Neoplasms

All Conditions

Gland and Hormone Related Diseases

Immune System Diseases

Carcinoma

Thyroid Neoplasms

Thyroid Diseases

Hypersensitivity

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Endocrine System Diseases

Endocrine Gland Neoplasms

Head and Neck Neoplasms

Martin Biermann, MD

Human thyroglobulin (Tg) is the most sensitive biochemical marker for recurrence of differentiated cancer (DTC), especially after the complete removal of thyroid tissue through surgery and radioiodine therapy (RIT).

Unfortunately, current assays for measuring Tg in blood samples are not sensitive enough to reliably measure Tg while patients are under thyroid hormone replacement therapy. Instead patients have to withdraw thyroid hormone for several weeks or receive costly injections of recombinant thyroid stimulating hormone (TSH) in order to raise Tg production by thyroid remnant and/or thyroid cancer cells so that it can be measured by current Tg assays. Other patients have antibodies against Tg that interfere in current immunoassays.

The purpose of the study was to characterize a new highly sensitive assay for measuring Tg in the serum in thyroid cancer patients both on thyroid hormone therapy and off therapy in comparison to the normal routine assay already in use at Münster University Hospital.

Sera of 100 consecutive DTC patients after total thyroidectomy were to be collected at the Department of Nuclear Medicine both under TSH-suppression therapy and under endogenous TSH stimulation (TSH \> 25 mU/l). All patients were staged by clinical examination, cervical ultrasound (7.5 MHz), I-131 whole-body scintigraphy and - where applicable - F18-FDG-PET. Written informed consent was obtained from all pts. Sera were taken in separation tubes without anticoagulants and stored at -20°C until analysis. Sera were allowed to come to room temperature prior to analysis.

Tg, TgR and TgAb concentrations were determined by fully automated two-site chemiluminescence immunoassays (CLIA; Nichols Advantage®; Nichols Institute Diagnostics, San Clemente, California). All 3 assays are based on the identical highly purified hTg material for calibration (Tg), recovery (TgR) and antigen (TgAb; biotinylated and acridinium ester labeled) for optimum comparability of test results.

In addition, Tg and TgR was measured by a fully automated two-site TRACE immunoassay (BRAHMS Kryptor®, Brahms AG, Hennigsdorf, Germany) and TSH with a 3rd-generation CLIA assay (TSH-3, Advia Centaur, Bayer Corporation).

Clinical Evaluation of a New Highly Sensitive Thyroglobulin Assay in Differentiated Thyroid Carcinoma

Nichols Institute Diagnostika GmbH, Bad Vilbel, Germany

University Hospital Muenster

Rare Diseases

Thyroid Cancer, Papillary

Adenocarcinoma, Follicular

Adenocarcinoma

Adenocarcinoma, Papillary

Papillary Thyroid Carcinoma

Thyroid Cancer, Follicular

CHIH-YUAN WANG, Doctor

PEI-JIE HUANG, Bachelor

Chih-Yuan Wang, Doctor

Now, the investigators carried out a prospective study enrolling patients with thyroid cancer, who had received ablative thyroidectomy and /or radioactive iodine therapy for two more years. The investigators' study already enrolled seventy-three patients with thyroid cancer, and the investigators plan to enroll 30 new patients in this consecutive research study. All patients received total thyroidectomy under clinically surgical judgement in initial therapeutic option. The investigators also further found some difference between papillary thyroid cancer and follicular thyroid cancer, and the investigators will continue annually to closely monitor the change of U-Ex Tg and urinary exosomal galectin-3 between differently cellular types of thyroid cancers.

Although, most thyroid cancers are clinically endocrine tumors of low malignancy, most patients usually receive radioactive iodine-131 treatment and thyroidectomy. Such patients are followed up with thyroid ultrasound and continuous serum thyroglobulin assessment after surgery. Previous studies have shown that one third of well-differentiated thyroid cancers may be transformed into poorly differentiated or even fatal malignant tumors during disease progression, but the efficacy of surgery, chemotherapy and external radiation therapy is not significant. . In other words, effective treatment strategies and tracking models will be very important, including surgical removal of thyroid cancer, radioactive iodine-131 treatment, and tracking of biomarkers in thyroid cancer.

When thyroid cancer cells are poorly differentiated, cell dedifferentiation is a key factor for malignant transformation and invasion. Usually in papillary thyroid carcinoma and follicular thyroid carcinoma, the cancer cells will gradually dedifferentiate, and undifferentiated thyroid carcinoma is the final result. Therefore, the investigators try to find biomarkers and therapeutic tracking targets based on the expression of exosomal proteins in urine. The basis of this clinical study depends on the previous basic experiments of culturing undifferentiated thyroid cancer cells.

Exosomes are nanosomes that are secreted into the extracellular environment. Cancer cell-derived exosomes can be found in the plasma, saliva, urine and other body fluids of cancer patients. The investigators will analyze exosomal proteins in urine, including thyroglobulin and galectin-3, and discover early prognostic biomarkers in urine through the prospectively observation study. The investigators have published preliminary research papers on 16 patients with thyroid mastoid carcinoma and follicular carcinoma in international scientific journals. During the period of surgery and further radioactive iodine-131 therapy, including before and one day after surgery, 3 months and 6 months after surgery, the urinary biomarkers of thyroglobulin and galectin-3 in the urine were analyzed at different stages . A prospective study currently in progress has enrolled 73 patients with thyroid mastoid carcinoma and follicular carcinoma. After thyroidectomy, urine was collected during outpatient follow-up and analyzed for exosome biomarkers in the urine. During the first two years of this project, such new urinary biomarkers of thyroid papillary carcinoma and thyroid follicular carcinoma had shown certain different patterns. The investigators' research team expects to enroll 30 new thyroid cancer patients in this consecutive plan. Under continuous follow-up research, in addition to identifying the clinical application of new biomarker as prognostic predictors for future thyroid cancer patients after surgery, the investigators also plan to observe current patients with thyroid follicular cancer. Up to date, follicular thyroid cancer cannot be diagnosed preoperatively via images or aspiration cytology, because pathology after surgery is the only diagnostic golden rule. According to the observations conducted in the current experiment, the urine exosomal thyroglobulin has the opportunity to be a way to diagnose thyroid follicular carcinoma before surgery.

Urinary Exosomal Biomarkers of Thyroglobulin and Galectin-3 for Prognosis and Follow-up in Patients of Thyroid Cancer

Urinary Exosomal Biomarkers of Thyroglobulin and Galectin-3 for Prognosis and Follow-up in Patients of Well-differentiated Thyroid Cancer

National Taiwan University Hospital

Symptoms and General Pathology

Recurrence

Disease Attributes

prophylactic central neck dissection was performed for the ipsilateral lesion

prophylactic central neck dissection

jie liu

jie liu, MD

papillary thyroid carcinoma (PTC) is the most common thyroid cancer and has a good prognosis. Surgery is the primary treatment for PTC, and occult lymph node metastasis is not uncommon (20%-80%).The lymph node metastasis of PTC is mostly along the lymphatic drainage path station by station, and most of the first metastasis is to the central lymph node. According to the 2015 American Thyroid Association recommendation, prophylactic central lymph node dissection is recommended for patients with primary T3-4 or cN1b without central lymph node involvement. However, PTC with primary site T1-2, no external invasion and cN0 could not be dissected by central lymph node.Previous studies have suggested that prophylactic dissection should be performed to improve disease-specific survival, reduce local recurrence, improve recurrence risk and treatment response assessment, and help RAI decision making. Although routine prophylactic central lymph node dissection may detect occult lymph node metastasis, the need for further dissection of the recurrent laryngeal nerve and the parathyroid gland may lead to an increased incidence of complications, while its effect on reducing the risk of recurrence and improving prognosis is unclear, and the impact on long-term outcomes may be small.Previous retrospective studies in our institution have shown that routine central neck dissection does not significantly reduce the risk of recurrence. This study was designed to evaluate the benefits and risks of prophylactic central lymph node dissection in cT1b-T2N0 patients with papillary thyroid carcinoma. In order to ameliorate the effects of relapse and long time of death of PTC, thyroglobulin and its antibodies were also evaluated for short-term treatment response after surgery.

test group: prophylactic central neck dissction; control group: no central neck dissection

A Prospective, Open-label, Multicenter, Randomized Controlled Phase III Study of Prophylactic Central Neck Dissection in Low-risk Papillary Thyroid Cancer

To assess the effect of prophylactic central neck dissection for excellent response of cN0 low-risk papillary thyroid cancer

to assess the influence of prophylactic central neck dissection on imporvement of RFS of cN0 low-risk papillary thyroid cancer

Cancer Institute and Hospital, Chinese Academy of Medical Sciences

clinical professor

Luca Giovanella, MD

Thyroidectomy followed by administration of large activities of 131-iodine (131I) is the treatment of choice for differentiated thyroid carcinoma (DTC). The serum thyroglobulin (Tg) measurement during hypothyroidism (offT4-Tg), just before radioiodine thyroid ablation, has proved to be effective for predicting persistent/recurrent disease. However, the Tg measurement cannot be used as a corresponding value for preablative offT4-Tg when rhTSH is used as stimulous before treatment. The present study was undertaken to evaluate if post-thyroidectomy Tg values, measured before rhTSH-stimulation and radioiodine administration, is of prognostic value in patients affected by DTC. We enrolled 28 patients with DTC and submitted to total thyroidectomy. Thyroxine (T4) treatment was started just after surgery to suppress TSH levels. Six to nine weeks later Tg levels were measured both basally (onT4-Tg) and after rhTSH (rhTSH-Tg) stimulation. Subsequently, T4 was stopped and serum Tg measured (offT4-Tg) just before 3700 MBq of 131I-iodide administration. A post-treatment whole body scan (PT-WBS) was performed and neck radioiodine uptake (RAIU) measured. A significant relationship was found between onT4-Tg and both rhTSH-Tg and offT4-Tg. The onT4-Tg levels of 0.2 ng/mL or higher predicted PT-WBS results with a 100% negative and 43% positive predictive values, respectively. Additionally onT4-Tg levels of 0.9 ng/mL or more predicts 12-months recurrences with 100% negative and 60% positive predictive value. In comparison, 1.0 ng/mL or higher offT4-Tg values predicted PT-WBS results and 12-months restaging with 94% and 100% negative and 45% and 27% positive predictive value, respectively. Basing on our data we conclude that preablative onT4-Tg may be of value as prognostic marker when rhTSH-aided radioiodine ablation is done. Additionally, the role of preblative onT4-Tg measurement as a yard-stick for radioiodine ablation should be further evaluate.

Introduction Total (or near-total) thyroidectomy followed by TSH-stimulated administration of large activities of 131-iodine (131I) is the treatment of choice for DTC \[1-3\]. The serum thyroglobulin (Tg) measurement during hypothyroidism, just before radioiodine thyroid ablation, has proved to be effective for predicting persistent/recurrent disease \[4-8\]. Recently recombinant human TSH (rhTSH) showed to be safely employed instead of thyroxine (T4) withdrawal (offT4) to prepare patients for radioiodine ablation \[9-10\]. However, the Tg level are measured 48 hours after radioiodine administration when rhTSH is used as stimulation \[11\]. Consequently, due to the radioiodine-induced thyroid cells damage and Tg release, the Tg measurement would not have reliable predictive value in patients treated by rhTSH stimulation \[12\]. The present study was undertaken to evaluate if preablativeTg measurement under T4 treatment is of prognostic value and serves as surrogate marker of offT4-stimulated preablative Tg.

Patients and methods

Patients selection We retrospectively enrolled 28 consecutive patients affected by histologically proven DTC (23 papillary, 5 follicular) submitted to total thyroidectomy and central compartment lymph-node dissection. Thyroxine (T4) treatment was started immediately after surgery to suppress TSH levels. Six to nine weeks later Tg levels were measured both basally (onT4-Tg) and after rhTSH (rhTSH-Tg) stimulation as previously described \[13\]. Subsequently, T4 was stopped for 4 weeks and serum Tg measured (offT4-Tg) just before 3700 MBq of 131I-iodide administration. A post-treatment whole body scan (PT-WBS) with radioiodine uptake (RAIU) calculation was performed according to a previously described protocol \[1\]. All non physiologic iodine uptake areas out of the thyroid bed were considered as positive findings \[14, 15\]. Patients with positive PT-WBS underwent specific treatment and personalized follow-up. Patients with negative PT-WBS immediately restarted T4 suppressive treatment. Final restaging was performed in all patients 12 months after the last treatment by neck ultrasound, onT4-Tg assay and both offT4-diagnostic WBS (DgWBS) and Tg assay (4 weeks T4 withdrawal; required TSH\>30 mUI/L). Clinical and pathological characteristics of selected patients were summarized in the Table 1.

Serum Tg assay and screening for interferences Serum Tg was assayed in duplicate by a specific high-sensitive IRMA assay (DYNOtest® Tg-plus, BRAHMS Diagnostica GmbH, Berlin, Germany) according to the producer' instructions. This method provided a sensitivity of 0.05 ng/mL and a functional sensitivity of 0.2 ng/mL \[16, 17\]. As previously published, preablative offT4 serum Tg values above 4.5 ng/mL and 3.2 ng/mL were considered as positive with respect to PT-WBS and 12 months restaging results, respectively \[8\]. Otherwise, offT4-Tg values higher than 0.2 ng/ml measured 12 months after thyroid ablation were considered positive for persisting/relapsing disease. \[18, 19\]. The presence of anti-thyroglobulin antibodies (AbTg) was screened by a specific radioimmunoassay (DYNOtest® anti-TGn, BRAHMS Diagnostica GmbH, Berlin, Germany) and by recovery test with a specific Tg-recovery buffer provided by the producer. Sera showing AbTg levels more than 60 U/mL and/or recover less than 80% or more than 120% were excluded from the study. Quality control was ensured by assaying two levels of control sera in each series, by re-assessing all sera showing a coefficient of variation exceeding 10% and by a bimonthly partecipation in the European inter-laboratory control OncocheckTM.

Statistics Quantitative data are expressed as mean ± SD. Differences between groups were assessed by two-tailed unpaired t-test. The relationship between variables was assessed by linear regression analysis. In order to allow statistical analysis the value of undetectable serum Tg expressed as \< 0.2 ng/nL was arbitrarily changed in 0.10 ng/mL. Statistical significance was defined by a p-value \< 0.05.

Ethics All diagnostic and therapeutic procedures were performed according to the regulations of the local ethics committee. Informed consensus was obtained from each patient.

Results The overall results are summarized in the Table I. Relationship Between Post-surgery onT4-Tg, rhTSH-Tg and offT4-Tg A significant positive relationship was found between onT4-Tg and both rhTSH-Tg (p\<.0001) and offT4-Tg (p\<0.0001) (Figure 1, A-B-C) as well as between rhTSH and offT4-stimulated Tg (p\<.0001).

Relationship Between Post-surgery Serum Tg and Thyroid Remnant Radioiodine Uptake (RAIU) Among 22 patients showing no DTC metastasis on PT-WBS the serum distribution of onT4-Tg, rhTSH-Tg and offT4-Tg was 0.342±0.402; 0.664±0.803 and 1.195±1.485 ng/mL respectively. Both rhTSH and offT4-stimulated Tg levels were related to RAIU (p \<.05 and \<.005, respectively) while no significant relationship was found between RAIU and onT4-Tg levels (Figure 1, D-E-F).

Relationship Between Post-surgery Serum Tg and PT-WBS results The patients with positive PT-WBS showed higher onT4-Tg (0.617±0.445 vs 0.341±0.402 ng/mL), rhTSH-Tg (2.150±1.249 vs 0.664±0.803 ng/mL) and offT4-Tg (4.417±2.136 vs 1.195±1.485 ng/mL) levels as compared with patients with negative scan. Among 14 patients with undetectable onT4-Tg (i.e. ≤0.2 ng/mL) none had positive PT-WBS neither recurrences at 12-months restaging. Additionally, none of these patients showed stimulated Tg values more than 0.4 ng/mL and 1.0 ng/mL after rhTSH stimulation and T4 withdrawal, respectively. Viceversa, among 14 patients with onT4-Tg levels more than 0.2 ng/mL, 6 had positive PT-WBS (onT4-Tg: 0.3 to 1.4 ng/mL) and 3 showed DTC recurrences at 12 months restaging (onT4-Tg: 0.9 to 1.7 ng/mL). Consequently, the onT4-Tg levels predicts PT-WBS results with a 100% negative and 43% positive predictive values, respectively. Additionally onT4-Tg levels of 0.9 ng/mL or more predicts 12-months recurrences with 100% negative and 60% positive predictive value. In comparison, 1.0 ng/mL or higher offT4-Tg values predicted PT-WBS results and 12-months restaging with 94% and 100% negative and 45% and 27% positive predictive value, respectively.

Discussion Many reports indicate the usefulness of Tg concentration measurement before radioiodine treatment to early detection of DTC relapse or metastasis \[4-8, 20, 21\]. Three factors determine Tg concentration in most clinical situations: thyroid cell mass, thyroid cell damage and activation of TSH receptors \[22\]. When Tg is measured before radioiodine ablation the effects of surgical damage are generally vanished and endogenous TSH levels are increased in all patients: consequently the thyroid remnant mass is the major determinant of the serum Tg concentrations \[23\]. However, the rhTSH-stimulated Tg cannot be used instead of preablative offT4-Tg when rhTSH is employed to prepare radioiodine ablation \[12\]. Therefore we evaluated the role of post-surgery onT4-Tg as surrogate prognostic marker. We choiced to suppress TSH levels in order to normalize the effect of TSH stimulation on thyroid remnants. Clearly, the TSH suppression reduced Tg levels: however, the high-sensitive Tg assays provide a good distinction between the lower limit of the euthyroid reference range and the functional sensitivity limit detecting small amounts of thyroid tissue even in the TSH-suppressed state (22, 23). We showed a significant positive relationship between post-surgery Tg measured during T4 treatment and after TSH stimulation. No relationship was found between RAIU (i.e. expression of remnant mass) and onT4-Tg, probably due the clustering of all Tg levels lower than 0.2 ng/mL (see statistics paragraph). However, undetectable onT4-Tg after surgery identifies patients free of metastasis at PT-WBS and without late recurreces during early 12-months follow-up. None of these patients showed a significant increase in both rhTSH and offT4-stimulated Tg before radioiodine ablation. This seems to indicate that the relationship between Tg expression and thyroid tissue mass is manteined even in TSH suppression state: Therefore undetectable serum onT4-Tg really identifies patients without significant thyroid tissue amount as well as stimulated Tg. All patients performed extracapsular total thyroidectomy in a dedicated thyroid surgery unit and the thyroid remnant, expressed as RAIU, was lower in our series than in others. This means that our data cannot directly translated to patients treated by more limited surgery. Globally, basing on our data we conclude that preablative onT4-Tg may be of value as prognostic marker when rhTSH-aided radioiodine ablation is done. Additionally, the role of preblative onT4-Tg measurement as a yard-stick for radioiodine ablation should be further evaluate.

References

1. Schlumberger MJ. Medical progress: papillary and follicular thyroid carcinoma. N Engl J Med 1998; 338: 297-306.
2. Pacini F. Follow-up of differentiate thyroid cancer. Eur J Nucl Med 2002; 29(S2): 492-6.
3. Klain M, Richard M, Leboulleux S et al. Radioiodine therapy for papillary and follicular thyroid carcinoma. Eur J Nucl Med 2002; 29(S2): S479-85.
4. Ronga G, Filesi M, Ventroni G et al. Value of the first serum thyroglobulin level after total thyroidectomy for the diagnosis of metastasis from differentiated thyroid carcinoma. Eur J Nucl Med 1999; 26(11): 1448-52.
5. Grünwald F, Menzel C, Fimmers R et al. Prognostic value of thyroglobulin after thyroidectomy before ablative radioiodine therapy in thyroid cancer. J Nucl Med 1996; 37(12): 1962-4.
6. Lin JD, Huang MJ, Hsu BR, Chao TC, Hsueh C, Liu FH et al. Significance of postoperative serum thyroglobulin levels in patients with papillary and follicular thyroid carcinomas. J Surg Oncol 2002; 80: 45-51.
7. Kim TY, Kim WB, Kim ES, Ryu JS, Yeo JS, Kim SC et al. Serum thyroglobulin levels at the time of 131I remnant ablation just after thyroidectomy are useful for early prediction of clinical recurrence in low-risk patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 2005; 90: 1440-5.
8. Giovanella L, Ceriani L, Ghelfo A, Keller F. Thyroglobulin assay 4 weeks after thyroidectomy predicts outcome in low-risk papillary thyroid carcinoma.Clin Chem Lab Med 2005;43: 843-7.
9. Barbaro D, Boni G, Meucci G, Simi U, Lapi P, Orsini P et al. Recombinant human thyroid-stimulating hormone is effective for radioiodine ablation of post-surgical thyroid remnants. Nucl Med Commun. 2006; 27(8):627-32.
10. Pacini F, Ladenson PW, Schlumberger M, Driedger A, Luster M, Kloos RT et al. Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study. J Clin Endocrinol Metab. 2006; 91: 926-32.
11. Robbins RJ, Svrivastava S, Shaha A, Ghossein R, Larson SM, Fleischer M et al. Factors influencing the basal and recombinant human thyrotropin-stimulated serum thyroglobulin in patients with metastatic thyroid carcinoma. J Clin Endocrinol Metab. 2004; 89: 6010-6.
12. Taieb D, Lussato D, Guedj E, Roux F, Mundler O. Early sequential changes in serum thyroglobulin after radioiodine ablation for thyroid cancer: possible clinical implications for recombinant human thyrotropin-aided therapy. Thyroid 2006; 16: 177-9.
13. Mazzaferri E, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L et al. A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 2003; 88: 1433-41.
14. Giovanella L, Ceriani L, Ghelfo A, Keller F, Sacchi A, Maffioli M et al. Thyroglobulin assay during thyroxine treatment in low-risk differentiated thyroid cancer management: comparison with recombinant human thyrotropin-stimulated assay and imaging procedures. Clin Chem Lab Med 2006; 44:248-52.
15. Reiners C, Luster M, Lassman M. Clinical experience with recombinant human thyroid-stimulating hormone (rhTSH): whole-body scanning with iodine-131. J Endocrinol Invest 1999; 22(S11):17-24.
16. Giovanella L, Ceriani. High-sensitivity human thyroglobulin (hTG) immunoradiometric assay in the follow-up of patients with differentiated thyroid carcinoma. Clin Chem Lab Med 2002; 40(5): 480-4.
17. Morghentaler NG, Froelich J, Rendl J, Willnich M, Alonso C, Bergmann A et al. Technical evaluation of a new immunoradiometric and a new immunoluminometric assay for thyroglobulin. Clin Chem 2002; 48(7): 1077-83.
18. Iervasi A, Iervasi G, Carpi A, Zucchelli GC. Serum thyroglobulin measurement: clinical background and main methodological aspects with clinical impact. Biomed Pharmacother. 2006; 60: 414-24
19. Sahlmann CO, Schreivogel I, Angerstein C et al. Clinical evaluation of a new thyroglobulin immunoradiometric assay in the follow-up of differentiated thyroid carcinoma. Nuklearmedizin 2003; 42: 71-7.
20. Makarewicz J, Adamczewski Z, Knapska-Kucharska M, Lewinski A. Evaluation of the diagnostic value of first thyroglobulin determination in detecting metastases after differentiated thyroid carcinoma surgery. Exp Clin Endocrinol Diabetes 2006; 114: 485-9.
21. de Rosario PW, Guinaraes VC, Maia FF, Fagundes TA, Purisch S, Padrao EL et al. Thyroglobulin before ablation and correlation with posttreatment scanning. Laryngoscope 2005; 115: 264-7.
22. Spencer CA, LoPresti JS, Fatemi S, Nicoloff JT. Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. Thyroid 1999; 9: 435-41.
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OnT4-Thyroglobulin Assay Before rhTSH-Aided Radioiodine Ablation

Is the Thyroglobulin Measurement Under Thyroxine of Prognostic Value Before rhTSH-Aided Radioiodine Ablation in Differentiated Thyroid Carcinoma?

Oncology Institute of Southern Switzerland

CHIH-YUAN WANG

Thyroid cancer is the most common endocrine malignancy in the world. Generally, thyroid cancer could be divided into well-differentiated and poorly-differentiated. Well-differentiated thyroid cancers usually have two different patterns, including papillary thyroid cancer and follicular thyroid cancer. Thyroid sonography is convenient to obtain repeatedly for the images of nodular goiter. However, cytology and pathology are still the golden rules to make the final diagnosis. Under the basis of sono-guided fine needle aspiration cytology, diagnosis of papillary thyroid cancer is typically using fine needle aspiration cytology based on the presentation of typical cytologic features. On the other hand, thyroid follicular lesion cannot be interpretated via cytology because the evidence of capsular invasion or vascular permeation of capsule will not be available in fine needle aspiration cytology. Surgical intervention with pathological specimens is the only pathway to make the final diagnosis. Interestingly, both patterns of well-differentiated thyroid cancer shared the same follow-up tumor marker, i.e. serum thyroglobulin. Up to date, pre-operative diagnosis of follicular thyroid cancer is still one of the unresolved issues in endocrine oncology.

Thyroid cancer is one of the most popular malignancy in the past several decades all over the world. For poorly-differentiated thyroid cancer, therapeutic strategy of costly target therapy together with immune therapy will be the pivotal one because of its poor prognosis. The average 5-year relative survival rate of anaplastic thyroid cancer is only 3 to 31 % on the stage from distant metastasis to localized disease.

However, it will be very different for well-differentiated thyroid cancer, and the average 5-year relative survival rate of both thyroid papillary or follicular thyroid cancer is more than 98 %. Therefore, the most important treatment strategy for endocrinologists will consider the development of biomarkers for early diagnosis and postoperative follow-up, rather than measuring serum thyroglobulin alone, which is the only biomarker in the current medical guidelines, and there is no choice. Our research team tried to find the newer biomarker together with serum thyroglobulin for post-operative longitudinal follow-up of well-differentiated thyroid cancer in the past five years. The investigators used urinary exosomal proteins as target and did find several peptides to be helpful, including our published urinary exosomal thyroglobulin (UExTg). In Taiwan, goiter and thyroid cancer are prevalent diseases. Although papillary thyroid cancer could be diagnosed via reliable sono-guided fine needle aspiration cytology, follicular thyroid cancer is still an unresolved issue in daily medical practice, especially in cytology. the investigators need to find a practicably earlier biomarker, which should be convenient, non-invasive and repeatable in sample collection. In our previous research and published data, urine will be a reliable source of data.

Exosomes are nano-vesicles, containing DNA, RNA and proteins, and usually secreted by cells into extracellular spaces. Generally, the vesicles of exosomes are only 40 to 150 nm in diameter. Exosomes may carry and transfer the messages between different tissues. Now, the existing evidences revealed that exosomes may represent certain messages from malignant cells, including diagnosed biomarkers or prognostic predictors. Previously, published data of exosomal studies in thyroid cancer focused on serum microRNA, long coding RNA and circular RNA, but only few published data on peptides, which were named as liquid biopsy. However, cell-secreted exosomes of malignancy could be collected not only in plasma, body fluid, but also from urine, which is the non-invasive pathway but valuable wastes of human body. Our research group had developed experienced technique to collect urinary exosomes via our pilot study in the past several years.

Since the investigators proved the role of urinary exosomal thyroglobulin, UExTg, in post-operative follow-up in well-differentiated thyroid cancer in the past three years, from 2018-2020, the investigators also found several peptides to be the candidates of prognostic predictors in our preliminary studies, including Calprotectin A8/A9, Annexin-2, Angiopoietin-1.

Correlation Between Various Urinary Exosomal Protein Biomarkers and Pathological Manifestation in Thyroid Follicular Neoplasm: Early and Pre-operative Diagnosis of Follicular Thyroid Cancer

All Drugs and Chemicals

Hormones

Euthyroid Group: Subjects received rhTSH to prepare for radioiodine therapy.

Hypothyroid Group: Thyroid hormone treatment was withheld before radioiodine therapy.

Euthyroid Group: Received rhTSH to prepare for radioiodine therapy.

Euthyroid Group

Paul W Ladenson, MD

The purpose of this study is to determine \[for patients with previously treated well-differentiated thyroid cancer and evidence of residual disease based on serum thyroglobulin (Tg) level\] whether positron emission tomography-computed tomography (PET-CT) fusion scanning performed after recombinant thyroid-stimulating hormone (TSH) (rTSH, thyrotropin alfa for injection) will be more sensitive for the detection of disease sites than PET-CT scanning without rTSH. The study will also determine if this information will significantly alter the therapeutic approach in some patients.

PET/CT was performed before (basal PET) and 24 - 48 h after rhTSH administration (rhTSH-PET) in 63 patients (52 papillary and 11 follicular thyroid cancers). Images were blindly analyzed by two readers. The proposed treatment plan was prospectively assessed before basal PET, after basal PET, and again after rhTSH-PET.

Recombinant Thyrotropin PET-CT Fusion Scanning in Thyroid Cancer

Utility of Recombinant Human Thyrotropin (rTSH) PET-CT Fusion Scanning to Identify Residual Well-differentiated Epithelial Thyroid Cancer

PET/CT was performed before (basal PET) and 24-48 h after rhTSH administration (rhTSH-PET) in 63 patients (52 papillary and 11 follicular thyroid cancers). Images were blindly analyzed by two readers. The proposed treatment plan was prospectively assessed before basal PET, after basal PET, and again after rhTSH-PET.

Gustave Roussy, Cancer Campus, Grand Paris

M.D. Anderson Cancer Center

Genzyme, a Sanofi Company

Johns Hopkins University

Adults (age \>18 years) with a history of treated well-differentiated epithelial thyroid carcinoma (papillary, follicular, or Hürthle cell), for which total or near total thyroidectomy plus postoperative radioiodine remnant ablation with 131-I has either been performed or found to be unnecessary by radioiodine imaging after TSH stimulation.

Subjects received rhTSH to prepare for radioiodine therapy

Adults (age \>18 years) with a history of treated well-differentiated epithelial thyroid carcinoma (papillary, follicular, or Hürthle cell), for which total or near total thyroidectomy plus postoperative radioiodine remnant ablation with 131-I has either been performed or found to be unnecessary by radioiodine imaging after TSH stimulation.

Thyroid hormone treatment was withheld before radioiodine therapy.

Hypothyroid Group

Total

Age, Categorical

Sex: Female, Male

France

United States

Region of Enrollment

Paul W. Ladenson, MD, Professor and PI

Subjects received rhTSH to prepare for radioiodine therapy.

Thyroid hormone treatment was withheld before radioiodine therapy.

PET-CT Fusion Scanning Sensitivity

Increased Fluorodeoxyglucose (FDG) PET Standardized Uptake Value (SUV) After rTSH Specificity

Subjects received rhTSH to prepare for radioiodine therapy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Clinical Evaluation of a New Highly Sensitive Thyroglobulin Assay in Differentiated Thyroid Carcinoma	NCT00148213	Thyroid Neoplas...		0 Years -	University Hospital Muenster
Urinary Exosomal Biomarkers of Thyroglobulin and Galectin-3 for Prognosis and Follow-up in Patients of Thyroid Cancer	NCT04948437	Thyroid Cancer Papillary Thyro... Follicular Thyr...		20 Years - 80 Years	National Taiwan University Hospital
A Prospective, Open-label, Multicenter, Randomized Controlled Phase III Study of Prophylactic Central Neck Dissection in Low-risk Papillary Thyroid Cancer	NCT06082180	Thyroid Cancer Recurrence	prophylactic ce...	18 Years - 70 Years	Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Clinical Evaluation of a New Highly Sensitive Thyroglobulin Assay in Differentiated Thyroid Carcinoma	NCT00148213	Thyroid Neoplas...		0 Years -	University Hospital Muenster
OnT4-Thyroglobulin Assay Before rhTSH-Aided Radioiodine Ablation	NCT00439127	Differentiated ...		-	Oncology Institute of Southern Switzerland
A Prospective, Open-label, Multicenter, Randomized Controlled Phase III Study of Prophylactic Central Neck Dissection in Low-risk Papillary Thyroid Cancer	NCT06082180	Thyroid Cancer Recurrence	prophylactic ce...	18 Years - 70 Years	Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Correlation Between Various Urinary Exosomal Protein Biomarkers and Pathological Manifestation in Thyroid Follicular Neoplasm: Early and Pre-operative Diagnosis of Follicular Thyroid Cancer	NCT05463107	Thyroid Cancer Follicular Thyr...		20 Years - 80 Years	National Taiwan University Hospital
Recombinant Thyrotropin PET-CT Fusion Scanning in Thyroid Cancer	NCT00181168	Thyroid Cancer	Euthyroid Group	18 Years -	Johns Hopkins University

Spots Global Cancer Trial Database for thyroglobulin