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

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

Increased Global DNA Hypomethylation in Distant Metastatic and Dedifferentiated Thyroid Cancer.

Context: Global DNA hypomethylation is a major event for the development and progression of cancer, although the significance in thyroid cancer remains unclear. Therefore, we aimed to investigate its role in thyroid cancer progression and its potential as a prognostic marker. Methods: Global hypomethylation of Alu repeats was used as a surrogate marker for DNA global hypomethylation, and was assessed using the Quantification of Unmethylated Alu technique. Mutations in BRAF and RAS were determined by Sanger sequencing. Results: Ninety primary thyroid tumors were included [28 low-risk differentiated thyroid cancer (DTC), 13 pediatric DTC, 33 distant metastatic DTC, 7 poorly differentiated thyroid cancer (PDTC), and 9 anaplastic thyroid cancer (ATC)], as well as 24 distant metastases and 20 normal thyroid tissues. An increasing hypomethylation was found for distant metastatic DTC [median, 4.0; interquartile range (IQR), 3.1 to 6.2] and PDTC/ATC (median, 9.3; IQR, 7.0 to 12.1) as compared with normal thyroid tissue (median, 2.75; IQR, 2.30 to 3.15), whereas low-risk and pediatric DTC were not affected by hypomethylation. Alu hypomethylation was similar between distant metastases and matched primary tumors. Within distant metastatic DTC, Alu hypomethylation was increased in BRAF vs RAS mutated tumors. Kaplan-Meier and Cox regression analyses showed that thyroid cancer-related and all-cause mortality were associated with tumor hypomethylation, but this association was lost after adjustment for thyroid cancer risk category. Conclusion: Distant metastatic DTC, PDTC, and ATC were increasingly affected by global Alu hypomethylation, suggesting that this epigenetic entity may be involved in thyroid cancer progression and dedifferentiation.

Risk factors for venous thromboembolism in patients treated for differentiated thyroid carcinoma.

Although cancer in general is a strong risk factor for developing venous thromboembolism (VTE), the risk factors for venous thromboembolic events in patients with differentiated thyroid carcinoma (DTC) have never been assessed. This is remarkable, as several parts of the treatment comprise a hypercoagulable state that could in subgroups of DTC patients lead to an increased risk of VTE. The aim of this study was to assess which risk factors could cause DTC patients to develop VTE. We performed a nested case-control study, involving cases of DTC patients treated between 1980 and 2014 with confirmed VTE after diagnosis of DTC. Controls were defined as DTC patients without VTE. In all subjects, we collected information about thyroid cancer characteristics, treatment characteristics, traditional risk factors for VTE and additional clinical data, and we performed univariable and multivariable regression analyses. We included 28 cases and 56 controls matched for age at DTC diagnosis, sex and date of DTC diagnosis. In the univariable regression analysis, histology, distant metastases, DTC risk classification, recent surgery and other active malignancy were associated with VTE. In the multivariable analysis, distant metastases (odds ratio 7.9) and recent surgery (odds ratio 6.1) were independently associated with VTE. In conclusion, surgery and presence of distant metastases are independent risk factors for developing VTE in DTC patients. The risk factors identified in this study could be considered when making decisions regarding thromboprophylaxis for patients with thyroid cancer.

NT-proBNP is increased in differentiated thyroid carcinoma patients and may predict cardiovascular risk.

INTRODUCTION: Chronic suppression of TSH in patients treated for differentiated thyroid carcinoma (DTC) may induce cardiac damage and increase risk for cardiovascular events and premature mortality. We aimed to compare circulating concentrations of N-terminal pro Brain Natriuretic Peptide (NT-proBNP) of DTC patients with controls, and to investigate whether higher NT-proBNP is associated with an increased risk for cardiovascular events and all-cause mortality in DTC patients. METHODS: Serum NT-proBNP levels were determined in 266 DTC patients, median 10.4 [IQR 4.1-18.5] years after DTC diagnosis, and compared to 798 age- and sex-matched controls. Using multivariable Cox regression analyses, the association of NT-proBNP with cardiovascular events and all-cause mortality was determined. Hazard ratios (HR) and 95% confidence intervals (CIs) were expressed per SD increase of log-transformed NT-proBNP. RESULTS: Mean age±SD of DTC patients and controls was 54.8±14.5 and 54.8±12.8years, respectively; 74% were women. Median NT-proBNP level was 70 [40-119] ng/L for DTC patients vs. 49 [25-89] ng/L for controls (p<0.001). During median follow-up of 8.6 [6.6-9.0] years, 30 DTC patients (11.4%) had a cardiovascular event and 38 (14.4%) died. Higher NT-proBNP was associated with an increased risk for cardiovascular events and all-cause mortality, age- and sex-adjusted HRs (95% CIs) 3.22 (2.17-4.79) and 1.61 (1.17-2.23), respectively. In further models with adjustment for cardiovascular risk factors, NT-proBNP remained independently associated with outcome. CONCLUSION: NT-proBNP levels are elevated in patients with DTC, and are associated with an increased risk for cardiovascular events and all-cause mortality. Determination of NT-proBNP may identify DTC patients at increased cardiovascular risk, who could benefit from more stringent cardiovascular risk surveillance.

Effects of Radioiodine Treatment on Salivary Gland Function in Patients with Differentiated Thyroid Carcinoma: A Prospective Study.

Complaints of a dry mouth (xerostomia) and sialoadenitis are frequent side effects of radioiodine treatment in differentiated thyroid cancer (DTC) patients. However, detailed prospective data on alterations in salivary gland functioning after radioiodine treatment (131I) are scarce. Therefore, the primary aim of this study was to prospectively assess the effect of high-activity radioiodine treatment on stimulated whole saliva flow rate. Secondary aims were to study unstimulated whole and stimulated glandular (i.e., parotid and submandibular) saliva flow rate and composition alterations, development of xerostomia, characteristics of patients at risk for salivary gland dysfunction, and whether radioiodine uptake in salivary glands on diagnostic scans correlates to flow rate alterations. METHODS: In a multicenter prospective study, whole and glandular saliva were collected both before and 5 mo after radioiodine treatment. Furthermore, patients completed the validated xerostomia inventory. Alterations in salivary flow rate, composition, and xerostomia inventory score were analyzed. Salivary gland radioiodine uptake on diagnostic scans was correlated with saliva flow rate changes after radioiodine treatment. RESULTS: Sixty-seven patients (mean age ± SD, 48 ± 17 y; 63% women, 84% underwent ablation therapy) completed both study visits. Stimulated whole saliva flow rate decreased after ablation therapy (from 0.92 [interquartile range, 0.74-1.25] to 0.80 [interquartile range, 0.58-1.18] mL/min, P = 0.003), as well as unstimulated whole- and stimulated glandular flow rates (P < 0.05). The concentration of salivary electrolytes was similar at both study visits, whereas the output of proteins, especially amylase (P < 0.05), was decreased. The subjective feeling of dry mouth increased (P = 0.001). Alterations in saliva flow rate were not associated with semiquantitatively assessed radioiodine uptake in salivary glands on diagnostic scans. For the small cohort of patients undergoing repeated radioiodine therapy, we could not demonstrate alterations in salivary parameters. CONCLUSION: We prospectively showed that salivary gland function is affected after high-activity radioiodine ablation therapy in patients with DTC. Therefore, more emphasis should be placed on salivary gland dysfunction during follow-up for DTC patients receiving high-activity radioiodine treatment.

Increased Risk of Atrial Fibrillation After Treatment for Differentiated Thyroid Carcinoma.

BACKGROUND: Patients with differentiated thyroid carcinoma (DTC) have a favorable prognosis after treatment with thyroidectomy, radioiodine, and TSH suppression. However, treatment is associated with long-term cardiovascular toxicity. The aim of this study was to evaluate whether there is an increased risk of atrial fibrillation (AF) in DTC patients and whether AF occurrence is related to DTC treatment. PATIENTS AND METHODS: Incident AF was compared between 518 DTC patients and 1563 matched controls. A cumulative incidence curve was plotted, and competing risk regression analyses with adjustment for all-cause mortality were performed. Within the DTC cohort, associations between time-varying DTC treatment variables and incident AF were analyzed. RESULTS: For both cohorts, the mean age was 48.6 years (75% of subjects were women). The AF incidence rate was 6.2/1000 person-years for DTC patients and 2.7/1000 person-years for controls. DTC patients had a 2.25-fold (95% confidence interval [CI], 1.40-3.63) and 2.47-fold (95% CI, 1.55-3.95) increased AF risk in crude and fully adjusted analyses, respectively. Within the DTC cohort, the TSH level (which was suppressed in 85.7% of patients) was not associated with AF, whereas a higher cumulative radioiodine dose slightly increased AF risk: subdistribution hazard ratio, 1.04 (95% CI, 1.01-1.08) per 50 mCi (1.85 GBq) increase, after adjustment. CONCLUSION: Patients with DTC have an increased AF risk, independent from established AF risk factors. We could not demonstrate a relation between TSH and AF, whereas a higher cumulative radioiodine dose was associated with a slightly increased AF risk. Electrocardiogram screening for AF may be warranted during follow-up of DTC patients to allow early diagnosis and treatment of AF and to prevent its complications.

Bone Marrow Function After (131)I Therapy in Patients With Differentiated Thyroid Carcinoma.

OBJECTIVE: The primary objective was to evaluate the short- and long-term toxic effects of radioiodine ((131)I) therapy on bone marrow function in differentiated thyroid carcinoma (DTC) patients. The secondary objective was to define characteristics of patients at risk for impaired bone marrow function after (131)I treatment. PATIENTS AND METHODS: DTC patients treated with (131)I between 1989 and 2013 were included. We excluded patients with morbidities or treatments that could have influenced blood count parameters. Baseline platelets, leukocytes, and hemoglobin levels were compared with blood counts at 3 and 6 months and at 1 and 5 years after treatment. Logistic multivariate regression analyses were performed to determine patient characteristics associated with thrombocytopenia. RESULTS: We included 331 patients. Mean ± SD age was 47.5 ± 17.2 years, and 74.0% were female. Posttreatment platelets were significantly decreased at 6 months and 1 year, as compared with baseline. Leukocyte counts were also decreased at 3 and 6 months and at 1 year after treatment. No decreases in hemoglobin were found. Five years after treatment, platelet and leukocyte counts were comparable with baseline. Fourteen patients (4.2%) developed transient posttreatment thrombocytopenia. Risk factors for thrombocytopenia were older age, T4 tumor stage, male gender, and cumulative dose (131)I. After a multivariate regression analysis, the cumulative dose (131)I remained independently associated with thrombocytopenia. CONCLUSION: Posttreatment platelets and leukocytes were transiently decreased compared with pretreatment values in a general DTC population. Cumulative (131)I dose was independently associated with thrombocytopenia. Platelets and leukocytes normalized to baseline levels 5 years after treatment, implying that in most patients the clinical effects of bone marrow toxicity are limited.

Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma: an observational study.

PURPOSE: The primary aim was to study the risk of cardiovascular mortality in patients with differentiated thyroid carcinoma (DTC). Secondary aims were to evaluate all-cause mortality and explore the relation between thyroid-stimulating hormone (TSH; also known as thyrotropin) level and these outcome parameters. PATIENTS AND METHODS: Subjects from two cohorts were retrospectively compared by Cox regression analyses; 524 patients with DTC and 1,572 sex- and age-matched controls from a large population-based study in the same geographic region. RESULTS: Mean age plus or minus standard deviation was 49 ± 14 years. Median follow-up was 8.5 years (interquartile range [IQR], 4.1 to 15.9 years) for patients with DTC and 10.5 years (IQR, 9.9 to 10.9 years) for controls. One hundred patients with DTC (19.1%) died, 22 (4.2%) as a result of cardiovascular disease, 39 (7.4%) as a result of DTC, and 39 (7.4%) as a result of other/unknown causes. Eighty-five controls (5.4%) died, 24 (1.5%) as a result of cardiovascular disease and 61 (3.9%) as a result of other/unknown causes. Patients with DTC had an increased risk of cardiovascular and all-cause mortality (hazard ratios [HRs], 3.35 [95% CI, 1.66 to 6.74] and 4.40 [95% CI, 3.15 to 6.14], respectively, adjusted for age, sex, and cardiovascular risk factors). Within the DTC group, TSH level was predictive for cardiovascular mortality; the adjusted HR was 3.08 (95% CI, 1.32 to 7.21) for each 10-fold decrease in geometric mean TSH level. CONCLUSION: The risk of cardiovascular and all-cause mortality is increased in patients with DTC, independent of age, sex, and cardiovascular risk factors. A lower TSH level is associated with increased cardiovascular mortality, supporting the current European Thyroid Association and the American Thyroid Association guidelines of tempering TSH suppression in patients with low risk of cancer recurrence. Furthermore, patients with DTC may benefit from assessment and treatment of cardiovascular risk factors.