Thyroid cancer

Papillary and follicular thyroid carcinoma: Controversies in follow-up
Steven B. Porter, MD PGY-1, Department of Surgery Team IV Rounds June 20, 2008

Thyroid cancer

Outline
‡ Case Presentation ‡ ³Differentiated Thyroid Cancer´
± Papillary Thyroid Carcinoma ± Follicular Thyroid Carcinoma

‡ Cohort Data ‡ Analysis of Data ‡ Summary
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Thyroid cancer

Negative Outline
‡ No discussion of medullary thyroid ca ‡ No discussion of MEN2a, MEN2b ‡ No discussion of surgical technique (as I haven¶t seen surgery on a thyroid since 2005)

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Thyroid cancer

Case presentation
‡ HPI: M is a 30 yo M referred to endocrine surgery for a palpable thyroid nodule on physical exam by PMD. No dysphonia, dysphagia, odynophagia, change in voice. No smoking history. Recent cough for a few weeks. No fevers, chills, weight loss. No hx of radiation to neck
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Thyroid cancer

Case Presentation cont¶d
‡ PMH: major depressive disorder, sleep apnea
± Meds: desipramine, buproprion

‡ PSH: left shoulder surgery 1996, pilonidal cyst excision 2000 ‡ All: NKDA ‡ FHx: M: Hashimoto¶s, F: benign goiter MAunt: hypothyroidism ‡ SHx: no tobacco, social etoh, no drugs
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Thyroid cancer

Case Presentation cont¶d
‡ PE
± VS: unable to obtain (afebrile, normotensive) ± Gen: NAD, healthy appearing ± HEENT: palpable ~3 cm nodule in thyroid R lower lobe ± CV: RRR, no murmurs ± Pulm: CTA b/l, no wheezes ± Abd: SNTND ± Extr: 2+ DP pulses b/l

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Thyroid cancer

Case Presentation cont¶d: US and FNA
US: Hypoechoic nodule in R lower lobe with punctate calcifications and some cystic degeneration measuring 2.9 x 3.0 x 3.4 cm sagittal. At the extreme R right lower pole, an adjacent
hypoechoic nodule measured 1.2 x 1.6 x 1.4 cm sagittal with irregular margins. In the mid-R lobe, a cystic nodule measured 0.9 x 1.0 x 0.9 sagittal. A mid-L complex nodule with isoechoic solid elements measured 0.9 x 1.4 cm sagittal. A lower L hypoechoic nodule measured 0.7 cm

FNA: Positive for malignant cells. Papillary thyroid carcinoma.
Foamy cells c/w cyst contents and/or cystic degeneration. Scant colloid. Rare nuclear grooves present. Rare intranuclear inclusions present.
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Thyroid cancer

Case Presentation cont¶d
‡ Hospital Course
± DAS for total thyroidectomy ± Palpable pretracheal and paratracheal lymph nodes in OR central LN dissection, PACU iCa: 1.11 ± POD#1: tolerating diet, afebrile, FROM of neck, JP d/c¶d, iCa: 0.96, 1.0, 1.03 ± POD#2: iCa: 1.04, d/c¶d to home on vitamin D and calcium carbonate
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Thyroid cancer

Case Presentation cont¶d
‡ Pathology
± L lateral paratracheal LN: 1/1 met papillary ca ± Lateral paratracheal tissue: 1/3 met papillary ca ± Thyroid gland: well differentiated papillary thyroid ca extensively involving b/l thyroid lobes and isthmus (largest R lobe tumor measuring 4.6 cm). ± Tumor extending to perithyroid soft tissue and is <1 mm from inked specimen surface. ± Lymphovascular invasion identified. ± Background parenchyma shows Hashimoto¶s thyroiditis ± 13/17 LN positive for met papillary ca ± AJCC Stage: p T3 N1 Mx
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Thyroid cancer

Case Presentation cont¶d
‡ So how do we follow the patient s/p total thyroidectomy? ‡ What are the recommendations for total vs hemithyroidectomy? ‡ And what data are these follow-up algorithms and consensus guidelines based on?
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Thyroid cancer

The Thyroid Gland

Gray¶s Anatomy

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Thyroid cancer

Background
‡ 1% of all new malignant disease ‡ 94% differentiated thyroid carcinoma
± Derive from follicular epithelial cells
‡ Papillary or follicular thyroid carcinoma

‡ 5% medullary thyroid carcinoma
± Neuroendocrine tumors

‡ 1% anaplastic
± Dedifferentiated thyroid carcinoma
Figge J. Epidemiology of thyroid cancer. In: Wartofsky L, ed. Thyroid cancer: a comprehensive guide to clinical management. Totowa: Humana Press, 1999; 77-83.
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Thyroid cancer

Diagnosis
‡ In sporadic cancer, patients usually present with a solitary thyroid nodule ‡ The initial diagnostic procedure of choice is FNA
± Allows diagnosis of papillary, medullary, anaplastic cancers ± To distinguish between follicular adenoma and carcinoma, histological examination is necessary

‡ False-positive and false-negative rates of FNA are <5%
Ravetto C, Colombo L, Dottorino ME. Usefulness of fine-needle aspiration in the diagnosis of thyroid carcinoma: a retrospective study of 37,895 patients. Cancer 2000;90:357-63. Gharib H, Goellner JR. Fine-needle aspiration biopsy of the thyroid: an appraisal. Ann Intern Med 1993;118:282-89.

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Thyroid cancer

Epidemiology
‡ ‡ ‡ ‡ F:M ~2:1 Median age of diagnosis: 45 years If iodine deficient area: follicular > papillary Risk factors:
± External radiation, especially during childhood ± E.g. Chernobyl disaster ± Inherited polyposis syndromes: FAP, Gardner¶s, Cowden¶s
Sherman, SI. Thyroid carcinoma. Lancet 2003;361:501-11. Figge J. Epidemiology of thyroid cancer. In: Wartofsky L, ed. Thyroid cancer: a comprehensive guide to clinical management. Totowa: Humana Press, 1999; 77-83. 14

Thyroid cancer

Molecular Genetics
‡ After radiation exposure, RET proto-oncogene (formerly PTC) rearrangements papillary carcinoma ‡ Other factors for papillary carcinoma: overexpression of TRK, MAPK, DNA hypermethylation, and activating mutations of RAS ‡ For follicular carcinoma: RAS mutations, chromosomal rearrangements (PAX8 fused to PPAR-gamma-1)
Fagin JA. Molecular pathogenesis of tumors of thyroid follicular cells. In: Fagin JA, ed. Thyroid Cancer. Boston: Kluwer, 1998. Kroll TG, Sarraf P, Pecciarini L, et al. PAX8-PPARgamma1 fusion oncogene in human thyroid carcinoma [corrected]. Science 2000;289:1357-60. 15

Thyroid cancer

Clinicopathological Staging
‡ There are >14 staging systems for thyroid cancer ‡ Histological subtypes that connote a poor prognosis:
± Papillary: tall cell, columnar cell variants ± Hurthle cell (oxyphilic cell) ± Follicular: poorly differentiated variants
Sherman SI, Brierley JD, Sperling M, et al. Prospective multicenter study of treatment of thyroid carcinoma: initial analysis of staging and outcome. Cancer 1998;83:1012-21. Burman KD, Ringel MD, Wartofsky L. Unusual types of thyroid neoplasms. Endocrinol Metab Clin North Am 1996;25:49-68.

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Thyroid cancer

TNM Staging System

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Thyroid cancer

‡14 staging systems applied to 589 PTC patients from 1961-2001at one center in Hong Kong ‡Evaluated those with best predictive system for cancerspecific survival ‡Cancer-specific survival calculated by Kaplan-Meier curves and compared with log-rank test ‡Top three systems: ‡MACIS (Metastases, Age, Completeness of Resection, Invasion, Size) ‡TNM (Tumor, Node, Metastasis) ‡EORTC (European Organization for Research and Treatment of Cancer)
Lang BH et al. Staging systems for papillary thyroid carcinoma. Ann Surg 2007;245:366-378. 18

Thyroid cancer

Papillary Cancer: FNA and histology

FNA showing papillary ca. The malignant cells including the one at the tip of the arrow are very loosely arranged
Images from UConn¶s Pathweb http://pathweb.uchc.edu

Blue arrow points to papillary structure. The center is fibrovascular. The cells covering it are epithelial. The red arrow shows a similar papillary structure in cross section.
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Thyroid cancer

Papillary Cancer
‡ Most common thyroid cancer ‡ Best prognosis: 5% mortality at 20 years if no evidence of local invasion at diagnosis ‡ µLateral aberrant thyroid¶ ± cervical lymph node infiltrated with metastatic thyroid cancer

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Thyroid cancer

Papillary Cancer
‡ Psammoma bodies: laminated calcified spheres, diagnostic of papillary cancer ‡ Certain histological variants have higher risk of recurrence: Tall cell, columnar cell, diffuse sclerosing cell ‡ Can spread to lung (also bone, liver, brain) ‡ Very rare conversion to anaplastic type

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Thyroid cancer

Follicular cancer: FNA and histology

FNA showing follicular cells. The follicles are composed of small clusters of cells. The colloid cannot be identified easily in this preparation. The nuclei are monotonous without obvious atypia. Images from UConn¶s Pathweb http://pathweb.uchc.edu

Normal thyroid follicles appear at the lower right. The follicular adenoma is at the center to upper left. This adenoma is a well differentiated neoplasm because it closely resembles normal tissue. 22

Thyroid cancer

Risk Stratification of Variables Influencing Cancer Recurrences and Cancer Death
Patient Variables - Age <15 or >45 yrs - Family hx of thyroid ca Tumor Variables - Tumor >4 cm - Bilateral disease - Extrathyroidal extension - Vascular invasion - Cervical or mediastinal LN mets - Certain tumor subtypes (e.g. Hurthle) - Histologic grade - Tumors that do not concentrate iodine well - Distant metastases
Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86:1447-1463. 23

Thyroid cancer

Primary surgical management
‡ Total thyroidectomy: Pro
± Papillary foci are b/l in 60-85% of patients ± 5-10% recurrence rates for papillary ca after unilateral surgery for ³microcarcinoma´ ± Effectiveness of treatment with 131I and f/u with serum Tg are highest with maximal resection

Katoh R, Sasaki J, Kurihara H, et al. Multiple thyroid involvement (intraglandular metastasis) in papillary thyroid carcinoma. A clinicopathologic study of 105 consecutive patients. Cancer 1992;70:1585-90. Silverberg SG, Hutter RVP, Foote FW Jr. Fatal carcinoma of the thyroid: histology, metastases, and causes of death. Cancer 1970;25:792-802.

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Thyroid cancer

Primary surgical management
‡ Total thyroidectomy: Con
± Minimal benefit for more extensive surgery ± Higher risk of hypoparathyroidism ± Higher risk of injury to recurrent laryngeal nerve ± Tumor multicentricity seems to have little prognostic significance ± If recurrence, usually those lesions are treatable
Cady B. Papillary carcinoma of the thyroid gland: treatment based on risk definition. Surg Oncol Clin N Am 1998;7:633-44. 25

Thyroid cancer

Consensus Guidelines
‡ Most concensus guidelines state:
± For papillary ca:
‡ If > 1 cm, or mets, or extends beyond thyroid, or hx of irradiation total thyroidectomy ‡ If < 1 cm and confined to one lobe hemithyroidectomy

± For follicular ca:
‡ Total thyroidectomy unless only suspicion on cytology, then can proceed with hemithyroidectomy and isthmusectomy with potential completion thyroidectomy based on histology
British Thyroid Association and Royal College of Physicians. Guidelines for the management of thyroid cancer in adults. London: Guidelines for the management of thyroid cancer in adults, 2002. Task Force TC. AACE/AAES medical/surgical guidelines for clinical practice: Management of thyroid carcinoma. Endocr Pr 2001;7:203-20. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418-28.

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Thyroid cancer

Data to Support Consensus Guidelines

‡National Cancer Data Base (1985±1998) ‡52,173 patients with surgery for PTC ‡Survival estimated by Kaplan-Meier method, compared using log-rank tests ‡Cox Proportional Hazards modeling stratified by tumor size used to assess impact of surgical extent on outcomes ‡Results: 43,227 (82.9%) underwent total thyroidectomy, 8946 (17.1%) underwent lobectomy. ‡ For PTC<1 cm, extent of surgery did not impact recurrence or survival (P = 0.24, P = 0.83) ‡ For tumors >1 cm, lobectomy resulted in higher risk of recurrence and death (P = 0.04, P = 0.009) ‡ 1 to 2 cm lesions were examined separately: lobectomy again resulted in a higher risk of recurrence and death (P = 0.04, P = 0.04).
Bilimoria KY et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246:375-384. 27

Thyroid cancer

Data to Support Consensus Guidelines cont¶d: Cumulative Recurrence Rate vs Years of Follow-Up by Tumor Size

Bilimoria KY et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246:375-384.

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Thyroid cancer

Data to Support Consensus Guidelines cont¶d: Cumulative Recurrence Rate vs Years of Follow-Up by Extent of Surgery

Bilimoria KY et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246:375-384.

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Thyroid cancer

Data to Support Consensus Guidelines cont¶d: Cumulative Survival Rate vs Years of FollowUp by Extent of Surgery

Bilimoria KY et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 2007;246:375-384.

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Thyroid cancer

Postoperative

131I

adjuvant therapy

‡ Specific uptake into follicular cells ‡ Undergoes -decay, releasing high energy electrons radiation cytotoxicity ‡ Also emits -rays which are detectable ‡ (i) destroys residual microscopic foci of ca ‡ (ii) increases specificity of future scans for residual ca ‡ (iii) improves sensitivity of future Tg screen
Maxon HR, Thomas SR, Samaratunga RC. Dosimetric considerations in the radioiodine treatment of macrometastases and micrometastases from differentiated thyroid cancer. Thyroid 1997;7:183-88. 31

Thyroid cancer

Postoperative 131I adjuvant therapy cont¶d
‡ For maximum radioiodine uptake after thyroidectomy, want TSH >30-50 mU/L ‡ Stop thyroxine for 4-6 weeks iatrogenic hypothyroidism ‡ Because liothyronine has a shorter t1/2, can give until 2 weeks prior to treatment ‡ Avoid iodinated contrast for CT for 1-3 months prior to treatment ‡ These same principles apply to radioiodine scanning for f/u
Schlumberger M, Tubiana M, et al. Long-term results of treatment of 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J Clin Endocrinol Metab 1986;63:960-67. Goldman JM Line BR, Aamodt RI, Robbins J. Influence of triiodothyronine withdrawal time on 131I uptake post-thyroidectomy for thyroid cancer. J Clin Endocrinol Metab 1980;50:734-39.

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Thyroid cancer

Long-term Monitoring: RAI scanning
‡ 6-12 months after initial ablation ‡ If negative 90% 10 year relapse-free survival ‡ If consecutively negative x2 >95% 10 year relapse-free survival ‡ Consensus guidelines: surveillance scanning beyond this period only indicated if clinical/diagnostic findings occur
Grigsby PW, Baglan K, Siegel BA. Surveillance of patients to detect recurrent thyroid carcinoma. Cancer 1999;85;945-51. Sherman SI. NCCN practice guidelines for thyroid cancer, version 2001. National Comprehensive Cancer Network, 2001.

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Thyroid cancer

Long-term Monitoring: Thyroglobulin
‡ Produced exclusively by thyroid follicular cells ‡ Used to detect residual, recurrent, or metastatic disease ‡ Reaches nadir within 3 months post-ablation (upper range 1-2 years) ‡ Sensitivity of 85-95% for detection of disease during thyroid hormone withdrawal ‡ Sensitivity of 50% with TSH suppression or dedifferentiated tumors
Spencer CA, LoPresti JS, Fatemi S, Nicoloff IT. Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. Thyroid 1999;9:435-41. Ozata M, Suzuki S, Miyamoto T, Liu RT, Fierro-Renoy F, DeGroot LJ. Serum thyroglobulin in the follow-up of patients treated with differentiated thyroid cancer. J Clin Endocrinol Metab 1994;79;98-105. Haugen BR, Pacini F, Feiners C, et al. A comparison of recombinant human thyrotropin and thyroid hormone withdawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84:3877-85.

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Long-term Monitoring: Thyroglobulin caveats

Thyroid cancer

‡ Reported Tg concentrations can be falsely lowered by autoAbs that bind Tg and prevent detection by immunoassays ‡ These autoAbs are present in as many as 25% of pts with thyroid cancer, and 10% of general population ‡ Methods to detect Tg mRNA are in development though their utility has been questioned

Mariotti S, Barbesino G, Caturegli P, et al. Assay of thyroglobulin in serum with thyroglobulin autoantibodies: an unobtainable goal? J Clin Endocrinol Metab 1995;80:468-72. Spencer CA, LoPresti JS, Faterni S, Nicoloff JT. Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. Thyroid 19999;9:435-41. Ringel MD, Ladenson PW, Levine MA. Molecular diagnosis of residual and recurrent thyroid cancer by amplification of thyroglobulin messenger ribonucleic acid in peripheral blood. J Clin Endocrinol Metab 1998;83:4435-42.

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Long-term Monitoring: Combining RAI and Tg

Thyroid cancer

‡ If negative RI scan and negative Tg level given elevated TSH can use rTSH scan instead of w/d from supplemental T4 ‡ Diagnostic dilemma: Negative RI scan with positive Tg level
± Advanced thyroid ca can de-differentiate and, thus, lose the ability to concentrate I ± Usually, other supplemental imaging (US, CT, PET/CT, thallium MIBI)
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Long-term Monitoring: What Is At Stake

Thyroid cancer

‡ 10-yr cancer specific mortality rates for papillary and follicular thyroid cancer are 7 and 15%, respectively, base on cohort data on 53,856 patients managed in the US between 1985 and 1995 ‡ Prevalence of DTC survivors is 300,00 in USA ‡ Each needs lifelong surveillance
Ries LAG, Eisener MP, Kosary CL, Hankey BF, Miller BA, Cleeg L, Mariotto A, Fay MP, Feuer EJ, Edwards BK. 2003 SEER Cancer Statistics Review, 1975-2001. Bethesa, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2001/results_single/sect_25_table.12.pdf Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985-1995. Cancer 1998;83:2638-48.

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Unique Pros, and Side Effects, of Remnant Ablation

Thyroid cancer

‡ Persistent disease and tumor stage cannot be identified shortly after surgery when there is a large thyroid remnant ‡ Without RA, half of lung metastases in children cannot be identified ‡ But:
± ± ± ± ± Transient loss of taste Acute and chronic radiation-induced parotitis Sialadenitis with possible xerostomia Transient testicular damage Side effects tend to be dose-related

Sclumberger M et al. Follow-up of low-risk patients with differentiated thyroid carcinoma: a European perspective. Eur J Endocrinol 2004;150:105-112. Bal CS et al. Is chest x-ray or high-resolution computed tomography scan of the chest sufficient investigation to detect pulmonary metastasis in pediatric differentiated thyroid cancer? Thyroid 2004; 14:217-225. Mandel SJ, Mandel L. Radioactive iodicine and the salivary glands. Thyroid 2003;13:265-271. Mazzaferri EL. Gonadal damage from 131I therapy for thyroid cancer. Clin Endocrinol (Oxf) 2002;57:313-314.

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Thyroid cancer

The Risk of Late-Tumor Identification
‡ Persistent tumor not recognized in many studies with 10 year follow-up only ‡ For example, in one study, 15% of locoregional tumors and 24% of distant metastases were first identified >2 decades after initial therapy ‡ Tumor is often present when a baseline Tg < 1 ng/mL rises >2-5 ng/mL with rhTSH or >5-10 ng/ml with levothyroxine withdrawal ‡ Risk of developing tumor <0.5% when no clinical evidence of tumor combined with TSH-stimulated undetectable serum Tg and negative neck US
Mazzaferri EL. An overview of thet management of papillary and follicular thyroid carcinoma. Thyroid 1999;9:421-27. Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F, Wartofsky L, Haugen BR, Sherman SI, Coooper DS, Braunstein GD, Lee S, Davis TF, Arafah BM, Ladenson PW, Pinchera A. 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;88:14331441.

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Thyroid cancer

Tumor recurrence after thyroid surgery and thyroid hormone tx with and without 131I tx

Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab 2001;86:1447-1463. 40

Thyroid cancer

Summary
‡ Most thyroid carcinoma is differentiated type ‡ US/FNA ‡ TNM or MACIS for staging ‡ Total thyroidectomy for most ‡ Post-surgical radioactive iodine ablation/remnant ablation ‡ RxWBS + serum Thyroglobulin

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