European experience with the Afirma Gene Expression Classifier for indeterminate thyroid nodules: A clinical utility study in the Netherlands.

BACKGROUND: The Gene Expression Classifier (GEC) and Genomic Sequencing Classifier (GSC) were developed to improve risk stratification of indeterminate nodules. Our aim was to assess the clinical utility in a European population with restrictive diagnostic workup. METHODS: Clinical utility of the GEC was assessed in a prospective multicenter cohort of 68 indeterminate nodules. Diagnostic surgical rates for Bethesda III and IV nodules were compared to a historical cohort of 171 indeterminate nodules. Samples were post hoc tested with the GSC. RESULTS: The GEC classified 26% as benign. Surgical rates between the prospective and historical cohort did not differ (72.1% vs. 76.6%). The GSC classified 59% as benign, but misclassified six malignant lesions as benign. CONCLUSION: Implementation of GEC in management of indeterminate nodules in a European country with restrictive diagnostic workup is currently not supported, especially in oncocytic nodules. Prospective studies with the GSC in European countries are needed to determine the clinical utility.

Establishing a Multicenter Network for Patients With Thyroid Nodules and Cancer: Effects on Referral Patterns.

OBJECTIVE: To perform a qualitative evaluation of the Thyroid Network, with a quantitative analysis of second opinion referrals for patients in the southwestern part of the Netherlands who have thyroid nodules and cancer. METHODS: This prospective observational study registered all patients with thyroid nodules and cancer who were referred to the academic hospital from 2 years before and 4 years after the foundation of the Thyroid Network. We implemented biweekly regional multidisciplinary tumor boards using video conference and a regional patient care pathway for patients with thyroid nodules and cancer. For qualitative evaluation, interviews were conducted with a broad selection of stakeholders via maximum variation sampling. The primary outcome was the change in second opinions after the foundation of the Thyroid Network. RESULTS: Second opinions from Thyroid Network hospitals to the academic hospital decreased from 10 (30%) to 2 (7%) two years after the start of the Thyroid Network (P = .001), while patient referrals remained stable (n = 108 to 106). Qualitative evaluation indicated that the uniform care pathway and the regional multidisciplinary tumor board were valued high. DISCUSSION: Establishing a regional network, including multidisciplinary tumor boards and a care pathway for patients with thyroid nodules and cancer, resulted in a decrease in second opinions of in-network hospitals and high satisfaction of participating specialists. IMPLICATIONS FOR PRACTICE: The concept of the Thyroid Network could spread to other regions as well as to other specialties in health care. Future steps would be to assess the effect of regional collaboration on quality of care and patient satisfaction.

Radiofrequency Ablation for Benign Symptomatic Thyroid Nodules in the Netherlands: Successful Introduction of a Minimally Invasive Treatment Option Improving Quality of Life.

PURPOSE: To determine whether adoption of radiofrequency (RF) ablation in patients with symptomatic benign thyroid nodules (SBTNs) in a Dutch regional thyroid network resulted in clinical success and improvement in health-related and thyroid-related quality of life (QoL). MATERIALS AND METHODS: The eligibility criteria for RF ablation were as follows: (a) nodule size between 2.0 and 5.0 cm, (b) solid component >20%; (c) benign cytology in 2 separate cytological assessments, and (d) symptoms unequivocally related to mechanical compression. The primary end point of this study was volume reduction 1 year after ablation. The secondary outcomes were health-related and thyroid-related QoL, measured using the short form health survey questionnaire (SF-36) and thyroid-specific patient-reported outcome questionnaire (ThyPRO-39), respectively, as well as adverse event rates. RESULTS: A total of 72 SBTNs in 67 patients were included. Median age was 50.0 (interquartile range, 41.0-56.0) years, and 91.0% were women. The median volume reduction at 6 weeks, 6 months, 1 year, 2 years, and 3 years was 51.0%, 63.9%, 65.2%, 81.3%, and 90.3%, respectively. The patients showed a significant improvement on the SF-36 physical component scale and ThyPRO-39 overall QoL-impact scale. An absolute improvement was seen in goiter and cosmetic complaints, determined using ThyPRO-39. The overall adverse event rate was 9.0%, of which 4.5% were considered major. CONCLUSIONS: RF ablation is an effective treatment option for SBTNs, with a significant volume reduction and improvement in health-related and thyroid-related QoL.

Change in Thyroid Hormone Metabolite Concentrations Across Different Thyroid States.

Background: In contrast to the thyroid hormones (TH) 3,3',5-triiodothyronine (T3) and thyroxine (T4), current literature on thyroid hormone metabolite concentrations in the hypothyroid and hyperthyroid states is inconclusive. It is unknown how thyroidectomy affects thyroid hormone metabolite concentrations and if levothyroxine (LT4) replacement therapy after thyroidectomy restores thyroid hormone metabolite concentrations in those without a thyroid gland. The treatment of patients with differentiated thyroid cancer (DTC) covers the euthyroid, hypothyroid, and (subclinical) hyperthyroid states and therefore provides a unique model to answer this. Here, we prospectively studied nine TH and its metabolites (THM) across different thyroid states in a cohort of patients treated for DTC. Also, three potentially important determinants for THM concentrations were studied. Methods: We prospectively included patients aged 18 to 80 years who were scheduled for DTC treatment at the Erasmus MC. Peripheral blood samples were obtained before surgery (euthyroid, endogenous TH production), after surgery just before radioactive iodine therapy (hypothyroid), and six months later on LT4 therapy ([subclinically] hyperthyroid, exogenous T4 supplementation). Nine THMs were quantified in serum with an established liquid chromatography/tandem mass spectrometry method. Repeated measurement analysis was used to compare the three different thyroid states with each other for each THM, while linear regression was used to determine the association between THM concentrations and age, sex, and kidney function. Results: In total, 77 patients (mean age 49 years; 65% women) were eligible for the study. 3,5-diiodothyronine and 3,3',5-triiodothyroacetic acids were below the lower limit of detection. Compared with the euthyroid state, all THMs were significantly decreased in the hypothyroid state and significantly increased in the (subclinically) hyperthyroid state, with T3 concentrations remaining within the reference interval. Higher age was associated with higher 3-monoiodothyronine (3-T1) concentrations (p < 0.001). Women had higher L-thyronine concentrations than men (p = 0.003). A better kidney function was associated with lower 3-T1 concentrations (p < 0.001). Conclusions: All THMs decrease after a thyroidectomy and increase under thyrotropin (TSH)-suppressive LT4-therapy, suggesting that formation of thyroid hormone metabolites is dependent on peripheral extrathyroidal metabolism of T4. This is also reflected by T3 concentrations that remained within the reference interval in patients receiving TSH-suppressive LT4-therapy as T3 has some thyroidal origin.

Postoperative parathyroid hormone levels as a predictor for persistent hypoparathyroidism.

OBJECTIVE: Hypoparathyroidism is a common complication after thyroidectomy. It is not yet possible to predict in which patients hypoparathyroidism will persist. We aim to determine whether a decrease in PTH levels, measured at the first postoperative day, can identify patients with a high risk for persistent hypoparathyroidism one year after thyroidectomy. DESIGN: Prospective multi-center cohort study. METHODS: Patients undergoing total or completion thyroidectomy were included. We measured PTH levels preoperatively and on the first postoperative day. Primary outcome is the proportion of patients with persistent hypoparathyroidism, defined as the need for calcium supplementation one year after surgery. RESULTS: We included 110 patients of which 81 were used for analysis of the primary outcome. At discharge 72.8% of patients were treated with calcium supplementation. Persistent hypoparathyroidism was present in 14 patients (17.3%) at one-year follow-up, all of them had a decrease in PTH >70% at the first postoperative day. These 14 were 43.8% of the 32 patients who had such a decrease. In the group of 49 patients (59.8%) without a PTH >70% decrease, none had persistent hypoparathyroidism one year after surgery (P-value <0.001). A decrease of >70% in PTH levels had a sensitivity of 100.0% (95% CI: 85.8-100.0%), a specificity of 73.1% (95% CI: 62.5-83.7%) and an area under the curve of 0.87 (95% CI: 0.79-0.94) to predict the risk for persistent hypoparathyroidism. CONCLUSION: In our study a decrease in PTH levels of >70% after total or completion thyroidectomy is a reliable predictor for persistent hypoparathyroidism, and this should be confirmed in larger cohorts.

Longitudinal Analysis of the Effect of Radioiodine Therapy on Ovarian Reserve in Females with Differentiated Thyroid Cancer.

Background: Although international guidelines have become more conservative on the use of radioactive iodine (RAI) therapy, it is still one of the cornerstones of the treatment of patients with advanced differentiated thyroid cancer (DTC). As a large proportion of females diagnosed with DTC is in their reproductive years, knowledge about the effect of RAI on their gonadal and reproductive function is important. Earlier studies evaluating Anti-Müllerian hormone (AMH) as a representative of ovarian reserve were either cross-sectional, had relatively low numbers, had no patients with multiple RAI therapies, or had a relatively short follow-up. The primary aim of our study was, therefore, to prospectively evaluate the effect of RAI on AMH in women undergoing treatment for DTC. Methods: We included females, aged 16 years until menopause, who were scheduled to undergo their first RAI treatment for DTC at our hospital. Serum AMH was measured before initial therapy and regularly thereafter. Repeated measurement analysis was used to assess the changes of AMH concentrations over time, and how this is influenced by age and cumulative RAI dose. Results: Longitudinal AMH assessments were available in 65 patients (mean age 32 years, median of five measurements during median follow-up of 34 months). AMH concentrations changed nonlinear over time, decreased until 12 months in the single RAI group (-55%), and stabilized thereafter. In the multiple RAI group, after stabilization, a further decrease occurred (-85% after 48 months). Age in both RAI groups significantly influenced AMH change over time, with younger patients (<35 years of age) showing a less steep decrease. Conclusions: In a population of female DTC patients treated with total thyroidectomy and a single RAI therapy, AMH concentrations significantly dropped during the first year after initial therapy, and thereafter they remained stable. In patients receiving multiple RAI therapies, a further decrease was seen. Age at baseline significantly influenced AMH change over time. These results support a less aggressive treatment with RAI in low-risk patients as is advocated in the current American Thyroid Association (ATA) guidelines, especially in females older than 35 years of age with the desire to have a child.

Longitudinal analysis of quality of life in patients treated for differentiated thyroid cancer.

OBJECTIVE: Earlier cross-sectional studies showed that patients with differentiated thyroid cancer (DTC) have a significant reduction of quality of life (QoL) compared to controls. However, recent longitudinal studies showed mixed results and had relative short follow-up or lacked knowledge about QoL before initial surgery. Therefore, we initiated a longitudinal study to assess changes of QoL in patients undergoing treatment for DTC. METHODS: We prospectively included patients, aged 18-80 years, who were treated for DTC at a Dutch university hospital. Using questionnaires, QoL was assessed before surgery, just before radioiodine (RAI) therapy, and regularly during follow-up. Repeated measurement analysis was used to assess changes of QoL over time, and we explored the influence of different characteristics on QoL. RESULTS: Longitudinal QoL assessments were available in 185 patients (mean age 47 years; 71% women). All patients were treated according to the Dutch guidelines with total thyroidectomy followed by RAI (83% after thyroid hormone withdrawal). Median time between baseline and final questionnaire was 31 months, and patients completed a median of three questionnaires. QoL at baseline was lower than that in the general population, developed non-linear over time, was lowest around RAI therapy, and recovered over time. Females, younger patients, and patients with persistent hypoparathyroidism had lower QoL scores. CONCLUSIONS: In a population of DTC patients, QoL before initial therapy is already lower than that in the general population. Thereafter, QoL develops non-linearly over time in general, with the lowest QoL around RAI therapy, while 2 to 3 years later, it approximates baseline values.

Pressure-volume analysis in athyroid patients off and on thyroxine supplementation: a pilot study.

Thyroid hormone importantly affects the cardiovascular system. However, evaluation of stroke volume (SV) and its determinants is confounded by variations in volume status that occur along different thyroid states. This study applied the pressure-volume (PV) framework to obtain relatively load-independent estimates of cardiac function in hypothyroidism as compared to euthyroidism. Ten athyroid patients were assessed echocardiographically after 4 weeks in deep hypothyroid state, and again after supplementation with oral Levothyroxine (LT4) for 3 months. Thyroid hormone levels were assessed and noninvasive pressure-volume (PV) analysis based on dedicated repeated echocardiograms was performed. Changes were assessed using paired tests. Results are presented as medians and interquartile ranges. Hypothyroidism was associated with reduced stroke volume (SV: 67.6 ± 17 vs. 75.7 ± 20.6 mL, P = 0.024), preload (end-diastolic volume, EDV: 122.6 ± 32.5 vs. 135.7 ± 33.6 mL, P = 0.004), and contractility (end-systolic elastance, Ees : 1.7 ± 0.33 vs. 2.58 ± 1.33 mmHg/mL, P = 0.01). Afterload was constant (effective arterial elastance, Ea : 1.66 ± 0.32 vs. 1.79 ± 0.52 mmHg/mL, P = 0.43) and the total energy spent was lower (PVA∙HR: 86.7 ± 28 vs. 110.9 ± 32.1 J, P = 0.04). Hemodynamic manifestations of frank hypothyroidism in humans are characterized by reduced preload and contractility, and unchanged total afterload. LT4 therapy increased work efficiency and heart rate, but not the net energy expenditure. Noninvasive PV analysis may be useful to follow-up different thyroid states.

Effects of Thyrotropin on Peripheral Thyroid Hormone Metabolism and Serum Lipids.

BACKGROUND: Subclinical hypothyroidism is associated with dyslipidemia and atherosclerosis. Whether these effects are in part mediated via direct effects of thyrotropin (TSH) on peripheral thyroid hormone (TH) metabolism and/or concentrations of serum lipids is not clear. OBJECTIVE: This study examined whether TSH has direct effects on peripheral TH metabolism and serum lipids. METHODS: Eighty-two patients with differentiated thyroid cancer were retrospectively analyzed. All patients had undergone total thyroidectomy and 131I remnant ablation. During follow-up, two successive injections of recombinant human TSH (rhTSH) were administered to patients on a stable dose of levothyroxine. In all patients, TSH, thyroxine (T4), free T4 (fT4), triiodothyronine (T3), reverse T3 (rT3), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), and triglyceride levels were measured immediately before the first and approximately 72 hours after the second injection of rhTSH. RESULTS: After rhTSH stimulation, T3 values decreased (from 1.91 to 1.81 nmol/L; p < 0.001). T4, fT4, and rT3 did not change. After rhTSH, median apolipoprotein B increased from 0.90 to 0.92 g/L (p = 0.03), lipoprotein(a) from 0.21 to 0.24 g/L (p < 0.001), and triglycerides from 1.98 to 2.50 mmol/L (p < 0.001). Serum high-density lipoprotein cholesterol decreased from 0.98 to 0.81 mmol/L (p < 0.001). Multiple regression analysis showed that the changes in lipids were most closely associated with the decrease in T3 levels. CONCLUSIONS: TSH has direct effects on peripheral TH metabolism by decreasing T3 levels in levothyroxine-treated thyroidectomized patients. This decrease in T3 levels is accompanied by unfavorable changes in serum lipids.

Maternal and obstetrical outcome in 35 cases of well-differentiated thyroid carcinoma during pregnancy.

OBJECTIVES/HYPOTHESIS: Thyroid cancer, with 6% to 10% of cancer diagnoses, is one of the most common malignancies during pregnancy. Its treatment poses a risk for the pregnancy, as the thyroid gland plays a crucial role in the evolution of pregnancy. The aim of this study is to evaluate treatment of primary well-differentiated thyroid carcinoma during pregnancy and fetal and maternal outcomes. STUDY DESIGN: This is an international cohort study. METHODS: Primary thyroid cancer patients were identified from the database of the International Network on Cancer, Infertility, and Pregnancy registration study. Data on histopathological characteristics, diagnostic and therapeutic interventions, outcome (obstetrical, neonatal, and maternal) and maternal follow-up were analyzed. RESULTS: Thirty-five patients with well-differentiated thyroid carcinoma were eligible. All 35 patients underwent surgery, 29 (83%) of which during pregnancy. Procedures during pregnancy were mainly total thyroidectomies (n = 24). The median number of days between diagnosis and surgical treatment was different between the groups with surgery during and after pregnancy (27 vs. 139 days, P < .001). Both maternal and neonatal outcomes were uncomplicated, regardless of gestational age during surgery. CONCLUSIONS: Well-differentiated thyroid carcinoma diagnosed during pregnancy has a favorable outcome for both mother and child. Surgical management during pregnancy has no negative impact on the pregnancy regardless of the trimester at the time of surgery. However, the potential negative effects of thyroid surgery early in pregnancy demand management of these patients in an experienced multidisciplinary team to provide the best possible care for these patients and their unborn babies. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1493-1500, 2018.

Effects of Thyroid Hormone on Urinary Concentrating Ability.

BACKGROUND: Hypothyroidism has been associated with impaired urinary concentrating ability. However, previous reports on thyroid hormone and urinary concentrating ability in humans only studied a limited number of patients with autoimmune thyroid disease or used healthy controls instead of paired analysis within the same patients. OBJECTIVE: To study the urinary concentrating ability in athyreotic patients with differentiated thyroid cancer on and off levothyroxine treatment as they are exposed to different thyroid states as part of their treatment in the absence of an autoimmune disease. DESIGN AND METHODS: We studied 9 patients (mean age of 42.7 years) during severe hypothyroid state (withdrawal of levothyroxine before radioactive iodine therapy) and TSH-suppressed state (on levothyroxine therapy). At these two points, serum and urine samples were collected after 14 h of overnight fasting without any food or drink. RESULTS: Serum and urine osmolality were not significantly different between on and off levothyroxine treatment. Serum creatinine levels were significantly higher in patients off versus on levothyroxine treatment (87.0 vs. 71.0 µmol/L, respectively; p = 0.044) and, correspondingly, the estimated glomerular filtration rate was significantly lower (89.6 vs. 93.1 mL/min, respectively; p = 0.038). CONCLUSION: Short-term, severe hypothyroidism has no effect on urinary concentrating ability. Our study confirms the well-known effects of thyroid hormone on serum creatinine concentrations.

Aberrant Levels of Hematopoietic/Neuronal Growth and Differentiation Factors in Euthyroid Women at Risk for Autoimmune Thyroid Disease.

BACKGROUND: Subjects at risk for major mood disorders have a higher risk to develop autoimmune thyroid disease (AITD) and vice-versa, implying a shared pathogenesis. In mood disorder patients, an abnormal profile of hematopoietic/neuronal growth factors is observed, suggesting that growth/differentiation abnormalities of these cell lineages may predispose to mood disorders. The first objective of our study was to investigate whether an aberrant profile of these hematopoietic/neuronal growth factors is also detectable in subjects at risk for AITD. A second objective was to study the inter relationship of these factors with previously determined and published growth factors/cytokines in the same subjects. METHODS: We studied 64 TPO-Ab-negative females with at least 1 first- or second-degree relative with AITD, 32 of whom did and 32 who did not seroconvert to TPO-Ab positivity in 5-year follow-up. Subjects were compared with 32 healthy controls (HCs). We measured serum levels of brain-derived neurotrophic factor (BDNF), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF) and IL-7 at baseline. RESULTS: BDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001), while EGF (506.9 vs 307.6 pg/ml, P = 0.003) and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028) were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017). In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1ß, IL-6 and CCL-3, of which high levels also preceded seroconversion. CONCLUSION: Relatives of AITD patients show aberrant serum levels of 4 hematopoietic/neuronal growth factors similar to the aberrancies found in mood disorder patients, suggesting that shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie thyroid autoimmunity and mood disorders. A distinct pattern of four inter correlating immune factors in the relatives preceded TPO-Ab seroconversion in the next 5 years.

Reproducibility of same session repeated cystometry and pressure-flow studies in women with symptoms of urinary incontinence.

AIM: The aim of this study was to determine the reproducibility of same session repeated urodynamic measurements in women with symptoms of urinary incontinence. METHODS: Women presenting with symptoms of urinary incontinence underwent standardized urodynamic examination, which consisted of free uroflowmetry and two filling cystometries and pressure-flow studies. Intra-class Correlation Coefficient (ICC) and McNemar tests were used to describe the same session reproducibility. RESULTS: Two evaluable urodynamic tests were available in 152 patients. Overall, reproducibility of the urodynamic parameters were good to excellent (ICC range: 0.72-0.93), except for the bladder volume at first sensation of bladder filling (ICC = 0.46) and the maximum Watt's factor (ICC = 0.68). The bladder volume at first sensation and the maximum cystometric capacity were systematically higher in the second run (mean difference (95% CI) = -45 (-73; -37) and -3 (-15; 10), respectively). Reproducibility of the diagnosis stress urinary incontinence and/or detrusor overactivity were good to excellent (median ICC = 0.76, P = 0.68 and P = 1.00, respectively). Reproducibility of the volume and amplitude at involuntary detrusor contractions, however, were only poor (ICC = 0.18 and 0.25, respectively). CONCLUSIONS: The reproducibility of same session repeated urodynamic measurements in women with symptoms of urinary incontinence was good to excellent. Our results provide the scientific support for guidelines that recommend the omission of repeated filling cystometries and pressure-flow studies in cases where the first test confirms the pathology expected.

Does vaginal reconstructive surgery with or without vaginal hysterectomy or trachelectomy improve sexual well being? A prospective follow-up study.

OBJECTIVE: To compare sexual well being in women with pelvic organ prolapse before and after vaginal reconstructive surgery. METHODS: Sixty-seven women, mean age 61 (36-85) years, who underwent vaginal reconstructive surgery, were asked to complete detailed questionnaires before and after surgery. In addition, they underwent a physical examination using the Pelvic Organ Prolapse Quantification (POPQ), before surgery and at follow-up. RESULTS: Mean duration of follow-up was 14.4 months (6.6-27.6 months). The overall satisfaction with the operation was high with a mean of 7.5 on a visual analogue scale from 0 to 10. There was a significant improvement of dyspareunia after vaginal reconstructive surgery. The ability to have intercourse, the satisfaction with intercourse as well as the frequency of intercourse also improved although not significantly. Urine loss during intercourse improved significantly. CONCLUSION: Vaginal reconstructive surgery for pelvic organ prolapse has a positive effect on the sexual well being of the afflicted women.