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Treatment of radioactive iodine-
refractory differentiated thyroid
carcinoma
Mauricio Lema Medina MD – Clínica de oncologí...
Page  2
@onconerd
Mauricio Lema Medina
Conflicts of interest
Consulting and honoraria as a speaker: Pfizer, MSD, Novartis, ROCHE,
Aztra-Zene...
>5.0cm
2.1-5.0cm
Thyroid cancer in the United States
0-1.0cm
1.1-2.0cm
Davies, JAMA 2006 295:2164
Medullary Anaplastic
Papillary Follicular
Differentiated Thyroid Cancer (DTC)
Thyroid Cancer: Treatment
Strategy
• High Risk: (Age >45, male, metastasis,
extrathyroidal extension, >4cm)
– Total Thyroi...
NCCN: Thyroid cancer – Papillary and Follicular
Page  9
NCCN, 1.2016
RAI-Refractory Disease
• 25-50% of Metastatic Thyroid Cancers loose ability
to take up Iodine
• This is attributed to down...
Fig. 1. Survival after the discovery of metastases according to the presence or absence of 131I uptake in the metastases.
...
Fig. 2. Survival after the discovery of distant metastases according to the age at discovery and to the extent of disease....
Fig. 3. Survival after the discovery of distant metastases. Group 1, Patients with 131I uptake who attained negative imagi...
Schlumberger M et al. N Engl J Med 2015;372:621-630.
Iodine-Refractory mDTC: diagnostic criteria
Evidence of radiologic pr...
RAI-refractory disease
• Standard Chemotherapy has minimal
efficacy. 1974 Doxorubicin became the
only FDA approved drug fo...
Overcoming iodine resistance in DTC
Page  19
Selumetinib-Enhanced Radioiodine Uptake in Advanced
Thyroid Cancer
RET NTRK1 RAS BRAF
70% of PTC have one of these mutuall...
Selumetinib-Enhanced Radioiodine Uptake in Advanced
Thyroid Cancer
Inhibition of BRAF
Restores
Na-I Symporter
Ho AL et al....
Selumetinib-Enhanced Radioiodine Uptake in Advanced
Thyroid Cancer
Ho AL et al. N Engl J Med 2013;368:623-632.
Protocol Design and Changes in Iodine Uptake.
Selumetinib-Enhanced Radioiodine Uptake in Advanced
Thyroid Cancer
Ho AL et al. N Engl J Med 2013;368:623-632.
Patients sc...
Ho AL et al. N Engl J Med 2013;368:623-632.
Response to Iodine-131 Therapy with Selumetinib Treatment.
Ho AL et al. N Engl J Med 2013;368:623-632.
Iodine-124 PET-CT Scans Obtained before and after Selumetinib Treatment
in Sel...
Ho AL et al. N Engl J Med 2013;368:623-632.
Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an
NRAS ...
Targeted therapy in mDTC
Page  28
Page  29
Thyroid Cancer is associated with
aberrant cell signaling
Genetic Alteration PTC FTC
BRAF V600E 44% 0%
BRAF copy gain 3% 3...
Thyroid Cancer is associated with
aberrant cell signaling
Genetic Alteration PTC FTC
BRAF V600E 44% 0%
BRAF copy gain 3% 3...
Cell signalling in differentiated thyroid cancer
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
RE...
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
Motesanib
Sorafenib
Sunitinib
Vandetanib
XL-184
Axi...
Targets of Kinase Inhibitors
Compound
Name VEGFR BRAF PDGFR KIT RET Other
Sorafenib + + + + + FLT-3
Sunitinib + + + FLT-3
...
UPCC 03305: Sorafenib in Advanced
Thyroid Cancer
February 2006-February 2011
Gupta-Abramson V, et al. J Clin Oncol 2008;26...
UPCC 03305: Best Response in
46 Evaluable Patients
Papillary
Follicular/Hürthle Cell
Medullary
Poorly Differentiated/Anapl...
Eligibility criteria
• Locally advanced
or metastatic DTC
• Progression
within 14 months
• RAI refractory
• No prior targe...
Brose M, DECISION trial, ASCO, 2013
Brose M, DECISION trial, Lancet, 2014
Brose M, DECISION trial, ASCO, 2013
Brose M, DECISION trial, Lancet, 2014
Brose M, DECISION trial, ASCO, 2013
Brose M, DECISION trial, Lancet, 2014
Brose M, DECISION trial, ASCO, 2013
Brose M, DECISION trial, Lancet, 2014
LENVATINIB
Schlumberger M, et al. NEJM, 2015
Schlumberger M et al. N Engl J Med 2015;372:621-630.
Schlumberger M et al. N Engl J Med 2015;372:621-630.
Kaplan–Meier Estimate of Progression-free Survival in the Intention-t...
Schlumberger M et al. N Engl J Med 2015;372:621-630.
Schlumberger M et al. N Engl J Med 2015;372:621-630.
Copyright © 2016 Elsevier Ltd Terms and Conditions
BRAFm - RAI-Refractory PTC 51
No prior multikinase therapy (Cohort 1) 2...
The Lancet Oncology DOI: (10.1016/S1470-2045(16)30166-8) 
Copyright © 2016 Elsevier Ltd Terms and Conditions
Vemurafenib i...
The Lancet Oncology DOI: (10.1016/S1470-2045(16)30166-8) 
Copyright © 2016 Elsevier Ltd Terms and Conditions
No prior mult...
Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable
papillary thyroid cancer refractory to radioact...
Progression after TKIs
Page  52
De Souza JA, ASCO, 2016, Abstract 6013
Proc ASCO, 2013, Abstract 6024
Overcoming Sorafenib Resistance
De Souza JA, ASCO, 2016, Abstract 6013
Ann Wild Gramza, ASCO, 2016
Graphic adapted from
Keefe SM, et al. Clin Cancer Res. 2010;16:778-83.
Motesanib
Sorafenib
Sunitinib
Vandetanib
XL-184
Axi...
UPCC 19309: Everolimus +
Sorafenib for DTC patients who
progress on Sorafenib alone
n=35
Eligibility criteria
• Metastatic...
Min Lim S, Oncotarget, 2016
Somatic mutations that confer exceptional
response to everolimus (NGS)
Min Lim S, Oncotarget, 2016
Min Lim S, Oncotarget, 2016
Somatic mutations that confer exceptional
response to everolimus (NGS)
NCCN: Thyroid cancer – Papillary and Follicular
Page  62
NCCN, 1.2016
Conclusions
RAI-Refractory mDTC
Sorafenib
Lenvatinib
Selumetinib + RAI in
NRAS mutated
Vemurafenib in BRAF
mutatedPreferre...
YOUR LOGO
@onconerd
Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma
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En el marco del Simposio de Cáncer de Cabeza y Cuello y Pulmón de la Asociación Colombiana de Hematología Oncología, ACHO, Bogotá, 28.07.2016

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Treatment of radioactive iodine-refractory metastatic differentiated thyroid carcinoma

  1. 1. Treatment of radioactive iodine- refractory differentiated thyroid carcinoma Mauricio Lema Medina MD – Clínica de oncología Astorga, Clínica SOMA, Medellín ACHO, Bogotá, 29.07.2016
  2. 2. Page  2 @onconerd
  3. 3. Mauricio Lema Medina Conflicts of interest Consulting and honoraria as a speaker: Pfizer, MSD, Novartis, ROCHE, Aztra-Zeneca, Boehringer-Ingelheim. Harrisons’s, 19th Ed.
  4. 4. >5.0cm 2.1-5.0cm Thyroid cancer in the United States 0-1.0cm 1.1-2.0cm Davies, JAMA 2006 295:2164
  5. 5. Medullary Anaplastic Papillary Follicular Differentiated Thyroid Cancer (DTC)
  6. 6. Thyroid Cancer: Treatment Strategy • High Risk: (Age >45, male, metastasis, extrathyroidal extension, >4cm) – Total Thyroidectomy – RAI (131 I) Ablation – TSH Suppression Therapy with Thyroid Hormone – Follow Serial Thyroglobulin Levels (Tg) – XRT for recurrent local disease/positive margins – Surveillance: NeckUS, Tg, Neck MRI, Chest CT, RAI Whole body scan, FDG-PET
  7. 7. NCCN: Thyroid cancer – Papillary and Follicular Page  9 NCCN, 1.2016
  8. 8. RAI-Refractory Disease • 25-50% of Metastatic Thyroid Cancers loose ability to take up Iodine • This is attributed to down regulation of the Na+/I- Symporter (NIS) and other genes of NaI metabolism In other words, the cancer cells “forget” how to take up iodine and so they are immune to the treatment.
  9. 9. Fig. 1. Survival after the discovery of metastases according to the presence or absence of 131I uptake in the metastases. Published in: C. Durante; N. et al; The Journal of Clinical Endocrinology & Metabolism 2006, 91, 2892-2899. DOI: 10.1210/jc.2005-2838 Copyright © 2006
  10. 10. Fig. 2. Survival after the discovery of distant metastases according to the age at discovery and to the extent of disease. 131I uptake was not taken into account, but was closely linked to the two other prognostic factors, and was invariably present in young patients with small metastases (group 1) and rarely present in older patients with large metastases (group 2). Group 1, Patients younger than 40 yr of age with metastases that were not visible on radiographs or that were micronodular (<1 cm in diameter). Group 2, Patients older than 40 yr with macronodular lung metastases or multiple bone metastases. Group 3, Patients older than 40 yr with normal x-rays or micronodular metastases and patients younger than 40 yr with macronodular lung metastases. Published in: C. Durante; et al; The Journal of Clinical Endocrinology & Metabolism 2006, 91, 2892-2899. DOI: 10.1210/jc.2005-2838 Copyright © 2006 Less than 40 yo with small metastases Older than 40 yo with macronodular lung metastases or bone metastases RAI-Sensitive RAI-Refractory
  11. 11. Fig. 3. Survival after the discovery of distant metastases. Group 1, Patients with 131I uptake who attained negative imaging studies. Group 2, Patients with 131I uptake who did not attain negative imaging studies. Group 3, Patients with no 131I uptake. Published in: C. Durante; et al; The Journal of Clinical Endocrinology & Metabolism 2006, 91, 2892-2899. DOI: 10.1210/jc.2005-2838 Copyright © 2006 Attained negative imaging studies Did not attain negative imaging studies
  12. 12. Schlumberger M et al. N Engl J Med 2015;372:621-630. Iodine-Refractory mDTC: diagnostic criteria Evidence of radiologic progression within 13 months and at least one of the following criteria: At least one measurable lesion without iodine uptake on any iodine-131 scan, At least one measurable lesion that had progressed according to the Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1, criteria within 12 months after iodine-131 therapy despite iodine-131 avidity at the time of treatment, Or cumulative activity of iodine-131 that was >600 mCi
  13. 13. RAI-refractory disease • Standard Chemotherapy has minimal efficacy. 1974 Doxorubicin became the only FDA approved drug for the treatment of advanced thyroid cancer. •No longer used because recent data shows response is 5% •High toxicity in patient with otherwise good QOL Cooper DS, et al. Thyroid. 2009;9:1176-214. Hodak SP, Carty SE. Oncology. 2009;23:775-6. Mehra R, Cohen RB. Hematol Oncol Clin North Am. 2008;22:1279-95,xi.
  14. 14. Overcoming iodine resistance in DTC Page  19
  15. 15. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer RET NTRK1 RAS BRAF 70% of PTC have one of these mutually exclusive mutations MAP Kinase pathway DECREASE of the Na-I Symporter Thyroid biosynthesis genes Thyroid peroxidaseHo AL et al. N Engl J Med 2013;368:623-632.
  16. 16. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer Inhibition of BRAF Restores Na-I Symporter Ho AL et al. N Engl J Med 2013;368:623-632.
  17. 17. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer
  18. 18. Ho AL et al. N Engl J Med 2013;368:623-632. Protocol Design and Changes in Iodine Uptake.
  19. 19. Selumetinib-Enhanced Radioiodine Uptake in Advanced Thyroid Cancer Ho AL et al. N Engl J Med 2013;368:623-632. Patients screened 24 Patients that could be evaluated 20 BRAF mutations 9 NRAS mutations 5 Increased Iodine-24 uptake 12 Increased Iodine-24 uptake enough for RAI therapy 8 Increased Iodine-24 uptake in BRAF mutated patients 4/9 Increased Ioding-24 uptake in NRAS mutated patients 5/5 Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease.
  20. 20. Ho AL et al. N Engl J Med 2013;368:623-632. Response to Iodine-131 Therapy with Selumetinib Treatment.
  21. 21. Ho AL et al. N Engl J Med 2013;368:623-632. Iodine-124 PET-CT Scans Obtained before and after Selumetinib Treatment in Selected Patients with Positive Responses.
  22. 22. Ho AL et al. N Engl J Med 2013;368:623-632. Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an NRAS Mutation Who Later Received Radioiodine.
  23. 23. Targeted therapy in mDTC Page  28
  24. 24. Page  29
  25. 25. Thyroid Cancer is associated with aberrant cell signaling Genetic Alteration PTC FTC BRAF V600E 44% 0% BRAF copy gain 3% 35% RET/PTC (1 and 3) 20% 0% RAS 8-10% 17-45% PI3KCA mutations 3% 6% PI3KCA copy gain 12% 28% PTEN 2% 7% Pax8/PPARγ 0% 35% Total >70% >65% MAPKinase PI3K/AKT Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007
  26. 26. Thyroid Cancer is associated with aberrant cell signaling Genetic Alteration PTC FTC BRAF V600E 44% 0% BRAF copy gain 3% 35% RET/PTC (1 and 3) 20% 0% RAS 8-10% 17-45% PI3KCA mutations 3% 6% PI3KCA copy gain 12% 28% PTEN 2% 7% Pax8/PPARγ 0% 35% Total >70% >65% MAPKinase PI3K/AKT Nikiforov, Mod Path, 2008, Xing Endocrine Rel Ca(2005), Wang et al, 2007
  27. 27. Cell signalling in differentiated thyroid cancer Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83. RET/PTC • HIF1a • Inhibition of apoptosis • Migration EGFR PI3K VEGFR-2 Endothelial Cell • Migration • Angiogenesis Ras B-Raf MEK ERK PI3K AKT mTOR S6K Ras Raf MEK ERK AKT mTOR S6K Tumor Cell • Growth • Survival • Proliferation • Growth • Survival • Proliferation
  28. 28. Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83. Motesanib Sorafenib Sunitinib Vandetanib XL-184 Axitinib Motesanib Sorafenib Sunitinib Vandetanib Vandetanib Sorafenib Sorafenib Targeting cell signaling in thyroid cancer RET/PTC • HIF1a • Inhibition of apoptosis • Migration EGFR PI3K VEGFR-2 Endothelial Cell • Migration • Angiogenesis Ras B-Raf MEK ERK PI3K AKT mTOR S6K Ras Raf MEK ERK AKT mTOR S6K Tumor Cell • Growth • Survival • Proliferation • Growth • Survival • Proliferation Everolimus Sirolimus Everolimus Sirolimus
  29. 29. Targets of Kinase Inhibitors Compound Name VEGFR BRAF PDGFR KIT RET Other Sorafenib + + + + + FLT-3 Sunitinib + + + FLT-3 Axitinib (AG-013736) + + + Motesanib (AMG-706) + + + + Pazopanib (GW786034) + + + Vandetanib + + EGFR Cabozantinib (XL184) + + C-MET Lenvatinib (E7080) + + + + FGFR
  30. 30. UPCC 03305: Sorafenib in Advanced Thyroid Cancer February 2006-February 2011 Gupta-Abramson V, et al. J Clin Oncol 2008;26:4714–9 n=55 Eligibility criteria • Metastatic, iodine refractory thyroid cancer • Life expectancy >3 months • Evidence of PD within 6 months of study entry • ECOG 0–2 • Good organ and bone marrow function Sorafenib 400mg b.i.d. Primary endpoints • RECIST • PFS • Response rate b.i.d. = twice daily; RECIST = Response Evaluation Criteria In Solid Tumors; ULN = upper limit of normal
  31. 31. UPCC 03305: Best Response in 46 Evaluable Patients Papillary Follicular/Hürthle Cell Medullary Poorly Differentiated/Anaplastic 30 20 10 0 –10 –20 –30 –40 –50 –60 –70 –80 –90 –10 ChangeinsumoftargetlesionbyRECIST comparedtobaseline(%) PD SD PR Best response of advanced thyroid cancer patients to sorafenib Brose M, et al. J Clin Oncol 2009;27(May 20 Suppl.):301s (Abstract 6002)
  32. 32. Eligibility criteria • Locally advanced or metastatic DTC • Progression within 14 months • RAI refractory • No prior targeted therapy, chemotherapy or thalidomide Phase III Study of Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine Refractory Thyroid Cancer (DECISION) trial • An International, multicentre, randomised, double-blind, phase III study of sorafenib versus placebo in locally advanced/metastatic RAI-refractory DTC www.clinicaltrials.gov. NCT00984282 Off study Disease progression Crossover or continue sorafenib 400mg orally b.i.d. Randomisation(1:1) (n=380) Progression Sorafenib 400mg orally b.i.d. Placebo Investigator’s decision n=190 n=190 Primary Endpoint: PFS (RECIST) Independent review Met primary endpoint January 2013 Secondary Endpoints: OS, TTP, RR, DCR, PRO, PK Safety Exploratory Biomarkers
  33. 33. Brose M, DECISION trial, ASCO, 2013 Brose M, DECISION trial, Lancet, 2014
  34. 34. Brose M, DECISION trial, ASCO, 2013 Brose M, DECISION trial, Lancet, 2014
  35. 35. Brose M, DECISION trial, ASCO, 2013 Brose M, DECISION trial, Lancet, 2014
  36. 36. Brose M, DECISION trial, ASCO, 2013 Brose M, DECISION trial, Lancet, 2014
  37. 37. LENVATINIB Schlumberger M, et al. NEJM, 2015
  38. 38. Schlumberger M et al. N Engl J Med 2015;372:621-630.
  39. 39. Schlumberger M et al. N Engl J Med 2015;372:621-630. Kaplan–Meier Estimate of Progression-free Survival in the Intention-to-Treat Population.
  40. 40. Schlumberger M et al. N Engl J Med 2015;372:621-630.
  41. 41. Schlumberger M et al. N Engl J Med 2015;372:621-630.
  42. 42. Copyright © 2016 Elsevier Ltd Terms and Conditions BRAFm - RAI-Refractory PTC 51 No prior multikinase therapy (Cohort 1) 26 Prior multikinase therapy (Cohort 2) 25 Vemurafenib 960 mg PO twice a day Endpoint: investigator-assessed ORR Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial Brose MS, Lancet Oncol, 2016
  43. 43. The Lancet Oncology DOI: (10.1016/S1470-2045(16)30166-8)  Copyright © 2016 Elsevier Ltd Terms and Conditions Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial
  44. 44. The Lancet Oncology DOI: (10.1016/S1470-2045(16)30166-8)  Copyright © 2016 Elsevier Ltd Terms and Conditions No prior multikinase therapy Prior multikinase therapy
  45. 45. Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial Copyright © 2016 Elsevier Ltd Terms and Conditions BRAFm - RAI-Refractory PTC 51 No prior multikinase therapy (Cohort 1) 25 Prior multikinase therapy (Cohort 2) 26 PR in Cohort 1 10/26 DCR in Cohort 1 9/26 Median DOR Cohort 1 16 months PR in Cohort 2 6/22 6-mo DCR in Cohort 2 6/22 Median DOR in Cohort 2 27 weeks “Vemurafenib showed antitumour activity in patients with progressive, BRAFV600E-positive papillary thyroid cancer refractory to radioactive iodine who had never been treated with a multikinase inhibitor. As such, this agent represents a potential new treatment option for these patients”. Brose MS, Lancet Oncol, 2016
  46. 46. Progression after TKIs Page  52
  47. 47. De Souza JA, ASCO, 2016, Abstract 6013
  48. 48. Proc ASCO, 2013, Abstract 6024 Overcoming Sorafenib Resistance
  49. 49. De Souza JA, ASCO, 2016, Abstract 6013
  50. 50. Ann Wild Gramza, ASCO, 2016
  51. 51. Graphic adapted from Keefe SM, et al. Clin Cancer Res. 2010;16:778-83. Motesanib Sorafenib Sunitinib Vandetanib XL-184 Axitinib Motesanib Sorafenib Sunitinib Vandetanib Vandetanib Sorafenib Sorafenib Targeting cell signaling in thyroid cancer RET/PTC • HIF1a • Inhibition of apoptosis • Migration EGFR PI3K VEGFR-2 Endothelial Cell • Migration • Angiogenesis Ras B-Raf MEK ERK PI3K AKT mTOR S6K Ras Raf MEK ERK AKT mTOR S6K Tumor Cell • Growth • Survival • Proliferation • Growth • Survival • Proliferation Everolimus Sirolimus Everolimus Sirolimus
  52. 52. UPCC 19309: Everolimus + Sorafenib for DTC patients who progress on Sorafenib alone n=35 Eligibility criteria • Metastatic, iodine refractory thyroid cancer • Life expectancy >3 months • PD on sorafenib • ECOG 0–2 • Good organ and bone marrow function Sorafenib + Everolimus Intra-patient Dose escalation Primary endpoints • RECIST • PFS • Response rate b.i.d. = twice daily; RECIST = Response Evaluation Criteria In  Solid Tumors; ULN = upper limit of normal  22 patients accrued so far
  53. 53. Min Lim S, Oncotarget, 2016 Somatic mutations that confer exceptional response to everolimus (NGS)
  54. 54. Min Lim S, Oncotarget, 2016
  55. 55. Min Lim S, Oncotarget, 2016 Somatic mutations that confer exceptional response to everolimus (NGS)
  56. 56. NCCN: Thyroid cancer – Papillary and Follicular Page  62 NCCN, 1.2016
  57. 57. Conclusions RAI-Refractory mDTC Sorafenib Lenvatinib Selumetinib + RAI in NRAS mutated Vemurafenib in BRAF mutatedPreferred, unavailable Not ready for prime-time Needs more data
  58. 58. YOUR LOGO @onconerd
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En el marco del Simposio de Cáncer de Cabeza y Cuello y Pulmón de la Asociación Colombiana de Hematología Oncología, ACHO, Bogotá, 28.07.2016

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