severe symptoms or young adults (such as those <= 30 years old).How this guideline was created A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach.The evidence The systematic review included 21 trials with 2192 participants. For adults with SCH, thyroid hormones consistently demonstrate no clinically relevant benefits for quality of life or thyroid related symptoms, including depressive symptoms, fatigue, and body mass index (moderate to high quality evidence). Thyroid hormones may have little or no effect on cardiovascular events or mortality (low quality evidence), but harms were measured in only one trial with few events at two years' follow-up.Understanding the recommendation The panel concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones. Other factors in the strong recommendation include the burden of lifelong management and uncertainty on potential harms. Instead, clinicians should monitor the progression or resolution of the thyroid dysfunction in these adults. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of thyroid hormones in multilayered evidence summaries and decision aids available in MAGIC (https://app.magicapp.org/) to support shared decisions and adaptation of this guideline. Show less
Feller, M.; Snel, M.; Moutzouri, E.; Bauer, D.C.; Montmollin, M. de; Aujesky, D.; ... ; Dekkers, O.M. 2018
BACKGROUND Angiopoietin-like protein 4 (ANGPTL4) has been identified as an inhibitor of lipoprotein lipase. Preliminary data suggest that plasma nonesterified fatty acids (NEFAs) raise plasma... Show moreBACKGROUND Angiopoietin-like protein 4 (ANGPTL4) has been identified as an inhibitor of lipoprotein lipase. Preliminary data suggest that plasma nonesterified fatty acids (NEFAs) raise plasma ANGPTL4 concentrations in humans. OBJECTIVE The objective was to assess plasma ANGPTL4 concentrations after various nutritional interventions that increase NEFA concentrations in healthy subjects and in patients with type 2 diabetes mellitus. DESIGN We studied 4 groups, both at baseline and after 3 d of either fasting (n = 22 healthy men), a very-low-calorie diet (VLCD; n = 10 healthy men and n = 10 patients with diabetes), or a high-fat, high-energy diet (HFED; n = 15 healthy men). Plasma ANGPTL4, NEFA, and triglyceride concentrations were measured. RESULTS In healthy men, a VLCD increased ANGPTL4 from 13.2 (IQR: 8.1-24.2) at baseline to 18.2 (16.7-33.4) ng/mL (P < 0.05), fasting increased ANGPTL4 from 10.6 (7.6-17.6) to 28.0 (23.1-35.0) ng/mL (P < 0.05), and an HFED increased ANGPTL4 from 13.9 (8.2-22.0) to 17.2 (11.2-23.6) ng/mL (P < 0.05). In men with diabetes, a VLCD also increased ANGPTL4, from 10.9 ± 2.4 to 19.2 ± 3.2 ng/mL (P < 0.05). All interventions significantly increased plasma NEFAs in both healthy men and patients with diabetes. The change in ANGPTL4 positively correlated with the change in NEFA concentrations (β = 0.048, P < 0.001) and negatively correlated with the change in plasma triglycerides (β = -0.051, P = 0.01). CONCLUSIONS Three days of either fasting, a VLCD, or an HFED increased plasma ANGPTL4 concentrations in healthy men, concomitantly with increased plasma NEFA concentrations. Similarly, a VLCD in patients with diabetes increased ANGPTL4 concentrations, concomitantly with increased NEFA concentrations. Show less
