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MASOUD MOSLEHI NUCLEAR PHYSICIAN

MASOUD MOSLEHI NUCLEAR PHYSICIAN. Nuclear Medicine in Neuroendocrine Tumors. Somatostatin Receptor Scintigraphy. Somatostatin receptors common sites. Nervous system Endocrine glands Immune system GI tract. SSR: Normal sites. Brain Kidney GI

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MASOUD MOSLEHI NUCLEAR PHYSICIAN

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  1. MASOUD MOSLEHI NUCLEAR PHYSICIAN

  2. Nuclear Medicine in Neuroendocrine Tumors

  3. Somatostatin Receptor Scintigraphy

  4. Somatostatinreceptors common sites • Nervous system • Endocrine glands • Immune system • GI tract

  5. SSR: Normal sites • Brain • Kidney • GI • Pancreas • PNS • Vessels • Thyroid • Spleen • Immune system(activated lymphocytes and monocytes)

  6. NETs with SSR • -Pituitary adenoma: GH or TSH producing, nonfunctioning, minority of prolactin producing • -VIP secreting tumors • -GIT and lung carcinoid • -Pheochromocytoma • -MTC • -Small cell lung cancer • -Gastrinoma • -Glucagonoma • -Insulinoma

  7. Distribution of SST-Receptors in NETsin vitro studies • Gastrinoma, Glucagonoma 100 % • Paraganglioma 92 % • Carcinoids 88% • Pheochromocytoma 73 % • Insulinoma 72% • Small Cell Lung Cancer 57 % • Medullary Thyroid Carcinoma 38 % Reubi et al. JNM 1999 adapted from Curr Med Chem 2000

  8. Ability to Detect Disease

  9. SSR: other tumors • -Breast cancer • -Lymphoma • -Renal cell ca. • -Hepatoma • -Prostate cancer • -Gastric cancer • -Sarcoma • -Benign and malignant bone tumors • -Brain tumors (meningioma , neuroblastoma, medulloblastoma, astrocytoma)

  10. SSR: Not specific for tumors • Granulation tissue (recent surgery) • Sarcoidosis • TB, Wegner • R.A.,SLE, • I.B.D. Celiac • Hashimoto th., Graves • Aspergillosis • Cavernous hemangioma • Pneumonitis( radiation, bacterial)

  11. Imaging protocol • D/C octreotide 24 hours before, monitor patient for withdrawal • In suspected insulinoma, IV glucose should be available for potential risk of severe hypoglycemia • Well hydration before and after injection • Dose 111In: 222MBq or 6mCi and 5 Mbq/kg for children(enough for SPECT), not injected with IV line for TPN • Dose 99mTc : 20-25 mCi

  12. Imaging protocol • Void before imaging • Planar and SPECT in 6-24h (decreased BKG) • Repeat scan after 24h if abdominal concentration (111-In) • Spot views with enough count instead of low count whole body scan • SPECT is necessary • Major clearance by kidneys (2%) by hepatobiliary system) • It is not known whether is removed by dialysis

  13. Normal uptake • Pituitary (faint) • Thyroid (faint) • Salivary glands (faint) • Liver • Spleen • Bowel (heptobiliary excretion), necessitating laxatives • Kidneys (by receptors and re-absorption) • Bladder

  14. Normal octreotide scan

  15. Role of SRI in NET • Detect resectable tumors not recognized with conventional techniques • Prevention of surgery in widespread metastases • To select patients for radionuclide octreotide therapy

  16. Role of SRI in NET (cont) • SRS will not detect the ~10% of tumors that fail to express somatostatin receptors • the detection limit is about 0.5 cm. • The advantage of SRS over CT and MRI: the ability to image all body regions , evaluation of tumors for potential octreotide palliation therapy .

  17. Metastatic gastrinoma

  18. Insulinoma

  19. Insulinoma

  20. gastrinoma

  21. 73yr-old lady with hypoglycemic events

  22. PET in Neuroendocrine Tumors

  23. PET Scan • >90% of NE tumors are visualized by PET Scan1 • 8FDG • 68Ga-DOTA • 18F-Dopamin • 11C-epinephrin (quantitative)

  24. comparison of 111In-pentetreotide SSTR scintigraphy (A) and 68Ga-DOTATATE (B) PET/CT in patient with metastaticlow-grade cecal NET evaluated before PRRT. In liver, retroperitonealand thoracic lymph nodes, and bones, PET/CT shows multiple metastases.

  25. Small liver metastasis (A), not seen on contrast-enhanced (portal-venous phase) CT scan as well as small lymph node (B) and bone (C) metastases as detected by 68Ga-DOTA-NOC receptor PET/CT.

  26. Treatment Of Neuroendocrine Tumor with Radionuclide

  27. PRRT (Peptide Receptor Radionuclide Therapy)

  28. Somatostatin receptor-based radionuclide Therapy A new treatment modality for patients with inoperable or metastasized endocrine tumors.

  29. Criteria for PRRT • Non surgical, metastatic tumors • No response to medical therapies • Receptor expression • High affinity subtype • High density • Homogeneous distribution • Radiosensitive tumors

  30. PRRT • Diagnostic scans with radiolabelled somatostatin can be used to identify suitable candidates for PRRT.

  31. PRRT: • [111In-DTPA0] octreotide • [90Y-DOTA0,Tyr3] octreotide • [177Lu-DOTA0,Tyr3] octreotate

  32. [111In-DTPA0] octreotide: Because at in the mid- to late 1990s no other chelated somatostatin analogs labeled with β-emitting radionuclides were available, early studies used [111In-DTPA0] octreotide for PRRT. Initial studies with high dosages of [111In-DTPA0] octreotide in patients with metastasized neuroendocrine tumors were encouraging with regard to symptom relief, but partial remissions (PRs) were exceptional.

  33. 111In-pentetreotide therapy February 1999 April 1999 October 1999

  34. [90Y-DOTA0,Tyr3] octreotide: higher affinity for the somatostatin receptor subtype-2, and a different chelator, DOTA instead of DTPA, in order to ensure a more stable binding of the intended β-emitting radionuclide 90Yttrium (90Y).

  35. [90Y-DOTA,Tyr3]octreotide • CR and PR observed in 10-30% of patients • Reversible hematology toxicity with high doses • Radiation dose to the kidney is the limiting factor • Amino-acids and plasma expanders are effective in reducing kidney dose

  36. [177Lu-DOTA,Tyr3]octreotate • Higher affinity for somatostatin receptors • Gamma emission allow post-therapeutic biodistribution studies • PR, and SD responses are reported in more patients. • Tumor regression was correlate with a high uptake on Octreoscan imaging

  37. 177Lu-DOTA-Tyr3-Octreotate

  38. Side effects and toxicity • Haematological toxicity • Dose to bone marrow due to circulating radioactivity • Rare, mild and transient • Limited data on long term follow-up • Renal toxicity • Dose due to partial reabsorption of peptides in the tubular cells • Physical characteristics of the radionuclide are important • Administration of arginine and/or lysine reduce renal uptake • Plasma expanders and amifostine are under evaluation

  39. Side effects and toxicity • Gastrointestinal toxicity • Acute nausea and vomiting in 30% of patients • Liver toxicity • Very rare, linked to liver metastases

  40. What are we doing • 37 MBq/Kg up to 2600 MBq • One cicle every 3 months • Evaluation of toxicity and response • Blood, kidney and liver function • Markers • Stop for: • Toxicity • Progession of disease

  41. Patient’s selection • Histological diagnosis of neuroendocrine tumor • Non surgical, metastatic disease • Imaging demonstration of SSTR • At list one month since the last chemotherapy treatment • Life expectancy ≥ 6 months • RBC ≥ 3’500’000 • Hb ≥ 10 mg/dl • WBC ≥ 2500/dl • PLT ≥ 100’000/dl • Creatinine ≤ 1.5 mg/dl • Bilirubine ≤ 1.5 mg/dl • Written informed consent

  42. Future of Peptide Receptor Imaging Receptor VIPAC1-2 (sst3) VIPAC1 CCK2 CCK2 GRP NTR1 NK Radioligands 123I-VIP 99mTc-TP3654 (VIP analog) 111In-DTPA-D-Asp26- Nle29,31-CCK 111In-DTPA-Minigastrin 99mTc-RP527 (bombesin derivate) 99mTc-NT-XI (neurotensin analog) 111In-DTPA-Substance P From Virgolini I et al. 2001, Reubi JC 2003

  43. Treatment

  44. MIBG Scintigraphy

  45. MIBG Scintigraphy • Meta iodo benzyl guanidine • First developed in 1979 by Wieland et al. • Analogue of neurepinephrine • 123I-MIBG: superior sensitivity, better quality, preferred in children, SPECT (159kev, half life=13.2h) • 131I-MIBG: most used (lower cost, availability), longer shelf life (2wks), possibility of delayed images

  46. MIBG: Interfering drugs • Inhibition of uptake-1 mechanism: tricyclics, cocaine, opioids, labetolol, metoral, antipsychotics • Inhibition of granular uptake: reserpine, tetrabenazine • Competition of granular uptake: N.E., serotonin, guanethidine • Depletion from granules: Sympatomimetics, reserpine, guanethidine, labetolol • Increased uptake and retention: Ca channel blockers:

  47. MIBG: Technique • Lugol (1-2mg/kg/d KI) 2days before until 5-7days after • Dose injected over 1-2min (0.5-1mci for 131I and 3-10mci with 123I) • Voiding before imaging • Whole body scan (5cm/min) or planar scan • Time: *24, 48 ,(72-120h?) for 131I-MIBG *4h (seldom), 24h, 48h(?) for 123I-MIBG *SPECT 24h

  48. Normal MIBG Scan • Heart • Lung • Nasal mucosa, lacrimal glands and kidneys with 123I-MIBG • Bilateral upper thoracic symmetric activity in children (pleural or neck muscle?) • Uterus in menstrual cycle • No bone activity (even in child) • Lack of splenic activity in child is reported

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