Predictors of treatment response in lymphogenic metastasized papillary thyroid cancer: a histopathological study.

BACKGROUND: Lymph node metastases in papillary thyroid cancer (PTC) increase the risk for persistent and recurrent disease. Data on the predictive value of histopathological features of lymph node metastases, however, are inconsistent. The aim of this study was to evaluate the prognostic significance of known and new histopathological features of lymph node metastases in a well-defined cohort of PTC patients with clinically evident lymph node metastases. METHODS: A total of 1042 lymph node metastases, derived from 129 PTC patients, were reexamined according to a predefined protocol and evaluated for diameter, extranodal extension, cystic changes, necrosis, calcifications, and the proportion of the lymph node taken up by tumor cells. Predictors for a failure to achieve a complete biochemical and structural response to treatment were determined. RESULTS: The presence of more than 5 lymph node metastases was the only independent predictor for a failure to achieve a complete response to treatment (odds ratio [OR] 3.39 [95% CI, 1.57-7.33], P < .05). Diameter nor any of the other evaluated lymph node features were significantly associated with the response to treatment. CONCLUSIONS: Detailed reexamination of lymph nodes revealed that only the presence of more than 5 lymph node metastases was an independent predictor of failure to achieve a complete response to treatment. No predictive value was found for other histopathological features, including the diameter of the lymph node metastases. These findings have the potential to improve risk stratification in patients with PTC and clinically evident lymph node metastases.

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.

Management of Postthyroidectomy Hypoparathyroidism and Its Effect on Hypocalcemia-Related Complications: A Meta-Analysis.

OBJECTIVE: The aim of this Meta-analysis is to evaluate the impact of different treatment strategies for early postoperative hypoparathyroidism on hypocalcemia-related complications and long-term hypoparathyroidism. DATA SOURCES: Embase.com, MEDLINE, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and the top 100 references of Google Scholar were searched to September 20, 2022. REVIEW METHODS: Articles reporting on adult patients who underwent total thyroidectomy which specified a treatment strategy for postthyroidectomy hypoparathyroidism were included. Random effect models were applied to obtain pooled proportions and 95% confidence intervals. Primary outcome was the occurrence of major hypocalcemia-related complications. Secondary outcome was long-term hypoparathyroidism. RESULTS: Sixty-six studies comprising 67 treatment protocols and 51,096 patients were included in this Meta-analysis. In 8 protocols (3806 patients), routine calcium and/or active vitamin D medication was given to all patients directly after thyroidectomy. In 49 protocols (44,012 patients), calcium and/or active vitamin D medication was only given to patients with biochemically proven postthyroidectomy hypoparathyroidism. In 10 protocols (3278 patients), calcium and/or active vitamin D supplementation was only initiated in case of clinical symptoms of hypocalcemia. No patient had a major complication due to postoperative hypocalcemia. The pooled proportion of long-term hypoparathyroidism was 2.4% (95% confidence interval, 1.9-3.0). There was no significant difference in the incidence of long-term hypoparathyroidism between the 3 supplementation groups. CONCLUSIONS: All treatment strategies for postoperative hypocalcemia prevent major complications of hypocalcemia. The early postoperative treatment protocol for postthyroidectomy hypoparathyroidism does not seem to influence recovery of parathyroid function in the long term.

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.

Preferences of patients, clinicians, and healthy controls for the management of a Bethesda III thyroid nodule.

BACKGROUND: Active surveillance is propagated as an alternative for hemithyroidectomy in the management of Bethesda III thyroid nodules. METHODS: A cross-sectional survey questioned respondents on their willingness to accept risks related to active surveillance and hemithyroidectomy. RESULTS: In case of active surveillance, respondents (129 patients, 46 clinicians, and 66 healthy controls) were willing to accept a risk of 10%-15% for thyroid cancer and 15% for needing more extensive surgery in the future. Respondents were willing to accept a risk of 22.5%-30% for hypothyroidism after hemithyroidectomy. Patients and controls were willing to accept a higher risk on permanent voice changes compared with clinicians (10% vs. 3%, p < 0.001). CONCLUSION: Real-life risks associated which active surveillance and hemithyroidectomy for Bethesda III nodules are equivalent or less than the risks people are willing to accept. Clinicians accepted less risk for permanent voice changes.

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.

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.

Thyroglobulin and thyroglobulin antibodies: assay-dependent management consequences in patients with differentiated thyroid carcinoma.

OBJECTIVES: International guidelines recommend fixed cut-off values for thyroglobulin (Tg). These cut-offs do not take potential assay differences into account. This study aimed to evaluate if different assays for Tg and Tg antibodies (TgAb) affect management guidance for differentiated thyroid cancer (DTC) patients. METHODS: In 793 samples derived from 413 patients with DTC, Tg and TgAb were simultaneously measured with two immunometric assays: Immulite 2000XPi and Kryptor compact plus. In addition, a qualitative measurement for TgAb interference (recovery test) was performed on the Kryptor compact plus platform. The extent to which different assays lead to different classifications of response to therapy was evaluated when applying the current cut-offs for Tg. RESULTS: Mean Tg concentrations were 37.4% lower with Kryptor as compared with Immulite. Applying guideline based cut-off values for Tg, 33 (4.7%) samples had a Tg-on concentration ≥1.0 µg/L with Immulite and <1.0 µg/L with Kryptor. Of the samples tested as TgAb+ with at least one assay (n=125), 68 (54.4%) samples showed discrepancy in TgAb status. Differences between Immulite and Kryptor measurements resulted in a change in the response to therapy classification in 94 (12.0%) measurements derived from 67 (16.2%) individual patients. CONCLUSIONS: A substantial portion of DTC patients were classified differently dependent on which Tg and TgAb assays are used, when applying the cut-off values as defined in clinical guidelines. Such differences can significantly affect clinical management. In the context of large between-method variation, the recommended Tg cut-offs in guidelines should be used with wisdom rather than as fixed cut-offs.

Impact of Thyroglobulin and Thyroglobulin Antibody Assay Performance on the Differential Classification of DTC Patients.

CONTEXT: Measurements of thyroglobulin (Tg) and Tg antibodies are crucial in the follow-up of treated differentiated thyroid cancer (DTC) patients. Interassay differences may significantly impact follow-up. OBJECTIVE: The aim of this multicenter study was to explore the impact of Tg and Tg antibody assay performance on the differential classification of DTC patients, as described in national and international guidelines. DESIGN: Four commonly used Tg and Tg antibody assays were technically compared to reflect possible effects on patients with DTC follow-up. Storage stability at different storage temperatures was also investigated for LIAISON® and Kryptor assays, as this is an underexposed topic in current literature. RESULTS: B.R.A.H.M.S. assays yield approximately 50% lower Tg values over the whole range compared to the DiaSorin and Roche assays investigated. These differences between assays may result in potential misclassification in up to 7% of patients if fixed cutoffs (eg, 1 ng/mL) are applied. Poor correlation was also observed between the Tg antibody assays when the method-specific upper limits of normal are used as cutoffs. Storage of Tg and Tg antibodies was possible for 3 to 4 weeks at -20°C and -80°C. Calibration of the assays, however, was found to be crucial for stable results over time. CONCLUSIONS: Technical aspects of Tg and Tg antibody assays, including interassay differences, calibration and standardization, and cutoff values, may have a significant clinical impact on the follow-up of DTC patients.

Preferences of patients and clinicians for treatment of Graves' disease: a discrete choice experiment.

OBJECTIVE: Treatment options for Graves' disease (GD) consist of antithyroid drugs (ATD), radioactive iodine (RAI) and total thyroidectomy (TT). Guidelines recommend to discuss these options with patients, taking into account patients' preferences. This study aims to evaluate and compare patients' and clinicians' preferences and the trade-offs made in choosing treatment. DESIGN AND METHODS: A discrete choice experiment (DCE) was performed with GD patients with a first diagnosis or recurrence in the previous year, and with clinicians. Participants were offered hypothetical treatment options which differed in type of treatment, rates of remission, severe side effects, permanent voice changes and hypocalcemia. Preference heterogeneity was assessed by latent-class analysis. RESULTS: In this study, 286 (82%) patients and 61 (18%) clinicians participated in the DCE. All treatment characteristics had a significant effect on treatment choice (P < 0.05). Remission rate was the most important determinant and explained 37 and 35% of choices in patients and clinicians, respectively. Both patients and clinicians preferred ATD over surgery and RAI. A strong negative preference toward RAI treatment was observed in a subclass of patients, whereas clinicians preferred RAI over surgery. CONCLUSION: For both patients and clinicians, remission rate was the most important determinant of treatment choice and ATD was the most preferred treatment option. Patients had a negative preference toward RAI compared to alternatives, whereas clinicians preferred RAI over surgery. Clinicians should be aware that their personal attitude toward RAI differs from that of their patients. This study on patients' and clinicians' preferences can support shared decision making and thereby improve clinical treatment.

Clinical Guidelines and PTH Measurement: Does Assay Generation Matter?

PTH is an important regulator of calcium and phosphate homeostasis and bone remodeling. It is metabolized into PTH fragments, which are measured to a different extent by PTH assays of different generations because of differences in fragments recognized and lack of assay standardization. PTH is measured in the workup of several conditions, and clinical guidelines provide recommendations concerning these measurements. This review provides an overview of the impact of differences between PTH assays, applying distinct clinical guidelines for primary and secondary hyperparathyroidism and perioperative use of PTH measurements. Guidelines deal with PTH measurement in different ways, recommending either trend monitoring, the use of a fold increase of the upper reference limit, or an absolute PTH cutoff value. For classic primary hyperparathyroidism (PHPT), the type of PTH assay used will not affect diagnosis or management because the precise concentration of PTH is less relevant. In chronic kidney disease, the guideline recommends treating secondary hyperparathyroidism above a twofold to ninefold PTH increase, which will result in different clinical decisions depending on the assay used. For patients after bariatric surgery, guidelines state absolute cutoff values for PTH, but the impact of different generation assays is unknown because direct comparison of PTH assays has never been performed. During parathyroid surgery, PTH measurements with a third-generation assay reflect treatment success more rapidly than second-generation assays. Increased awareness among clinicians regarding the complexity of PTH measurements is warranted because it can affect clinical decisions.

Non-cardiovascular drugs that inhibit hERG-encoded potassium channels and risk of sudden cardiac death.

BACKGROUND: Virtually all QTc-prolonging drugs act by blocking the human ether a go-go-related gene (hERG)-encoded potassium channels (hERG channels), whereas not all QTc-prolonging drugs are associated with an increased risk of serious cardiac arrhythmias. This study assessed whether non-cardiovascular hERG channel blockers are associated with an increased risk of sudden cardiac death (SCD) and whether hERG-channel-inhibiting capacity is an indicator of the risk of SCD. METHODS AND RESULTS: The risk of SCD was studied in the Integrated Primary Care Information database, a longitudinal general practice research database. A case-control study was performed, matched for age, gender and calendar time. Odds ratios were calculated with conditional logistic regression, multivariably adjusted. In addition, the hERG-channel-inhibiting capacity of the different drugs was compared, defined as the effective free therapeutic plasma concentration (ETCP(unbound)) divided by the concentration that inhibits 50% of the potassium channels (IC50), with the risk of SCD. 1424 cases of SCD and 14 443 controls were identified. Current use of hERG channel blockers was associated with an increased risk of SCD. The risk of SCD was significantly increased in users of antipsychotic drugs. Patients using hERG channel blockers with a high ETCP(unbound)/IC50 ratio (≥ 0.033) had a higher risk of SCD than patients using drugs with a low ETCP(unbound)/IC50 ratio (<0.033). CONCLUSIONS: The current use of hERG channel blockers was associated with an increased risk of SCD in the general population. In addition, drugs with a high hERG-channel-inhibiting capacity had a higher risk of SCD than drugs with a low hERG-channel-inhibiting capacity.

CYP2C19*2 polymorphism is associated with increased survival in breast cancer patients using tamoxifen.

AIMS: Variant alleles of the CYP2C19 gene were recently associated with survival in breast cancer patients on tamoxifen therapy. CYP2C19 is one of the enzymes involved in the metabolism of tamoxifen into active metabolites. We investigated the hypothesis that CYP2C19*2 and *3 variants, known for their lack of enzyme activity, are associated with an increased breast cancer mortality rate in patients using tamoxifen. MATERIALS & METHODS: In the prospective population based Rotterdam study, the association between CYP2C19*2 carriers and breast cancer mortality was studied among 80 incident users of tamoxifen. Survival was analyzed with life tables and Cox regression analysis, with drug exposure as a time-dependent variable. Adjustments were made for calendar time, average tamoxifen dose, age, the indication for tamoxifen, CYP2D6 genotype and concomitant use of CYP2C19 inhibitors or inducers. RESULTS: In patients on tamoxifen, CYP2C19*2 carriers were associated with a significantly longer breast cancer survival rate than patients with the wild-type (hazard ratio 0.26, 95%CI: 0.08-0.87). CONCLUSION: This study suggests that CYP2C19 genotype may possibly be a predictive factor for survival in breast cancer patients using tamoxifen.

Domperidone and ventricular arrhythmia or sudden cardiac death: a population-based case-control study in the Netherlands.

BACKGROUND: Recently, a 4-fold increase in risk of sudden cardiac death (SCD) was reported for domperidone in a study that focused on corrected QT interval (QTc)-prolonging drugs as a class and their association with SCD. OBJECTIVE: To evaluate the association between the use of domperidone and serious non-fatal ventricular arrhythmia (VA) and SCD in the general population. METHODS: We performed a population-based, case-control study during 1996-2007 in the Integrated Primary Care Information (IPCI) database, a longitudinal general practice research database in the Netherlands. We included all patients aged ≥18 years without cancer in the source population. We studied the association between the use of domperidone by recency of use (current, past and none) and daily dose, and the risk of serious non-fatal VA or SCD. Cases were defined as a natural death due to cardiac causes heralded by abrupt loss of consciousness within 1 hour after the onset of acute symptoms or an unwitnessed, unexpected death of someone seen in a stable medical condition <24 hours previously with no evidence of a non-cardiac cause. Controls were randomly drawn from the source population and matched to cases on age, sex, practice and index date. We compared the exposure odds for SCD alone and VA plus SCD by means of conditional logistic regression while adjusting for all available confounders. In addition, we stratified by insurance type. RESULTS: The study population comprised 1366 cases (62 VA and 1304 SCD) and 14114 matched controls. Of all cases, ten patients were current domperidone users at the index date, all with SCD. The matched unadjusted odds ratio of domperidone and SCD was 3.72 (95% CI 1.72, 8.08). Daily doses >30 mg were associated with a significant increased risk of SCD (adjusted odds ratio [OR(adj)] 11.4 [95% CI 1.99, 65.2]). Since there was a near interaction with health insurance (p = 0.050), all analyses were stratified by insurance. In publicly insured patients, seven cases were current users at the index date. Current use was associated with a significant increased risk of SCD (OR(adj) 4.17 [95% CI 1.33, 13.1]). Amongst privately insured patients there was one domperidone-exposed case, and amongst non-insured there were two. CONCLUSIONS: Current use of domperidone, especially high doses, is associated with an increased risk of SCD. We could not demonstrate an effect of domperidone on non-fatal VA due to absence of exposed cases.

Genetic variance in CYP2C8 and increased risk of myocardial infarction.

BACKGROUND: Epoxyeicosatrienoic acids (EETs) are important mediators in vasodilatation, acting as endothelium-derived hyperpolarizing factors. CYP2C enzymes catalyze the metabolism of arachidonic acid to EETs. Genetic variation within the genes encoding for these enzymes may result in differences in vascular response, among others in myocardial tissue, and may therefore increase the risk of myocardial infarction (MI). CYP2C8 and CYP2C9 are encoded by the genes of the same name. CYP2C9 polymorphisms have been associated with an increased risk of MI. As CYP2C8 is genetically linked to CYP2C9 and on account of its role in EET production, we hypothesized that CYP2C8 polymorphisms are associated with the risk of MI. METHODS: This study was embedded within the Rotterdam study, a prospective population-based cohort study. The study population included all participants with successful genotyping and without prevalent MI (n=5199). Twenty-five tagging single nucleotide polymorphisms within and around the gene-coding areas of CYP2C8 and CYP2C9 were tested for an association with incident MI using survival analysis techniques with multivariable adjustment for potential confounders. RESULTS: During follow-up, 290 persons developed an incident MI. One tag-SNP in the CYP2C8 gene was associated with incident MI after Bonferroni correction, rs1058932C>T (variant genotype hazard ratio 1.54; 95% CI: 1.22-1.95). There was a significant gene-sex interaction with a relative excess risk of 1.40 (95% CI: 0.33-2.47) for men. CONCLUSION: SNP rs1058932C>T within the CYP2C8 gene is associated with an increased risk of MI, which is, possibly because of a vascular effect of sex steroids, highest in males.

Genetic variation in NOS1AP is associated with sudden cardiac death: evidence from the Rotterdam Study.

Common variation within the nitric oxide-1 synthase activator protein (NOS1AP) locus is strongly related to QT interval, a sudden cardiac death (SCD) risk factor. A recent report describes common variation in NOS1AP associated with SCD in a US population of European ancestry. The objective of the current study was to obtain additional evidence by investigating the association between NOS1AP variants and SCD in the prospective population-based Rotterdam Study. The study population consisted of 5974 European ancestry subjects, aged 55 years and older, genotyped on Illumina arrays. SCD was defined according to European Society of Cardiology guidelines. Smoking, body mass index, diabetes mellitus, hypertension, heart failure and myocardial infarction were used as covariates in Cox proportional hazard models. Results were combined with reported evidence using inverse-variance weighted meta-analysis. Two hundred and eight (109 witnessed) cases of SCD occurred during a mean follow-up of 10.4 years. Within the Rotterdam Study alone, no significant associations were observed. Upon pooling of results with existing data, we observed strengthening of existing evidence for rs16847549 (US data HR = 1.31, P = 0.0024; Rotterdam Study HR = 1.18, P = 0.16; joint HR = 1.26, P = 0.0011). When the case definition in the Rotterdam Study was restricted to witnessed SCD, association of rs16847549 with SCD became stronger (joint P = 0.00019) and additionally the association between rs12567209 and SCD gained significance (US data HR = 0.57, P = 0.0035; Rotterdam Study HR = 0.69, P = 0.23; joint HR = 0.60, P = 0.0018). In conclusion, this study provided additional evidence for association between genetic variation within NOS1AP and SCD. The mechanism by which this effect is exerted remains to be elucidated.