| 1. Smith-Bindman R, Lebda P, Feldstein VA, et al. Risk of thyroid cancer based on thyroid ultrasound imaging characteristics: results of a population-based study. JAMA Intern Med. 173(19):1788-96, 2013 Oct 28. |
Observational-Dx |
8806 patients |
To quantify the risk of thyroid cancer associated with thyroid nodules based on ultrasound imaging characteristics. |
A total of 8806 patients underwent 11,618 thyroid ultrasound examinations during the study period, including 105 subsequently diagnosed as having thyroid cancer. Thyroid nodules were common in patients diagnosed as having cancer (96.9%) and patients not diagnosed as having thyroid cancer (56.4%). Three ultrasound nodule characteristics--microcalcifications (odds ratio [OR], 8.1; 95% CI, 3.8-17.3), size greater than 2 cm (OR, 3.6; 95% CI, 1.7-7.6), and an entirely solid composition (OR, 4.0; 95% CI, 1.7-9.2)--were the only findings associated with the risk of thyroid cancer. If 1 characteristic is used as an indication for biopsy, most cases of thyroid cancer would be detected (sensitivity, 0.88; 95% CI, 0.80-0.94), with a high false-positive rate (0.44; 95% CI, 0.43-0.45) and a low positive likelihood ratio (2.0; 95% CI, 1.8-2.2), and 56 biopsies will be performed per cancer diagnosed. If 2 characteristics were required for biopsy, the sensitivity and false-positive rates would be lower (sensitivity, 0.52; 95% CI, 0.42-0.62; false-positive rate, 0.07; 95% CI, 0.07-0.08), the positive likelihood ratio would be higher (7.1; 95% CI, 6.2-8.2), and only 16 biopsies will be performed per cancer diagnosed. Compared with performing biopsy of all thyroid nodules larger than 5 mm, adoption of this more stringent rule requiring 2 abnormal nodule characteristics to prompt biopsy would reduce unnecessary biopsies by 90% while maintaining a low risk of cancer (5 per 1000 patients for whom biopsy is deferred). |
3 |
| 2. Stang MT, Armstrong MJ, Ogilvie JB, et al. Positional dyspnea and tracheal compression as indications for goiter resection. Arch Surg. 147(7):621-6, 2012 Jul. |
Observational-Dx |
1081 patients |
To examine the hypothesis that thyroidectomy (Tx) can be a surgically correctable cause of misdiagnosed obstructive sleep apnea (OSA). |
Positional dyspnea was reported by 188 of 1081 patients, and after Tx the positional dyspnea (PD) improved or resolved in 82.4%. In the 151 patients with substernal goiter, TC was present on imaging in 97.2%; the mean (range) TC was 34% (5%-90%). Patients with TC had a high likelihood of PD (93.5%). After substernal goiter resection, PD improved in stepwise association with total resected thyroid gland weight. Improvement in PD was strongly predicted by both gland weight of 100 g or more (P.001) and by TC of 35% or more (P.01). After Tx, 59 of 77 snorers (76.6%) reported improvement in snoring, 77.1% of patients with obstructive sleep apnea reported improved PD, and 2 of 3 retested patients with obstructive sleep apnea demonstrated objective improvement in sleep study apnea-hypopnea index. |
2 |
| 3. Hobbs HA, Bahl M, Nelson RC, et al. Journal Club: incidental thyroid nodules detected at imaging: can diagnostic workup be reduced by use of the Society of Radiologists in Ultrasound recommendations and the three-tiered system?. AJR Am J Roentgenol. 202(1):18-24, 2014 Jan. |
Observational-Dx |
390 patients |
To determine the number of thyroid nodule workups that could be eliminated and the number of malignant tumors that would be missed if the Society of Radiologists in Ultrasound (SRU) recommendations and the three-tiered system were applied to incidental thyroid nodules (ITN) detected at imaging. |
In this study 114 of 390 (29%) patients had nodules first detected incidentally during imaging studies, and 107 patients met the inclusion criteria. These patients had 47 ITN seen at ultrasound and 60 ITN seen at either CT, MRI, or PET/CT. If the SRU recommendations had been applied, 14 of 47 (30%) patients with ITN on ultrasound images would not have received fine-needle aspiration and one of four cases of cancer would have been missed. The missed malignant tumor was a 14-mm localized papillary carcinoma. If the three-tiered system had been applied, 21 of 60 (35%) patients with ITN on CT, MR, or PET/CT images would not have received fine-needle aspiration, but none of the three malignancies would have been missed. Overall, 35 of 107 (33%) of patients with ITN did not meet the SRU recommendations or the three-tiered criteria. |
3 |
| 4. Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M, Dal Maso L. Worldwide Thyroid-Cancer Epidemic? The Increasing Impact of Overdiagnosis. N Engl J Med. 375(7):614-7, 2016 Aug 18. |
Review/Other-Dx |
N/A |
To review the Increasing Impact of Overdiagnosis. |
No results stated in abstract. |
4 |
| 5. Sosa JA, Hanna JW, Robinson KA, Lanman RB. Increases in thyroid nodule fine-needle aspirations, operations, and diagnoses of thyroid cancer in the United States. Surgery. 154(6):1420-6; discussion 1426-7, 2013 Dec. |
Review/Other-Dx |
N/A |
To provide population-based estimates of trends in thyroid nodule fine-needle aspirations (FNA) and operative volumes, we used multiple claims databases to quantify rates of these procedures and their association with the increasing incidence of thyroid cancer in the United States. |
Use of thyroid FNA more than doubled during the 5-year study period (16% annual growth). The number of thyroid operations performed for thyroid nodules increased by 31%. Total thyroidectomies increased by 12% per year, whereas lobectomies increased only 1% per year. In 2011, total thyroidectomies accounted for more than half (56%) of the operations for thyroid neoplasms in the United States. Thyroid operations became increasingly (62%) outpatient procedures. |
4 |
| 6. Deandreis D, Al Ghuzlan A, Leboulleux S, et al. Do histological, immunohistochemical, and metabolic (radioiodine and fluorodeoxyglucose uptakes) patterns of metastatic thyroid cancer correlate with patient outcome?. Endocr Relat Cancer. 18(1):159-69, 2011 Feb. |
Observational-Dx |
80 patients |
To search for relationships between histology, radioiodine ((131)I) uptake, fluorodeoxyglucose (FDG) uptake, and disease outcome in patients with metastatic thyroid cancer. |
Eighty patients with metastatic thyroid cancer (34 males, 46 females, mean age at the time of the diagnosis of metastases: 55 years) were retrospectively studied. All patients were treated with radioactive iodine and evaluated by FDG-positron emission tomography (PET). Primary tumor tissue sample was available in all cases. Forty-five patients (56%) had a papillary, 12 (15%) a follicular, and 23 (29%) a poorly differentiated thyroid cancer. Cellular atypias, necrosis, mitoses, thyroid capsule infiltration, and vascular invasion were frequently detected (70, 44, 52, 60, and 71% respectively). Metastases disclosed FDG uptake in 58 patients (72%) and (131)I uptake in 37 patients (45%). FDG uptake was the only significant prognostic factor for survival (P=0.02). The maximum standardized uptake value and the number of FDG avid lesions were also related to prognosis (P=0.03 and 0.009). Age at the time of the diagnosis of metastases (P=0.001) and the presence of necrosis (P=0.002) were independent predictive factors of FDG uptake. Radioiodine uptake was prognostic for stable disease (P=0.001) and necrosis for progressive disease at 1 year (P=0.001). Histological subtype was not correlated with in vivo tumor metabolism and prognosis. In conclusion, FDG uptake in metastatic thyroid cancer is highly prognostic for survival. Histological subtype alone does not correlate with (131)I/FDG uptake pattern and patient outcome. Well-differentiated thyroid cancer presenting histological features such as necrosis and FDG uptake on PET scan should be considered aggressive differentiated cancers. |
2 |
| 7. Hoang JK, Langer JE, Middleton WD, et al. Managing incidental thyroid nodules detected on imaging: white paper of the ACR Incidental Thyroid Findings Committee. J. Am. Coll. Radiol.. 12(2):143-50, 2015 Feb. |
Review/Other-Dx |
N/A |
To review the interpretation and management of thyroid nodules, but to provide general guidance for managing incidentally discovered thyroid nodules (ITNs). |
No results stated in the abstract |
4 |
| 8. Tessler FN, Middleton WD, Grant EG, et al. ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS Committee. J Am Coll Radiol. 2017;14(5):587-595. |
Review/Other-Dx |
N/A |
To provide guidance regarding management of thyroid nodules on the basis of their ultrasound appearance. |
No results stated in the abstract. |
4 |
| 9. Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM. Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013. JAMA. 317(13):1338-1348, 2017 04 04. |
Review/Other-Dx |
77 276 patients |
To compare trends in thyroid cancer incidence and mortality by tumor characteristics at diagnosis. |
Among 77?276 patients (mean [SD] age at diagnosis, 48 [16] years; 58?213 [75%] women) diagnosed with thyroid cancer from 1974-2013, papillary thyroid cancer was the most common histologic type (64?625 cases), and 2371 deaths from thyroid cancer occurred during 1994-2013. Thyroid cancer incidence increased, on average, 3.6% per year (95% CI, 3.2%-3.9%) during 1974-2013 (from 4.56 per 100?000 person-years in 1974-1977 to 14.42 per 100?000 person-years in 2010-2013), primarily related to increases in papillary thyroid cancer (annual percent change, 4.4% [95% CI, 4.0%-4.7%]). Papillary thyroid cancer incidence increased for all SEER stages at diagnosis (4.6% per year for localized, 4.3% per year for regional, 2.4% per year for distant, 1.8% per year for unknown). During 1994-2013, incidence-based mortality increased 1.1% per year (95% CI, 0.6%-1.6%) (from 0.40 per 100?000 person-years in 1994-1997 to 0.46 per 100?000 person-years in 2010-2013) overall and 2.9% per year (95% CI, 1.1%-4.7%) for SEER distant stage papillary thyroid cancer. |
4 |
| 10. American College of Radiology. ACR Appropriateness Criteria®: Neuroendocrine Imaging. Available at: https://acsearch.acr.org/docs/69485/Narrative/. |
Review/Other-Dx |
N/A |
Evidence-based guidelines to assist referring physicians and other providers in making the most appropriate imaging or treatment decision for a specific clinical condition. |
No abstract available. |
4 |
| 11. Sohn SY, Choi JH, Kim NK, et al. The impact of iodinated contrast agent administered during preoperative computed tomography scan on body iodine pool in patients with differentiated thyroid cancer preparing for radioactive iodine treatment. Thyroid. 24(5):872-7, 2014 May. |
Review/Other-Dx |
1023 patients |
T investigate the impact of ICAs administered at preoperative computed tomography (CT) scan on the body iodine pool to determine the proper time interval between preoperative CT and RAIT in DTC patients. |
The median (interquartile range) of UIE (µg/gCr) in each group was 44.4 (27.7-73.2) in group A, 33.3 (22.8-64.7) in group B, 32.7 (20.8-63.0) in group C, 32.0 (20.6-67.0) in group D, and 30.4 (19.6-70.8) in group E. There was no significant difference between group A and the remaining groups (p>0.05) Also, the proportion of patients who achieved the appropriate UIE for RAIT according to our hospital's cutoff (=66.2?µg/gCr) was not different between groups (A, 72.4%; B, 76.1%; C, 77.5%; D, 74.8%; E, 74.6%) (p=0.78). |
4 |
| 12. Padovani RP, Kasamatsu TS, Nakabashi CC, et al. One month is sufficient for urinary iodine to return to its baseline value after the use of water-soluble iodinated contrast agents in post-thyroidectomy patients requiring radioiodine therapy. Thyroid. 22(9):926-30, 2012 Sep. |
Observational-Dx |
25 patients |
To evaluate the period required for urinary iodine (UI) levels to return to baseline values and to compare UI samples collected by 24U or urinary sample (sU) in the follow-up of differentiated thyroid cancer (DTC) patients (treated with total thyroidectomy and radioiodine) who have employed computed tomography (CT) using iodinated contrast agents (ICA) for evaluation of metastases. |
Baseline median UI levels were 21.8 mug/dL for 24U and 26 mug/dL for sU. One week after ICA, UI median levels were very high for all patients, 800 mug/dL. One month after ICA, however, UI median levels returned to baseline in all patients, 19.0 mug/dL for 24U and 20 mug/dL for sU. Although the values of median UI obtained from sU and 24U samples were signicantly different, we observed a significant correlation between samples collected in 24U and sU in all evaluated periods. |
3 |
| 13. Rhee CM, Bhan I, Alexander EK, Brunelli SM. Association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism. Arch Intern Med. 172(2):153-9, 2012 Jan 23. |
Review/Other-Dx |
4096 patients intervals |
To investigate the the association between iodinated contrast media exposure and incident hyperthyroidism and hypothyroidism. |
In total, 178 and 213 incident hyperthyroid and hypothyroid cases, respectively, were matched to 655 and 779 euthyroid controls, respectively. Iodinated contrast media exposure was associated with incident hyperthyroidism (odds ratio [OR], 1.98; 95% CI, 1.08-3.60), but a statistically significant association with incident hypothyroidism was not observed (OR, 1.58; 95% CI, 0.95-2.62). In prespecified secondary analysis, iodinated contrast media exposure was associated with incident overt hyperthyroidism (follow-up thyrotropin level = 0.1 mIU/L; OR, 2.50; 95% CI, 1.06-5.93) and with incident overt hypothyroidism (follow-up thyrotropin level >10 mIU/L; OR, 3.05; 95% CI, 1.07-8.72). |
4 |
| 14. American College of Radiology. ACR–SPR Practice Parameter for the Performance of Scintigraphy and Uptake Measurement for Benign and Malignant Thyroid Disease. Available at: https://gravitas.acr.org/PPTS/GetDocumentView?docId=60+&releaseId=2 |
Review/Other-Dx |
N/A |
Evidence-based guidelines to assist referring physicians and other providers in making the most appropriate imaging or treatment decision for a specific clinical condition. |
No abstract available. |
4 |
| 15. Lin JS, Bowles EJA, Williams SB, Morrison CC. Screening for Thyroid Cancer: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. [Review]. JAMA. 317(18):1888-1903, 2017 05 09. |
Meta-analysis |
67 studies |
To systematically review the benefits and harms associated with thyroid cancer screening and treatment of early thyroid cancer in asymptomatic adults to inform the US Preventive Services Task Force. |
Of 10?424 abstracts, 707 full-text articles were reviewed, and 67 studies were included for this review. No fair- to good-quality studies directly examined the benefit of thyroid cancer screening. In 2 studies (n?=?354), neck palpation was not sensitive to detect thyroid nodules. In 2 methodologically limited studies (n?=?243), a combination of selected high-risk sonographic features was specific for thyroid malignancy. Three studies (n?=?5894) directly addressed the harms of thyroid cancer screening, none of which suggested any serious harms from screening or ultrasound-guided fine-needle aspiration. No screening studies directly examined the risk of overdiagnosis. Two observational studies (n?=?39?211) included cohorts of persons treated for well-differentiated thyroid cancer and persons with no surgery or surveillance; however, these studies did not adjust for confounders and therefore were not designed to determine if earlier or immediate treatment vs delayed or no surgical treatment improves patient outcomes. Based on 36 studies (n?=?43?295), the 95% CI for the rate of surgical harm was 2.12 to 5.93 cases of permanent hypoparathyroidism per 100 thyroidectomies and 0.99 to 2.13 cases of recurrent laryngeal nerve palsy per 100 operations. Based on 16 studies (n?=?291?796), treatment of differentiated thyroid cancer with radioactive iodine is associated with a small increase in risk of second primary malignancies and with increased risk of permanent adverse effects on the salivary gland, such as dry mouth. |
Good |
| 16. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. [Review]. Thyroid. 26(1):1-133, 2016 Jan. |
Review/Other-Dx |
N/A |
To inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. |
The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. |
4 |
| 17. Chen AY, Bernet VJ, Carty SE, et al. American Thyroid Association statement on optimal surgical management of goiter. Thyroid. 24(2):181-9, 2014 Feb. |
Review/Other-Dx |
N/A |
To discuss optimal surgical management of goiter. |
Surgical management is recommended for goiters with compressive symptoms. Symptoms of dyspnea, orthopnea, and dysphagia are more commonly associated with thyromegaly, in particular, substernal goiters. Several studies have demonstrated improved breathing and swallowing outcomes after thyroidectomy. With careful preoperative testing and thoughtful consideration of the type of anesthesia, including the type of intubation, preparation for surgery can be optimized. In addition, planning the extent of surgery and postoperative care are necessary to achieve optimal results. Close collaboration of an experienced surgical and anesthesia team is essential for induction and reversal of anesthesia. In addition, this team must be cognizant of complications from massive goiter surgery such as bleeding, airway distress, recurrent laryngeal nerve injury, and transient hypoparathyroidism. With careful preparation and teamwork, successful thyroid surgery can be achieved. |
4 |
| 18. Atkins HL, Klopper JF, Lambrecht RM, Wolf AP. A comparison of technetium 99M and iodine 123 for thyroid imaging. Am J Roentgenol Radium Ther Nucl Med 1973;117:195-201. |
Observational-Dx |
100 patients |
To compare technetium 99M and iodine 123 for thyroid imaging. |
No results were stated in the abstract. |
2 |
| 19. Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis. Thyroid. 2016;26(10):1343-1421. |
Review/Other-Dx |
N/A |
To describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. |
Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. |
4 |
| 20. McKee A, Peyerl F. TSI assay utilization: impact on costs of Graves' hyperthyroidism diagnosis. Am J Manag Care. 2012;18(1):e1-14. |
Observational-Dx |
N/A |
To understand whether incorporating a test that specifically detects TSIs into existing algorithms results in cost savings and reduces time to diagnosis for payers and managed care organizations. |
Compared with non-TSI algorithms, 100% use of algorithms that include the TSI test result in 46% faster time to diagnosis and generate 47% overall cost savings due in large part to reductions in costly procedures and specialist office visits. |
2 |
| 21. Erdogan MF, Anil C, Cesur M, Baskal N, Erdogan G. Color flow Doppler sonography for the etiologic diagnosis of hyperthyroidism. Thyroid. 17(3):223-8, 2007 Mar. |
Review/Other-Dx |
55 patients |
To determine the value of Color flow Doppler sonography for the etiological diagnosis of hyperthyroidism. Fifty-five patients with hyperthyroidism (29 Graves' disease [GD] and 26 toxic adenoma [TA]), 24 patients with Hashimoto's thyroiditis (HT), and 39 euthyroid controls were included. Etiological diagnoses were carried out using standard methods. Conventional gray scale sonography was performed, followed by CFDS. Doppler patterns of the glands were scored and peak systolic velocity (PSV) measurements were obtained from intrathyroidal, perithyroidal, and perinodular vasculature |
Vascular patterns were significantly more prominent, and the mean PSV values were significantly higher in the GD patients compared to the HT patients ( p < 0.001) and controls ( p < 0.001). Perinodular and intranodular signals and the mean perinodular PSV values were significantly higher in TAs compared to controls. CFDS could differentiate the untreated GD from the HT, which had similar gray scale findings. Hot nodules could also be differentiated from cold nodules with more prominent vascular patterns and significantly higher PSV values. |
4 |
| 22. Ota H, Amino N, Morita S, et al. Quantitative measurement of thyroid blood flow for differentiation of painless thyroiditis from Graves' disease. Clin Endocrinol (Oxf). 2007;67(1):41-45. |
Review/Other-Dx |
139 patients |
To investigate the possibility that assessment of thyroid blood flow would allow differentiation between the two entities. |
TBF was significantly higher in Graves' disease (mean +/- 1SD: 14.9 +/- 6.4%, P < 0.0001) than in painless thyroiditis (0.8 +/- 0.5%), subacute thyroiditis (0.9 +/- 0.7%) and in normal controls (0.8 +/- 0.5%). All patients with Graves' disease had TBF values of more than 4% and all patients with painless thyroiditis and subacute thyroiditis had TBF values less than 4%. TBF values significantly correlated with values of radioactive iodine uptake (RAIU) either at 3 h (r = 0.492, P < 0.01) or 24 h (r = 0.762, P < 0.001) within the Graves' disease and painless thyroiditis groups. There was no relationship between TBF values and thyroid volumes or values of TBII in the Graves' disease group. All patients with Graves' disease had positive TBII of 15% or more. Three of 28 patients with painless thyroiditis and one of 30 patients with subacute thyroiditis had positive TBII. |
4 |
| 23. Kurita S, Sakurai M, Kita Y, et al. Measurement of thyroid blood flow area is useful for diagnosing the cause of thyrotoxicosis. Thyroid. 15(11):1249-52, 2005 Nov. |
Observational-Dx |
32 patients |
To to differentiate Graves' disease (GD) and destruction-induced thyrotoxicosis (DT) in patients with thyrotoxicosis by utilized color Doppler ultrasonography (CDU) to evaluate the thyroid blood flow area (TBFA) quantitatively. |
We studied 32 patients with diffuse toxic goiter, 21 with GD in the euthyroid state, 12 with chronic thyroiditis in the euthyroid state, and 31 normal individuals. TBFA was calculated as (thyroid blood flow area/thyroid area) × 100%. CDU showed high sensitivity (84%) and specificity (90%) in distinguishing GD from DT when TBFA was between 7.7% and 8.8%. Using CDU to diagnose GD in cases with TBFA =8% or positive serum anti-thyrotropin receptor antibody (TRAb), the sensitivity was 95% and the specificity was 90%, which are similar results to those obtained when GD was diagnosed by radioactive iodine uptake (sensitivity 100%, specificity 90%). Therefore, CDU is a more useful and economical method of distinguishing GD patients with TBFA of 8% or above from DT than measurement of TRAb or radioactive iodine uptake |
2 |
| 24. Alzahrani AS, Ceresini G, Aldasouqi SA. Role of ultrasonography in the differential diagnosis of thyrotoxicosis: a noninvasive, cost-effective, and widely available but underutilized diagnostic tool. [Review]. Endocr Pract. 18(4):567-78, 2012 Jul-Aug. |
Review/Other-Dx |
N/A |
To review the relevant literature and share our own experience to highlight the promising role of ultrasonography in thyrotoxicosis. In addition, we present a diagnostic algorithm suggesting liberal use of ultrasonography in the evaluation of thyrotoxicosis. |
Ultrasonography has proved effective not only in the differentiation of Graves disease from other types and causes of thyrotoxicosis but also in the detection of subtle thyroid nodules. The latter role is emphasized in light of the recent observation of an increased risk of occurrence of papillary thyroid carcinoma in patients with Graves disease. |
4 |
| 25. Kravets I.. Hyperthyroidism: Diagnosis and Treatment. [Review]. Am Fam Physician. 93(5):363-70, 2016 Mar 01. |
Review/Other-Dx |
N/A |
To review the diagnosis and treatment options for hyperthyroidism |
No results stated in the abstract. |
4 |
| 26. Intenzo C, Jabbour S, Miller JL, et al. Subclinical hyperthyroidism: current concepts and scintigraphic imaging. [Review]. Clin Nucl Med. 36(9):e107-13, 2011 Sep. |
Review/Other-Dx |
N/A |
To identify the current concepts and scintigraphic imaging of hyperthyroidism. |
No results stated in the abstract. |
4 |
| 27. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.[Erratum appears in Thyroid. 2010 Jun;20(6):674-5], [Erratum appears in Thyroid. 2010 Aug;20(8):942 Note: Hauger, Bryan R [corrected to Haugen, Bryan R]]. Thyroid. 19(11):1167-214, 2009 Nov. |
Review/Other-Tx |
N/A |
Revised American Thyroid Association management guidelines for patients with thyroid nodules and DTC. |
The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. |
4 |
| 28. Kouvaraki MA, Shapiro SE, Fornage BD, et al. Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery. 2003;134(6):946-954; discussion 954-945. |
Observational-Dx |
212 patients |
To review the preoperative transcutaneous ultrasonography and physical examination (PE) results in the detection of local-regional metastases (lymph node and soft tissue) in patients with thyroid cancer. |
Two hundred twelve patients underwent operation for primary, persistent, or recurrent papillary (n=130), medullary (n=61), or follicular/Hürthle cell (n=21) carcinoma. Ultrasonography detected additional sites of metastatic disease not appreciated on PE in 21 (20%) of 107 group 1 patients, 9 (32%) of 28 group 2 patients, and 52 (68%) of 77 group 3 patients. The surgical procedure performed was altered by the information obtained from preoperative ultrasonography in 82 (39%) of the 212 patients. Of the 107 group 1 patients, cervical recurrence has been detected in only 6 (6%) at a median follow-up of 36 months, in spite of 67 (63%) having tumors larger than 2 cm or lymph node metastases. |
2 |
| 29. Choi JS, Kim J, Kwak JY, Kim MJ, Chang HS, Kim EK. Preoperative staging of papillary thyroid carcinoma: comparison of ultrasound imaging and CT. AJR Am J Roentgenol. 193(3):871-8, 2009 Sep. |
Observational-Dx |
299 patients |
To compare the diagnostic accuracy of ultrasound imaging with that of CT in the preoperative evaluation of primary tumors and cervical lymph nodes in patients with papillary thyroid carcinoma and to determine whether CT has greater diagnostic value than ultrasound alone in the care of these patients. |
Ultrasound was more accurate than CT in prediction of the presence of extrathyroidal tumor extension and of malignant disease in both thyroid lobes (p < 0.05) for overall lesions and for the two subgroups. In prediction of central node (neck level VI) metastasis, CT had greater sensitivity than ultrasound alone (p = 0.04) for overall lesions. Although the combination of ultrasound and CT had greater sensitivity than ultrasound alone in prediction of the presence of central node metastasis in the two subgroups, the sensitivity of the combination of ultrasound and CT did not reach statistical significance for papillary thyroid microcarcinoma. Ultrasound alone and ultrasound with CT had greater sensitivity than CT in prediction of lateral node (levels II-V) metastasis, but there was no significant difference in diagnostic value between ultrasound and the combination of ultrasound and CT for overall lesions or for the two subgroups (p > 0.05). |
2 |
| 30. Kim E, Park JS, Son KR, Kim JH, Jeon SJ, Na DG. Preoperative diagnosis of cervical metastatic lymph nodes in papillary thyroid carcinoma: comparison of ultrasound, computed tomography, and combined ultrasound with computed tomography. Thyroid. 18(4):411-8, 2008 Apr. |
Observational-Dx |
165 patients |
To determine the diagnostic accuracies of US, CT, and combined US and CT (US/CT) for detecting metastatic neck nodes in patients with PTC. |
In terms of predicting node metastases, overall sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of US were 51%, 92%, 77%, 81%, and 76%, respectively. Those of CT were 62%, 93%, 81%, 84%, and 80%, respectively, and those of US/CT were 66%, 88%, 79%, 77%, and 81%, respectively, at all neck levels. US/CT significantly increased sensitivity and demonstrated similar specificity compared with US alone in lateral neck levels (p = 0.02 and p = 1.0, respectively). US/CT increased sensitivity (p = 0.01), but decreased specificity compared with US alone in the central neck levels (p = 0.02). CT provided additional benefit for detecting metastatic nodes at more than one level in 8% of all patients, in 14% of patients with suspected nodal metastasis on US, and in 25% of patients with metastatic lymph nodes. |
2 |
| 31. Kocharyan D, Schwenter F, Belair M, Nassif E. The relevance of preoperative ultrasound cervical mapping in patients with thyroid cancer. Can J Surg. 59(2):113-7, 2016 Apr. |
Observational-Dx |
263 patients |
To perform a qualitative and quantitative analysis of ultrasound mapping for thyroid cancer and evaluate the clinical importance of this exam in terms of identifying the group of patients who would benefit most from subsequent surgical dissection. |
A total of 136 cases of thyroid cancer in 120 patients met the inclusion criteria for ultrasound mapping analysis. The PPVs (and 95% confidence intervals) were 83.82 (0.76-0.89) for the lateral and central compartments, 85.39% (0.76-0.91) for the lateral compartment, and 80.48% (0.7-0.87) for the central compartment. When comparing the positive lymph nodes at ultrasound imaging with histopathologic evaluation, the result was ?(2) = 10.33 (p = 0.006). |
2 |
| 32. Lee DW, Ji YB, Sung ES, et al. Roles of ultrasonography and computed tomography in the surgical management of cervical lymph node metastases in papillary thyroid carcinoma. Eur J Surg Oncol. 39(2):191-6, 2013 Feb. |
Observational-Dx |
252 patients |
To evaluate the impact of preoperative ultrasonography (US) and computed tomography (CT) on the surgical management of cervical lymph node metastases in PTC. |
The sensitivity of both imaging techniques was lower in the central neck (US 23%, CT 41%) than in the lateral neck (US 70%, CT 82%). The specificities of US and CT were 97% and 90% in the central neck, and 84% and 64% in the lateral neck, respectively. Our surgical plans for therapeutic neck dissection were based on imaging findings in 59% of patients who underwent lateral compartment neck dissection and in 32.1% of patients who underwent central compartment neck dissection, respectively. |
2 |
| 33. Lesnik D, Cunnane ME, Zurakowski D, et al. Papillary thyroid carcinoma nodal surgery directed by a preoperative radiographic map utilizing CT scan and ultrasound in all primary and reoperative patients. Head Neck. 36(2):191-202, 2014 Feb. |
Observational-Dx |
162 patients |
To study the diagnostic accuracy of physical examination (PE), ultrasonography (US), contrastenhanced computed tomography (CT) and in preoperative detection of macroscopic nodal metastasis in primary/recurrent papillary thyroid carcinoma (PTC) patients to determine if the routine addition of CT would be beneficial in accurate preoperative lymph-node surgery planning |
In patients undergoing primary (Group I)/revision (Group II) surgical treatment for PTC, combined US/CT yielded significantly higher sensitivity for macroscopic lymph-node detection in both lateral and central neck, most marked in Group I-central compartment. |
2 |
| 34. Yeh MW, Bauer AJ, Bernet VA, et al. American Thyroid Association statement on preoperative imaging for thyroid cancer surgery. Thyroid. 25(1):3-14, 2015 Jan. |
Review/Other-Dx |
N/A |
Ultrasound remains the most important imaging modality in the evaluation of thyroid cancer, and should be used routinely to assess both the primary tumor and all associated cervical lymph node basins preoperatively. Positive lymph nodes may be distinguished from normal nodes based upon size, shape, echogenicity, hypervascularity, loss of hilar architecture, and the presence of calcifications. Ultrasound-guided fine-needle aspiration of suspicious lymph nodes may be useful in guiding the extent of surgery. Cross-sectional imaging (computed tomography with contrast or magnetic resonance imaging) may be considered in select circumstances to better characterize tumor invasion and bulky, inferiorly located, or posteriorly located lymph nodes, or when ultrasound expertise is not available. |
Cross-sectional imaging (computed tomography with contrast or magnetic resonance imaging) may be considered in select circumstances to better characterize tumor invasion and bulky, inferiorly located, or posteriorly located lymph nodes, or when ultrasound expertise is not available. |
4 |
| 35. Jeong HS, Baek CH, Son YI, et al. Integrated 18F-FDG PET/CT for the initial evaluation of cervical node level of patients with papillary thyroid carcinoma: comparison with ultrasound and contrast-enhanced CT. Clin Endocrinol (Oxf). 2006;65(3):402-407. |
Observational-Dx |
26 patients |
To compare the diagnostic accuracy of integrated 18F-fluorodeoxyglucose PET/CT with ultrasonography (US) and contrast enhanced CT (CECT) alone in the initial evaluation of cervical lymph node levels of patients with papillary thyroid carcinoma. |
At all lymph node levels (levels I-VI), PET/CT showed a sensitivity of 30.4%, a specificity of 96.2% and a diagnostic accuracy of 86.9%. The corresponding values for US and CECT were 41.3%, 97.4%, 89.1% (US) and 34.8%, 96.2%, 87.2% (CECT). Considering only the lateral cervical node group (levels I-V), PET/CT showed a sensitivity of 50.0%, a specificity of 97.0% and a diagnostic accuracy of 92.3%. The corresponding values for US and CECT were 53.9%, 97.9%, 93.5% (US) and 42.3%, 96.6%, 91.2% (CECT). The diagnostic results for US, CECT and PET/CT upon initial evaluation of the cervical lymph nodes did not differ significantly on a level-by-level basis. |
1 |
| 36. Leboulleux S, Schroeder PR, Busaidy NL, et al. Assessment of the incremental value of recombinant thyrotropin stimulation before 2-[18F]-Fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography imaging to localize residual differentiated thyroid cancer. J Clin Endocrinol Metab. 94(4):1310-6, 2009 Apr. |
Observational-Dx |
63 patients |
To assess prospectively the impact of recombinant human TSH (rhTSH) administration on positron emission tomography (PET)/computed tomography (CT) imaging in differentiated thyroid cancer patients who, after primary treatment, had a suppressed or stimulated serum thyroglobulin greater than 10 ng/ml and no radioactive iodine uptake consistent with thyroid cancer on a whole body scan. |
A total of 108 lesions were detected in 48 organs in 30 patients. rhTSH-PET was significantly more sensitive than basal PET for the detection of lesions (95 vs. 81%; P = 0.001) and tended to be more sensitive for the detection of involved organs (94 vs. 79%; P = 0.054). However, basal PET and rhTSH-PET did not have significantly different sensitivity for detecting patients with any lesions (49 vs. 54%; P = 0.42). Changes in treatment management plan occurred in 19% of the patients after basal PET. Lesions found only by rhTSH-PET contributed to an altered therapeutic plan in eight patients, among whom only four were true-positive on pathology (6%). |
1 |
| 37. Momesso DP, Vaisman F, Yang SP, et al. Dynamic Risk Stratification in Patients with Differentiated Thyroid Cancer Treated Without Radioactive Iodine. J Clin Endocrinol Metab 2016;101:2692-700. |
Review/Other-Dx |
507 patients |
To validate the response to therapy assessment in patients with DTC treated with lobectomy or TT without RAI. |
Recurrent/persistent SED was observed in 0% of the patients with excellent response to therapy (nonstimulated Tg for TT < 0.2 ng/mL and for lobectomy < 30 ng/mL, undetectable Tg antibodies [TgAb] and negative imaging; n = 326); 1.3% with indeterminate response (nonstimulated Tg for TT 0.2-5 ng/mL, stable or declining TgAb and/or nonspecific imaging findings; n = 2/152); 31.6% of the patients with biochemical incomplete response (nonstimulated Tg for TT > 5 ng/mL and for lobectomy > 30 ng/mL and/or increasing Tg with similar TSH levels and/or increasing TgAb and negative imaging; n = 6/19) and all (100%) patients with structural incomplete response (n = 10/10) (P < .0001). Initial American Thyroid Association risk estimates were significantly modified based on response to therapy assessment. |
4 |
| 38. Leger FA, Izembart M, Dagousset F, et al. Decreased uptake of therapeutic doses of iodine-131 after 185-MBq iodine-131 diagnostic imaging for thyroid remnants in differentiated thyroid carcinoma. Eur J Nucl Med. 25(3):242-6, 1998 Mar. |
Observational-Dx |
51 patients |
To performed a prospective random study to assess possible thyroid stunning by a 185-MBq iodine-131 dose used to diagnose thyroid remnants. Patients with differentiated thyroid carcinoma were included after total or near-total thyroidectomy. |
They were randomly assigned to two groups. In group 0 (G0, 32 patients), iodine-123 administration only was used to diagnose thyroid remnants and/or metastasis, so that no thyroid stunning by 131I would occur. In group 1 (G1, 19 patients), diagnostic imaging was performed with 123I and 185 MBq 131I. 123I imaging was less sensitive than 131I imaging in identifying thyroid remnants in both groups (94%). Thyroid uptake of 123I was measured in both groups (at 2 h) and was not significantly different between the groups. Patients with thyroid remnants who remained in the study (28/32 in G0, 17/19 in G1) were treated with 370 MBq 131I, 5 weeks after treatment (mean time, range 12-84 days). In 12/17 G1 patients thyroid uptake measurement was repeated immediately before treatment. Uptake was equal to 1.97% +/- 0.71% and significantly lower (P < 0.05) than the previous measurement (3.76% +/- 1.50%). Patients were imaged 7 days after administration of the therapeutic dose and the images were compared with the diagnostic images. In 28/28 G0 patients thyroid remnants were unchanged and clearly seen. In 5/17 G1 patients, however the remnants were hardly identified, although they had been clearly seen at the time of diagnosis. We conclude the following: (1) a diagnostic dose of 185 MBq 131I decreases thyroid uptake for several weeks after administration and can impair immediate subsequent 131I therapy; (2) 123I is slightly less sensitive than 131I in identifying thyroid remnants; and (3) the need to scan for thyroid remnants remains to be confirmed, since only 2/51 patients enrolled in this study were not treated with 131I. |
2 |
| 39. Silberstein EB.. Comparison of outcomes after (123)I versus (131)I pre-ablation imaging before radioiodine ablation in differentiated thyroid carcinoma. J Nucl Med. 48(7):1043-6, 2007 Jul. |
Observational-Dx |
50 patients |
To examine the outcomes of ablative (131)I therapy after diagnostic studies with either (123)I or (131)I to determine if the diagnostic dosages of these radionuclides used in our Thyroid Cancer Center reduce the efficacy of (131)I given for remnant ablation. |
There was no significant difference between the 2 groups demographically, in tumor burden or stage, or in the post-thyroidectomy ablation rate (group 1, 81%; group 2, 74%; P > 0.05). |
2 |
| 40. Alzahrani AS, AlShaikh O, Tuli M, Al-Sugair A, Alamawi R, Al-Rasheed MM. Diagnostic value of recombinant human thyrotropin-stimulated 123I whole-body scintigraphy in the follow-up of patients with differentiated thyroid cancer. Clin Nucl Med. 37(3):229-34, 2012 Mar. |
Observational-Dx |
105 patients |
To evaluate iodine-123 (¹²³I) diagnostic whole-body scintigraphy in the follow- up of patients with differentiated thyroid cancer. |
rhTSH-aided ¹²³I DxWBS scans showed 35.3% sensitivity, 98.0% specificity, 85.7% positive predictive value, and 81.6% negative predictive value. rhTSH-stimulated ¹²³I and ¹³¹I DxWBS did not differ in scan positivity (10.4% vs. 13.2%, P = 0.75) or disease detection rates (35.3% vs. 27.8%, P = 1.00). |
2 |
| 41. Mandel SJ, Shankar LK, Benard F, Yamamoto A, Alavi A. Superiority of iodine-123 compared with iodine-131 scanning for thyroid remnants in patients with differentiated thyroid cancer. Clin Nucl Med 2001;26:6-9. |
Observational-Dx |
14 patients |
To compare the performance of I-123 and I-131 as imaging agents for whole-body scanning in patients with differentiated thyroid cancer undergoing ablation for thyroid remnants after initial surgery. |
The diagnostic scans revealed 35 foci in the thyroid bed and neck. The I-123 images showed all 35 foci, but only 32 of the 35 foci (91 %) were seen on the I-131 scans. The findings of pre- and post-therapy scans were concordant in 11 of 13 patients, and the same general sites of uptake (left and right thyroid bed, midline) were revealed on both sets of images. In one patient, a focus seen on the diagnostic I-123 and I-131 images was not visualized on the post-therapy scan and was thought to represent possible stunning. An additional area of uptake in the lower right neck and upper mediastinum was present on the post-therapy scan of another patient, but it was not seen on diagnostic images. |
4 |
| 42. Fatourechi V, Hay ID, Mullan BP, et al. Are posttherapy radioiodine scans informative and do they influence subsequent therapy of patients with differentiated thyroid cancer?. Thyroid. 10(7):573-7, 2000 Jul. |
Review/Other-Dx |
81 patients |
To review posttherapy radioiodine scans. |
A total of 117 PTS were evaluated. At the time of PTS, clinical or radiologic evidence of metastatic or residual disease was present in 68 patients (84%). The anatomic sites of known disease included, neck (63), mediastinum (23), lung (35), bone (14), trachea (16), esophagus (5), and brain (2). PTS showed focal areas of abnormal uptake not seen in diagnostic scans in 15 scans (13%). Areas with abnormal new uptake included: neck (5), lung (5), mediastinum (4), bone (2), and adrenal (1). In 7 patients (9%) the PTS results impacted future decisions regarding plans for subsequent diagnostic scanning and 131I therapy or changed the patient's risk group category. |
4 |
| 43. Sherman SI, Tielens ET, Sostre S, Wharam MD Jr, Ladenson PW. Clinical utility of posttreatment radioiodine scans in the management of patients with thyroid carcinoma. J Clin Endocrinol Metab. 78(3):629-34, 1994 Mar. |
Review/Other-Dx |
93 patients |
To review the clinical utility of posttreatment radioiodine scans in the management of patients with thyroid. |
No results stated in abstract. |
4 |
| 44. Souza Rosario PW, Barroso AL, Rezende LL, et al. Post I-131 therapy scanning in patients with thyroid carcinoma metastases: an unnecessary cost or a relevant contribution?. Clin Nucl Med. 29(12):795-8, 2004 Dec. |
Experimental-Dx |
160 patients |
To review the post I-131 therapy scanning in patients with thyroid carcinoma metastases. |
Posttherapy scanning on first ablation changed the disease stage in 8.3% of the patients and therapeutic approach in another 15%, and provided clinically relevant information for 26% of patients with 1 previous ablation. Even when excluding cases whose lesions were known by the time of the first postablative scan, the therapeutic approach was influenced by posttherapy scanning in 15.6% of the patients. Only 4 of 211 metastases detected on pretherapy WBS did not appear on postablative scans. |
2 |
| 45. Schvartz C, Bonnetain F, Dabakuyo S, et al. Impact on overall survival of radioactive iodine in low-risk differentiated thyroid cancer patients. J Clin Endocrinol Metab. 97(5):1526-35, 2012 May. |
Observational-Tx |
1298 patients. |
To assess the survival benefit of radioactive iodine (RAI) for low-risk differentiated thyroid cancer (DTC) patients. |
Median follow-up was 10.3 yr. Nine hundred eleven patients received RAI after surgery vs. 387 patients without RAI after surgery. Using univariate analysis, 10-yr OS was found to be 95.8% in patients without RAI after surgery vs. 94.6% in RAI after surgery (P = 0.006), and 10-yr DFS was found to be 93.1% vs. 88.7% (P = 0.001). All clinical factors except sex were significantly associated with RAI. Using multivariate Cox analyses, RAI was neither significantly nor independently associated with OS (P = 0.243) and DFS (P = 0.2659). After stratification on propensity score, Cox univariate analyses showed that OS did not differ according to RAI (P = 0.3524), with a hazard ratio for RAI of 0.75 (95% confidence interval 0.40-1.38). Similarly, DFS did not differ (P = 0.48) with a stratified univariate hazard ratio of 1.11 (95% confidence interval 0.73-1.70). |
2 |
| 46. Tuttle RM, Tala H, Shah J, et al. Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid. 20(12):1341-9, 2010 Dec. |
Review/Other-Dx |
588 patients |
To validate the American Thyroid Association (ATA) risk of recurrence staging system and determine if an assessment of response to therapy during the first 2 years of follow-up can modify these initial risk estimates. |
Persistent structural disease or recurrence was identified in 3% of the low-risk, 21% of the intermediate-risk, and 68% of the high-risk patients (p < 0.001). Re-stratification during the first 2 years of follow-up reduced the likelihood of finding persistent structural disease or recurrence to 2% in low-risk, 2% in intermediate-risk, and 14% in high-risk patients, demonstrating an excellent response to therapy (stimulated Tg < 1 ng/mL without structural evidence of disease). Conversely, an incomplete response to initial therapy (suppressed Tg > 1 ng/mL, stimulated Tg > 10 ng/mL, rising Tg values, or structural disease identification within the first 2 years of follow-up) increased the likelihood of persistent structural disease or recurrence to 13% in low-risk, 41% in intermediate-risk, and 79% in high-risk patients. |
4 |
| 47. Vaisman F, Shaha A, Fish S, Michael Tuttle R. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer. Clin Endocrinol (Oxf). 75(1):112-9, 2011 Jul. |
Review/Other-Dx |
2898 patients |
To describe the risk of structural disease recurrence in a cohort of patients with differentiated thyroid cancer selected for treatment with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation (RRA). |
After a 5-year median follow-up, structural disease recurrence was detected in 2.3% (5/217) of patients treated with total thyroidectomy without RRA, and in 4.2% (3/72) of patients treated with thyroid lobectomy. Size of the primary tumour, the presence of cervical lymph node metastases and American Thyroid Association risk category were all statistically significant predictors of recurrence. Changes in serum thyroglobulin were not helpful in identifying the presence of persistent/recurrent structural disease. Importantly, 88% (7/8) of the patients that had recurrent disease were rendered clinically disease free with additional therapies. |
4 |
| 48. Ahn JE, Lee JH, Yi JS, et al. Diagnostic accuracy of CT and ultrasonography for evaluating metastatic cervical lymph nodes in patients with thyroid cancer. World J Surg. 32(7):1552-8, 2008 Jul. |
Observational-Dx |
37 patients |
To investigate the diagnostic ability of computed tomography (CT) and ultrasonography (USG) in the preoperative evaluation of the cervical nodal status of patients with thyroid cancer. |
By "per level" analysis, the sensitivities, specificities, and diagnostic accuracies were 77%, 70%, 74% for CT and 62%, 79%, 68% for USG, respectively, with a significant difference in the sensitivities (p = 0.002). When the lymph node levels were grouped into central and lateral compartments, all of the values for the lateral compartment tended to be higher than those for the central compartment for both CT (78%, 78%, 78% versus 74%, 44%, 64%) and USG (65%, 82%, 71 versus 55%, 69%, 60%). By per patient analysis, the sensitivities, specificities, and diagnostic accuracies of CT and USG were 100%, 90%, 97% and 100%, 80%, 95%, respectively. |
2 |
| 49. Yoshio K, Sato S, Okumura Y, et al. The local efficacy of I-131 for F-18 FDG PET positive lesions in patients with recurrent or metastatic thyroid carcinomas. Clin Nucl Med. 36(2):113-7, 2011 Feb. |
Review/Other-Dx |
37 patients |
To evaluate the local efficacy of I-131 for F-18 fluorodeoxyglucose positron emission tomography (FDG PET)-positive lesions. |
The analysis was performed on 37 patients with 44 lesions (lymph node:24, lung:16, bone:4). Sixteen lesions (70%) were increased and 7 (30%) showed no change or reduction when there was positive accumulation on FDG PET/CT and negative accumulation on I-131 (F(+)I(-)) group. In the positive accumulation for both FDG PET/CT and I-131 (F(+)I(+)) group, 5 lesions (63%) were increased and 3 (37%) showed no change or reduction. There was no significant difference for the tendency to increase in size between the F(+)I(-) and the F(+)I(+) groups. |
4 |
| 50. Schreinemakers JM, Vriens MR, Munoz-Perez N, et al. Fluorodeoxyglucose-positron emission tomography scan-positive recurrent papillary thyroid cancer and the prognosis and implications for surgical management. World J Surg Oncol. 10:192, 2012 Sep 17. |
Observational-Tx |
141 patients |
To compare outcomes for patients with recurrent or persistent PTC who had metastatic tumors that were FDG-PET positive or negative, and to determine whether the FDG-PET scan findings changed the outcome of medical and surgical management. |
Between 1984 and 2008, 41/141 patients who had recurrent or persistent PTC underwent FDG-PET (n=11) or FDG-PET/CT scans (n=30); 22 patients (54%) had one or more PET-positive lesion(s), 17 (41%) had PET-negative lesions, and 2 had indeterminate lesions. Most PET-positive lesions were located in the neck (55%). Patients who had a PET-positive lesion had a significantly higher TNM stage (P=0.01), higher age (P=0.03), and higher thyroglobulin (P=0.024). Only patients who had PET-positive lesions died (5/22 vs 0/17 for PET-negative lesions; P=0.04). In 2/7 patients who underwent surgical resection of their PET-positive lesions, loco-regional control was obtained without evidence of residual disease. |
2 |
| 51. Pellegriti G, Leboulleux S, Baudin E, et al. Long-term outcome of medullary thyroid carcinoma in patients with normal postoperative medical imaging. Br J Cancer. 88(10):1537-42, 2003 May 19. |
Observational-Dx |
63 patients |
To search for prognostic factors of imaging-detected relapse. |
After surgery, the basal calcitonin (CT) level was undetectable in 35 patients and elevated in 28. During follow-up, 18 patients developed a clinical or imaging-detected relapse (29%) in the neck and/or at distant sites: 15 had an elevated postoperative basal CT level and three had an undetectable postoperative basal CT level. At multivariate analysis, the significant parameters predictive of imaging-detected relapse were the postoperative plasma CT level and the tumour extension (pT). The 3- and 5-year relapse-free survival rates were 94 and 90% in patients with an undetectable postoperative basal CT level, and 78 and 61% in patients with a detectable basal CT level (P<0.05). The 3- and 5-year relapse-free survival rates were 92 and 85% in the pT1-3 patients, and 57 and 46% in the pT4 patients (P<0.01). |
3 |
| 52. Sesti A, Mayerhoefer M, Weber M, et al. Relevance of calcitonin cut-off in the follow-up of medullary thyroid carcinoma for conventional imaging and 18-fluorine-fluorodihydroxyphenylalanine PET. Anticancer Res. 34(11):6647-54, 2014 Nov. |
Observational-Dx |
39 patients |
To reaffirm or challenge the basal calcitonin cut-off value (above 150 pg/ml in the follow-up of medullary thyroid carcinoma (MTC)) for 18-Fluorine-Fluorodihydroxyphenylalanine positron emission tomography (18F-DOPA PET) and conventional imaging ultrasonography (US), computed tomography (CT), magnetic resonance imaging (MRI)) |
According to the calcitonin cut-off of 150 pg/ml, we found the following sensitivities and specificities: 79% and 80% for 18F-DOPA PET, 75% and 92% for US, 80% and 25% for CT, 50% and 75% for MRI. Taking the level of detectable calcitonin, we calculated the following sensitivities: 52% for 18F-DOPA PET, 46% for US, 79% for CT and 38% for MRI. |
3 |
| 53. Giraudet AL, Vanel D, Leboulleux S, et al. Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels. J Clin Endocrinol Metab. 92(11):4185-90, 2007 Nov. |
Observational-Dx |
55 patients |
To define optimal imaging procedures. |
Fifty patients underwent neck US, CT, and PET, and neck recurrence was demonstrated in 56, 42, and 32%, respectively. Lung and mediastinum lymph node metastases in the 55 patients were demonstrated in 35 and 31% by CT and in 15 and 20% by PET. Liver imaging with MRI, CT, US, and PET in 41 patients showed liver in 49, 44, 41, and 27% patients, respectively. Bone metastases in 55 patients were demonstrated in 35% by PET, 40% by bone scintigraphy, and 40% by MRI; bone scintigraphy was complementary with MRI for axial lesions but superior for the detection of peripheral lesions. Ten patients had no imaged tumor site despite elevated calcitonin level (median 196 pg/ml; range 39-816). FDG uptake in neoplastic foci was higher in progressive patients but with a considerable overlap with stable ones. |
1 |
| 54. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. [Review]. Thyroid. 25(6):567-610, 2015 Jun. |
Review/Other-Dx |
N/A |
To revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. |
The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. |
4 |
| 55. Vreugdenburg TD, Ma N, Duncan JK, Riitano D, Cameron AL, Maddern GJ. Comparative diagnostic accuracy of hepatocyte-specific gadoxetic acid (Gd-EOB-DTPA) enhanced MR imaging and contrast enhanced CT for the detection of liver metastases: a systematic review and meta-analysis. [Review]. Int J Colorectal Dis. 31(11):1739-1749, 2016 Nov. |
Review/Other-Dx |
N/A |
To evaluate the diagnostic accuracy and impact on patient management of hepatocyte-specific gadoxetic acid enhanced magnetic resonance imaging (GA-MRI) compared to contrast enhanced computed tomography (CE-CT) in patients with liver metastases through systematic review. |
Nine diagnostic accuracy studies (537 patients with 1216 lesions) and four change in management studies (488 patients with 281 lesions) were included. Per-lesion sensitivity and specificity estimates for GA-MRI ranged from 86.9-100.0 % and 80.2-98.0 %, respectively, compared to 51.8-84.6 % and 77.2-98.0 % for CE-CT. Meta-analysis found GA-MRI to be significantly more sensitive than CE-CT (RR = 1.29, 95 % CI = 1.18-1.40, P < 0.001), with equivalent specificity (RR = 0.97, 95 % CI 0.910-1.042, P = 0.44). The largest difference was observed for lesions smaller than 10 mm for which GA-MRI was significantly more sensitive (RR = 2.21, 95 % CI = 1.47-3.32, P < 0.001) but less specific (RR = 0.92, 95 % CI 0.87-0.98, P = 0.008). GA-MRI affected clinical management in 26 of 155 patients (16.8 %) who had a prior CE-CT; however, no studies investigated the consequences of using GA-MRI instead of CE-CT. |
4 |
| 56. Delorme S, Raue F. Medullary Thyroid Carcinoma: Imaging. [Review]. Recent Results Cancer Res. 204:91-116, 2015. |
Review/Other-Dx |
N/A |
To discuss calcitonin-secreting thyroid malignancy, often diagnosed by ultrasound and calcitonin screening as part of the routine workup for any thyroid nodule. |
Postoperative elevated calcitonin is related to persistence or recurrence of MTC. Imaging studies to localize tumor tissue during postoperative follow-up include ultrasound, CT, MRI as well as PET studies. |
4 |
| 57. Mirallie E, Vuillez JP, Bardet S, et al. High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer. J Clin Endocrinol Metab. 2005;90(2):779-788. |
Review/Other-Tx |
35 patients |
To evaluate the rate of BI in MTC patients enrolled in two phase-I/II RIT trials using anti-carcinoembryonic antigen x anti-diethylenetriamine pentaacetic acid bispecific antibodies and [(131)I]di-diethylenetriamine pentaacetic acid hapten. |
Thirty-five patients underwent bone scintigraphy, bone magnetic resonance imaging (MRI), and post-RIT immunoscintigraphy (IS). IS performed in MTC patients was compared with IS conducted in 12 metastatic colorectal carcinoma (CRC) patients. Quantitative analysis of bone uptake was performed in three MTC and three CRC patients. In the MTC group, bone scintigraphy detected BI in 56.6% of patients, MRI in 75.8%, and IS in 88.6%. BI was confirmed by undirected (random) bone marrow biopsy, by bone surgery, or by two positive imaging methods in 74.3% of the patients. Sensitivity per patient of bone scintigraphy, MRI, and IS were 72.7, 100, and 100%, respectively. In contrast, IS visualized BI in only 33.3% of CRC patients; bone uptake was lower in CRC than in MTC patients. Bone MRI combined with post-RIT IS disclosed a much higher BI rate in advanced MTC than previously reported in the literature. |
4 |
| 58. Treglia G, Villani MF, Giordano A, Rufini V. Detection rate of recurrent medullary thyroid carcinoma using fluorine-18 fluorodeoxyglucose positron emission tomography: a meta-analysis. [Review]. Endocrine. 42(3):535-45, 2012 Dec. |
Meta-analysis |
24 studies; 538 patients |
To analyze published data about the diagnostic performance of fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET), and positron emission tomography/computed tomography (PET/CT) in detecting recurrent medullary thyroid carcinoma (MTC). |
Pooled detection rate increased in patients with serum calcitonin = 1,000 ng/L (75 %), CEA = 5 ng/ml (69 %), CTDT <12 months (76 %), and CEADT <24 months (91 %). In patients with suspected recurrent MTC FDG PET and PET/CT are associated with a non-optimal DR since about 40 % of suspected recurrent MTC remain usually unidentified. However, FDG PET and PET/CT could modify the patient management in a certain number of recurrent MTC because these methods are often performed after negative conventional imaging studies. |
Good |
| 59. Koopmans KP, de Groot JW, Plukker JT, et al. 18F-dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer: relation to tumor differentiation. J Nucl Med. 49(4):524-31, 2008 Apr. |
Observational-Dx |
21 patients |
To study the value of 18F-dihydroxyphenylalanine PET (18F-DOPA PET), 18F-FDG PET, (99m)Tc-V-di-mercaptosulfuricacid (DMSA-V) scintigraphy, and MRI or CT. |
In 76% of all patients with MTC, one or more imaging modalities was positive for MTC lesions. In 6 of 8 patients with a calcitonin level of <500 ng/L, imaging results were negative. In 15 patients with positive imaging results, 18F-DOPA PET detected 13 (sensitivity, 62%; with 4.6 lesions per patient [lpp]). Morphologic imaging (n = 19) was positive in 7 (sensitivity, 37%; 4.7 lpp), DMSA-V (n = 18) in 5 (sensitivity, 28%; 1.1 lpp), and 18F-FDG PET (n = 17) in 4 (sensitivity, 24%; 1.6 lpp). In a lesion-based analysis, 18F-DOPA PET detected 95 of 134 lesions (sensitivity, 71%), morphologic imaging detected 80 of 126 (sensitivity, 64%), DMSA-V detected 20 of 108 (sensitivity, 19%), and 18F-FDG PET detected 48 of 102 (sensitivity, 30%). In 2 of 3 patients with a calcitonin/carcinoembryonic antigen (CEA) doubling time of < or =12 mo, 18F-FDG PET performed better than 18FDOPA PET; in the third patient, 18F-FDG PET was not performed. |
1 |
| 60. Ong SC, Schoder H, Patel SG, et al. Diagnostic accuracy of 18F-FDG PET in restaging patients with medullary thyroid carcinoma and elevated calcitonin levels. J Nucl Med. 48(4):501-7, 2007 Apr. |
Observational-Dx |
28 patients |
To review our own experience with (18)F-FDG PET in postthyroidectomy MTC patients with elevated calcitonin. |
Twenty-eight patients underwent a total of 38 (18)F-FDG PET studies. Calcitonin levels ranged from 106 to 541,000 pg/mL (median, 7,260 pg/mL). There were 23 true-positive, 1 false-positive, and 14 false-negative (18)F-FDG PET scans, yielding an overall sensitivity of 62%. There was no true-positive finding when calcitonin levels were below 509 pg/mL (n = 5). Using an arbitrary cutoff of 1,000 pg/mL, we found that the sensitivity in scans with calcitonin levels greater than 1,000 pg/mL increased to 78% (21/27; 95% confidence interval, 58%-91%). The mean SUV of all lesions with (18)F-FDG uptake was 5.3 +/- 3.2 (range, 2.0-15.9). Among the 14 patients with false-negative (18)F-FDG PET findings, 8 had concurrent anatomic imaging studies and only 2 of these had positive findings. |
2 |
| 61. Szakall S Jr, Esik O, Bajzik G, et al. 18F-FDG PET detection of lymph node metastases in medullary thyroid carcinoma. J Nucl Med. 43(1):66-71, 2002 Jan. |
Observational-Dx |
40 patients |
To search for a reliable method to localize tumorous tissue, 18F-FDG PET was applied to detect tumor tissue of residual or recurrent medullary thyroid carcinoma (MTC). |
PET detected 270 foci with a high tracer accumulation, whereas only 116 lesions were detected by MRI and 141 by CT. The numbers of such foci determined by PET, MRI, and CT were 98, 34, and 34, respectively, in the neck; 25, 5, and 6, respectively, in the supraclavicular regions; and 117, 35, and 39, respectively, in the mediastinum. 131I-MIBG scintigraphy findings were positive for only 3 patients. |
3 |
| 62. Rubello D, Rampin L, Nanni C, et al. The role of 18F-FDG PET/CT in detecting metastatic deposits of recurrent medullary thyroid carcinoma: a prospective study. Eur J Surg Oncol. 34(5):581-6, 2008 May. |
Review/Other-Dx |
19 patients |
To assess the diagnostic role of 18F-FDG PET/CT performed with a hybrid tomograph in the detection of tumoral deposits of recurrent medullary thyroid carcinoma (MTC). |
18F-FGD PET/CT depicted metastases in 15 patients, 111In-pentetreotide in 8, c.e. CT in 11, US in 6. In 2 patients, liver micrometastases were detected at laparoscopy only. At a lesion-by-lesion analysis, 18F-FDG PET/CT visualized a total of 26 metastatic deposits, c.e. CT 18, 111In-pentetreotide 12, US 8. Final diagnosis was obtained by cytological or surgical findings. Four patients with evidence of limited metastatic spread to neck/upper mediastinum were re-operated, and in 2 of them serum calcitonin levels normalized. |
4 |
| 63. Beheshti M, Pocher S, Vali R, et al. The value of 18F-DOPA PET-CT in patients with medullary thyroid carcinoma: comparison with 18F-FDG PET-CT. Eur Radiol. 19(6):1425-34, 2009 Jun. |
Review/Other-Tx |
26 patients |
To compare the value of DOPA PET-CT with FDG PET-CT in the detection of malignant lesions in patients with medullary thyroid carcinoma (MTC). |
Overall 59 pathological lesions with abnormal tracer uptake were seen on DOPA and/or FDG PET studies. In the final diagnosis 53 lesions proved to be malignant. DOPA PET correctly detected 94% (50/53) of malignant lesions, whereas only 62% (33/53) of malignant lesions were detected with FDG PET. DOPA PET-CT showed superior results to FDG PET-CT in the preoperative and follow-up assessment of MTC patients. |
4 |
| 64. Treglia G, Castaldi P, Villani MF, et al. Comparison of 18F-DOPA, 18F-FDG and 68Ga-somatostatin analogue PET/CT in patients with recurrent medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging. 39(4):569-80, 2012 Apr. |
Observational-Dx |
18 patients |
To retrospectively evaluate and compare (18)F-FDG, (18)F-DOPA and (68)Ga-somatostatin analogues for PET/CT in patients with residual/recurrent medullary thyroid carcinoma (MTC) suspected on the basis of elevated serum calcitonin levels. |
At least one focus of abnormal uptake was observed on PET/CT in 13 patients with (18)F-DOPA (72.2% sensitivity), in 6 patients with (68)Ga-somatostatin analogues (33.3%) and in 3 patients with (18)F-FDG (16.7%) (p < 0.01). There was a statistically significant difference in sensitivity between (18)F-DOPA and (18)F-FDG PET/CT (p < 0.01) and between (18)F-DOPA and (68)Ga-somatostatin analogue PET/CT (p = 0.04). Overall, 72 lesions were identified on PET/CT with the three tracers. (18)F-DOPA PET/CT detected 85% of lesions (61 of 72), (68)Ga-somatostatin analogue PET/CT 20% (14 of 72) and (18)F-FDG PET/CT 28% (20 of 72). There was a statistically significant difference in the number of lymph node, liver and bone lesions detected with the three tracers (p < 0.01). In particular, post-hoc tests showed a significant difference in the number of lymph node, liver and bone lesions detected by (18)F-DOPA PET/CT and (18)F-FDG PET/CT (p < 0.01 for all the analyses) and by (18)F-DOPA PET/CT and (68)Ga-somatostatin analogue PET/CT (p < 0.01 for all the analyses). The PET/CT results led to a change in management of eight patients (44%). |
2 |
| 65. Verbeek HH, Plukker JT, Koopmans KP, et al. Clinical relevance of 18F-FDG PET and 18F-DOPA PET in recurrent medullary thyroid carcinoma. J Nucl Med. 53(12):1863-71, 2012 Dec. |
Observational-Dx |
47 patients |
To compare (18)F-FDG PET and (18)F-dihydroxyphenylanaline ((18)F-DOPA) PET with biochemical parameters and survival to assess whether these imaging modalities could be of value in detecting progressive disease. |
Doubling times were available for 38 of 40 patients undergoing (18)F-FDG PET. There was a significant correlation with (18)F-FDG PET positivity. Doubling times were less than 24 mo in 77% (n = 10/13) of (18)F-FDG PET-positive patients, whereas 88% (n = 22/25) of (18)F-FDG PET-negative patients had doubling times greater than 24 mo (P < 0.001). Between doubling times and (18)F-DOPA PET positivity, no significant correlation existed. (18)F-DOPA PET detected significantly more lesions (75%, 56/75) than did (18)F-FDG PET (47%, 35/75) in the 21 patients included in WBMTB analysis (P = 0.009). Calcitonin and CEA levels correlated significantly with WBMTB on (18)F-DOPA PET, but doubling times did not. (18)F-FDG PET positivity was a more important indicator for poor survival in patients for whom both scans were obtained. |
3 |
| 66. Baudin E, Lumbroso J, Schlumberger M, et al. Comparison of octreotide scintigraphy and conventional imaging in medullary thyroid carcinoma. J Nucl Med. 1996;37(6):912-916. |
Review/Other-Dx |
24 patients |
To evaluate the clinical utility of positive somatostatin receptor scintigraphy in patients with medullary thyroid cancer (MTC). |
Somatostatin receptor scintigraphy had positive results in 9 of 24 patients (37%): of Group 1 patients, 7 of 12 had positive somatostatin receptor scintigraphy results. Of these patients cases, somatostatin receptor scintigraphy demonstrated several involved organs and tumor sites either identical (two patients) or smaller (five patients) in size than conventional imaging modalities. Only two patients in Group 2 had positive somatostatin receptor scintigraphy results which demonstrated significant mediastinal uptake previously classified as indeterminate on conventional imaging modalities. No new tumor site was identified nor were therapeutic options modified by the somatostatin receptor scintigraphy results. |
4 |
| 67. Ozkan ZG, Kuyumcu S, Uzum AK, et al. Comparison of 68Ga-DOTATATE PET-CT, 18F-FDG PET-CT and 99mTc-(V)DMSA scintigraphy in the detection of recurrent or metastatic medullary thyroid carcinoma. Nucl Med Commun. 36(3):242-50, 2015 Mar. |
Observational-Dx |
22 patients |
To compare the efficacies of gallium-68 (68Ga) DOTATATE PET-computed tomography (CT), fluorine-18 fluorodeoxyglucose (18F-FDG) PET-CT and technetium-99m (99mTc)-(V)DMSA scintigraphy in the detection of residual/metastatic medullary thyroid carcinoma (MTC). |
The ages of the patients at diagnosis were between 20 and 69 years. The median levels of Ct and CEA were 871.5 pg/ml and 11.2 ng/ml, respectively. In the patient-based analysis, we observed at least one focus of abnormal uptake in 15 of 22 DOTATATE PET-CT (68.2% sensitivity), eight of 18 18F-FDG PET-CT (44.4% sensitivity) and five of 15 (V)DMSA scans (33.3% sensitivity). These data showed a significant difference between DOTATATE PET-CT and (V)DMSA scintigraphy (P=0.016), whereas the relationships between DOTATATE PET-CT and 18F-FDG PET-CT and between 18F-FDG PET-CT and (V)DMSA scintigraphy showed no significant differences (P>0.05). In the lesion-based analysis, 134 lesions were detected with DOTATATE PET-CT, 76 lesions with 18F-FDG PET-CT and nine lesions with (V)DMSA scintigraphy. |
3 |
| 68. Conry BG, Papathanasiou ND, Prakash V, et al. Comparison of (68)Ga-DOTATATE and (18)F-fluorodeoxyglucose PET/CT in the detection of recurrent medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging. 37(1):49-57, 2010 Jan. |
Observational-Dx |
18 patients |
To detect and map the extent of disease in recurrent medullary thyroid carcinoma (MTC) using the novel PET somatostatin analogue (68)Ga-DOTATATE and conventional (18)F-FDG positron emission tomography/computed tomography (PET/CT). |
(68)Ga-DOTATATE PET/CT imaging achieved disease detection in 13 of 18 and (18)F-FDG PET/CT in 14 of 18 patients. These results corresponded to per-patient sensitivities of 72.2% [95% confidence interval (CI): 46.4-89.3%] for (68)Ga-DOTATATE versus 77.8% (95% CI: 51.9-92.6%) for (18)F-FDG (non-significant difference). (18)F-FDG revealed a total of 28 metastatic MTC regions and (68)Ga-DOTATATE 23 regions. In ten patients a discordant tracer pattern of per-region and/or per-lesion distribution of recurrent disease was observed, while in four patients a concordant pattern was noted (no lesions were detected by either modality in the remaining four patients). |
3 |
| 69. Yamaga LYI, Cunha ML, Campos Neto GC, et al. 68Ga-DOTATATE PET/CT in recurrent medullary thyroid carcinoma: a lesion-by-lesion comparison with 111In-octreotide SPECT/CT and conventional imaging. Eur J Nucl Med Mol Imaging. 44(10):1695-1701, 2017 Sep. |
Observational-Dx |
15 patients |
To prospectively compare the detection rate of (68)Ga-DOTATATE PET-CT with (111)In-octreotide SPECT-CT and conventional imaging (CI) in medullary thyroid carcinoma (MTC) patients with increased calcitonin (Ctn) levels but negative CI after thyroidectomy. |
18F-FGD PET/CT depicted metastases in 15 patients, 111In-pentetreotide in 8, c.e. CT in 11, US in 6. In 2 patients, liver micrometastases were detected at laparoscopy only. At a lesion-by-lesion analysis, 18F-FDG PET/CT visualized a total of 26 metastatic deposits, c.e. CT 18, 111In-pentetreotide 12, US 8. Final diagnosis was obtained by cytological or surgical findings. Four patients with evidence of limited metastatic spread to neck/upper mediastinum were re-operated, and in 2 of them serum calcitonin levels normalized. |
2 |
| 70. American College of Radiology. ACR Appropriateness Criteria® Radiation Dose Assessment Introduction. Available at: https://www.acr.org/-/media/ACR/Files/Appropriateness-Criteria/RadiationDoseAssessmentIntro.pdf. |
Review/Other-Dx |
N/A |
To provide evidence-based guidelines on exposure of patients to ionizing radiation. |
No abstract available. |
4 |
