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.

Regional Collaboration and Trends in Clinical Management of Thyroid Cancer.

OBJECTIVE: This study examines the trends in the management of thyroid cancer and clinical outcomes in the Southwestern region of The Netherlands from 2010 to 2021, where a regional collaborative network has been implemented in January 2016. STUDY DESIGN: Retrospective cohort study. SETTING: This study encompasses all patients diagnosed with thyroid cancer of any subtype between January 2010 and June 2021 in 10 collaborating hospitals in the Southwestern region of The Netherlands. METHODS: The primary outcome of this study was the occurrence of postoperative complications. Secondary outcomes were trends in surgical management, centralization, and waiting times of patients with thyroid cancer. RESULTS: This study included 1186 patients with thyroid cancer. Median follow-up was 58 [interquartile range: 24-95] months. Surgery was performed in 1027 (86.6%) patients. No differences in postoperative complications, such as long-term hypoparathyroidism, permanent recurrent nerve paresis, or reoperation due to bleeding were seen over time. The percentage of patients with low-risk papillary thyroid carcinoma referred to the academic hospital decreased from 85% (n = 120/142) in 2010 to 2013 to 70% (n = 120/171) in 2014 to 2017 and 62% (n = 100/162) in 2018 to 2021 (P < .01). The percentage of patients undergoing a hemithyroidectomy alone was 9% (n = 28/323) in 2010 to 2013 and increased to 20% (n = 63/317; P < .01) in 2018 to 2021. CONCLUSION: The establishment of a regional oncological network coincided with a de-escalation of thyroid cancer treatment and centralization of complex patients and interventions. However, no differences in postoperative complications over time were observed. Determining the impact of regional oncological networks on quality of care is challenging in the absence of uniform quality indicators.

A symptom-based algorithm for calcium management after thyroid surgery: a prospective multicenter study.

Objective: Evidence-based treatment guidelines for the management of postthyroidectomy hypocalcemia are absent. The aim of this study was to evaluate a newly developed symptom-based treatment algorithm including a protocolized attempt to phase out supplementation. Methods: In a prospective multicenter study, patients were treated according to the new algorithm and compared to a historical cohort of patients treated with a biochemically based approach. The primary outcome was the proportion of patients receiving calcium and/or alfacalcidol supplementation. Secondary outcomes were calcium-related complications and predictors for supplementation. Results: One hundred thirty-four patients were included prospectively, and compared to 392 historical patients. The new algorithm significantly reduced the proportion of patients treated with calcium and/or alfacalcidol during the first postoperative year (odds ratio (OR): 0.36 (95% CI: 0.23-0.54), P < 0.001), and persistently at 12 months follow-up (OR: 0.51 (95% CI: 0.28-0.90), P < 0.05). No severe calcium-related complications occurred, even though calcium-related visits to the emergency department and readmissions increased (OR: 11.5 (95% CI: 4.51-29.3), P <0.001) and (OR: 3.46 (95% CI: 1.58-7.57), P < 0.05), respectively. The proportional change in pre- to postoperative parathyroid hormone (PTH) was an independent predictor for supplementation (OR: 1.04 (95% CI: 1.02-1.07), P < 0.05). Conclusions: Symptom-based management of postthyroidectomy hypocalcemia and a protocolized attempt to phase out supplementation safely reduced the proportion of patients receiving supplementation, although the number of calcium-related hospital visits increased. For the future, we envision a more individualized treatment approach for patients at risk for delayed symptomatic hypocalcemia, including the proportional change in pre- to post- operative PTH.

Deescalating Follow-up After Hemithyroidectomy for Patients With Low-risk Papillary Thyroid Microcarcinoma.

Importance: Structural recurrent disease (RD) after surgical treatment of papillary thyroid microcarcinoma (mPTC) is rare. We hypothesized that the RD rate after hemithyroidectomy in low-risk patients with mPTC is low. Objective: To assess the occurrence of RD in Dutch patients with mPTC who received surgical treatment according to the Dutch guidelines. Design, Setting, and Participants: This nationwide retrospective cohort study included all patients who had undergone surgery with a diagnosis of cN0/cNx mPTC in the Netherlands between January 2000 and December 2020 were identified from the Netherlands Cancer Registry database. Patients with preoperative lymph node metastases were excluded. Two groups were defined: group 1 (incidental), mPTC in pathology report after thyroid surgery for another indication; and group 2 (nonincidental), patients with a preoperative highly suspect thyroid nodule (Bethesda 5) or proven mPTC (Bethesda 6). Dutch guidelines state that a hemithyroidectomy is sufficient in patients with unifocal, intrathyroidal mPTC. Main Outcomes and Measures: The occurrence of RD in patients with low-risk mPTC after hemithyroidectomy. Results: In total, 1636 patients with mPTC were included. Patients had a median (IQR) follow-up time of 71 (32-118) months. Median (IQR) age at time of diagnosis was 51 (41-61) years and 1292 (79.0%) were women. Overall, RD after initial treatment was seen in 25 patients (1.5%). The median (IQR) time to RD was 8.2 (3.6-16.5) months and 22 of the 25 (88%) patients developed RD within 2 years. Recurrent disease was not significantly different between both groups (group 1, n = 15 [1.3%]; group 2, n = 10 [2.1%]; difference, 0.8%; 95% CI, -0.5% to 2.5%). Of the 484 patients with nonincidental mPTC (group 2), 246 (50.8%) patients were treated with a hemithyroidectomy and follow-up in accordance with Dutch guidelines. Lymph node metastases were found in 1 of 246 (0.4%) patients after hemithyreoidectomy, and new mPTC in the contralateral thyroid was detected in 3 of 246 (1.2%) patients. Median (IQR) follow-up of this patient group was 37 (18-71) months. The 10-year probability of RD was 1.3% for patients without vascular invasion and 24.4% for patients with vascular invasion. Conclusions and Relevance: This nationwide cohort study found that overall, RD after hemithyroidectomy for patients with low-risk mPTC was rare (<2%). Based on these results, it seems reasonable to deescalate follow-up of patients with low-risk mPTC without vascular invasion after hemithyroidectomy. From a health care perspective, deescalation of follow-up may contribute to increased sustainability and accessibility to health care, both large challenges for the future.

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.

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.

Persistent post-thyroidectomy hypoparathyroidism: A multicenter retrospective cohort study.

BACKGROUND AND OBJECTIVE: The reported incidence of persistent hypoparathyroidism varies widely, and consensus on a definition is lacking. The objective was to evaluate the real-life incidence of persistent hypoparathyroidism by investigating a new pragmatic definition. METHODS: This retrospective multicenter cohort study evaluated the effect of different definitions for persistent hypoparathyroidism on the incidence of hypoparathyroidism. In addition, risk factors for hypoparathyroidism were analyzed. RESULTS: In total, 749 patients were included. Using the new pragmatic definition, we report an incidence of 7.9% of persistent hypoparathyroidism. When applying other commonly used definitions, incidence varied between 11.8% and 22.1%. Risk factors were parathyroid autotransplantation, presence of another surgical complication, and low postoperative serum calcium. CONCLUSIONS: Our data show that the incidence of persistent hypoparathyroidism in the literature may vary through the use of different definitions. This study indicates that a new pragmatic definition of persistent hypoparathyroidism has the potential to enable unbiased comparison between studies.

Active Surveillance for Papillary Thyroid Microcarcinoma in a Population with Restrictive Diagnostic Workup Strategies.

Background: The worldwide incidence of papillary thyroid carcinoma (PTC) has increased. Efforts to reduce overtreatment follow two approaches: limiting diagnostic workup of low-risk thyroid nodules and pursuing active surveillance (AS) after diagnosis of microscopic PTC (mPTC). However, most studies on AS have been performed in countries with a relatively high proportion of overdiagnosis and thus incidental mPTC. The role of AS in a population with a restrictive diagnostic workup protocol for imaging and fine-needle aspiration remains unknown. Therefore, the aim of this study was to describe the proportion and characteristics of patients with mPTC in the Netherlands and to describe the potential candidates for AS in a situation with restrictive diagnostic protocols since 2007. Methods: All operated patients with an mPTC in the Netherlands between 2005 and 2015 were identified from the Netherlands Cancer Registry database. Three groups were defined: (Group 1) mPTC with preoperative distant or lymph node metastases, (Group 2) mPTC in pathology report after thyroid surgery for another indication, and (Group 3) patients with a preoperative high suspicious thyroid nodule or proven mPTC (Bethesda 5 or 6). Only patients in Group 3 were considered potential candidates for AS. Results: A total of 1018 mPTC patients were identified. Group 1 consisted of 152 patients with preoperatively discovered metastases. Group 2 consisted of 667 patients, of whom 16 (2.4%) had lymph node metastases. There were 199 patients in Group 3, of whom 27 (13.6%) had lymph node metastases. After initial treatment in Group 3, 3.5% (7/199) of the patients had recurrence. Conclusions: Restrictive diagnostic workup strategies of patients with small thyroid nodules lead to limited patients eligible for AS and a higher incidence of lymph node metastases. We believe that there is limited additive value for AS in countries with restrictive diagnostic workup guidelines such as in the Netherlands. However, if an mPTC is encountered, AS can be offered on an individual basis.

Persistent Postthyroidectomy Hypoparathyroidism in the Netherlands.

Importance: Hypoparathyroidism is one of the most common complications after total or completion thyroidectomy. The reported incidence rate of hypoparathyroidism in the literature is highly variable. Data that provide a better understanding of the magnitude of this postoperative complication are warranted and can provide a stepping stone for further collaborations that aim to reduce complication rates and establish uniform treatment protocols. Objective: To evaluate the incidence of postoperative, persistent hypoparathyroidism after total or completion thyroidectomy in patients who were referred to university hospital centers and assess the association of different definitions with the incidence of hypoparathyroidism. Design, Setting, and Participants: This retrospective multicenter cohort study conducted throughout 2016 in 7 Dutch university hospital centers included 200 patients who were undergoing a total or completion thyroidectomy. Data analysis was conducted in January 2021. Main Outcomes and Measures: We report on the incidence of persistent hypoparathyroidism, defined as the need for active vitamin D with or without calcium supplementation longer than 1 year after surgery. Results: A total of 200 patients (143 women [71.5%]; mean [IQR] age, 49.0 [37.0-62.0] years) were included and 30 patients (15.0%) developed persistent hypoparathyroidism. The incidence of persistent hypoparathyroidism varied between 14.5% (calcium and active vitamin D 1 year postsurgery) to 28.5% (calcium and/or active vitamin D 6 months postsurgery) depending on the definition used. Conclusions and Relevance: In this cohort study, the risk of persistent hypoparathyroidism after total or completion thyroidectomy was 15% in patients who were referred to university hospital centers. The high rate of persistent hypoparathyroidism warrants efforts to reduce this complication rate. There is discrepancy in the definition and treatment of persistent hypoparathyroidism, and use of uniform evidence-based treatment guidelines enables comparison of interventions.

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.

rs2735383, located at a microRNA binding site in the 3'UTR of NBS1, is not associated with breast cancer risk.

NBS1, also known as NBN, plays an important role in maintaining genomic stability. Interestingly, rs2735383 G > C, located in a microRNA binding site in the 3'-untranslated region (UTR) of NBS1, was shown to be associated with increased susceptibility to lung and colorectal cancer. However, the relation between rs2735383 and susceptibility to breast cancer is not yet clear. Therefore, we genotyped rs2735383 in 1,170 familial non-BRCA1/2 breast cancer cases and 1,077 controls using PCR-based restriction fragment length polymorphism (RFLP-PCR) analysis, but found no association between rs2735383CC and breast cancer risk (OR = 1.214, 95% CI = 0.936-1.574, P = 0.144). Because we could not exclude a small effect size due to a limited sample size, we further analyzed imputed rs2735383 genotypes (r2 > 0.999) of 47,640 breast cancer cases and 46,656 controls from the Breast Cancer Association Consortium (BCAC). However, rs2735383CC was not associated with overall breast cancer risk in European (OR = 1.014, 95% CI = 0.969-1.060, P = 0.556) nor in Asian women (OR = 0.998, 95% CI = 0.905-1.100, P = 0.961). Subgroup analyses by age, age at menarche, age at menopause, menopausal status, number of pregnancies, breast feeding, family history and receptor status also did not reveal a significant association. This study therefore does not support the involvement of the genotype at NBS1 rs2735383 in breast cancer susceptibility.