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NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy · PDF fileLogo NEUROENDOCRINE TUMORS Somatostatin Receptor Scintigraphy Dr. Augusto Llamas Olier Nuclear Medicine Department

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    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

    Dr. Augusto Llamas Olier

    Nuclear Medicine Department

    Instituto Nacional de Cancerología

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    Neuroendocrine tumors

    Heterogeneous group of neoplasias derived from NE cells of the diffuse

    endocrine system.

    Characterized by:

    Having neurosecretory granules

    Producing bioactive amines (serotonine, catecholamines, histamine) and

    polypeptidic hormones (somatostatin, gastrin).

    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

    Basis of the clinical utility of radiolabelled specific ligands

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    DIAGNOSIS AND THERAPEUTIC APPROACH OF NETs

    • I-131/I-123 Metaiodobencylguanidine (MIBG)

    Cellular structures for amine uptake and storage

    Prefered indications: pheocromocytoma (specif. 80-100%) and

    neuroblastoma (specif. 84%).

    Sensitivity: 36% - 85%

    • Somatostatin analogs (SA)

    Overexpression of receptors for regulatory peptides (i.e.,

    somatostatin).

    Sensitivity: 78% - 100% (Indium-111 DTPA –Octreotide)

    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

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    DIAGNOSIS AND THERAPEUTIC APPROACH OF NETs

    Other radioligands

    • [68Ga-DOTA]-D-Phe1-Tyr3-Octreotide (68Ga-DOTA TOC)

    • [68Ga-DOTA]-Tyr3-Octreotate (68Ga-DOTA TATE)

    • [90Y-DOTA]-D-Phe1-Tyr3-Octreotide (90Y-DOTA TOC)

    • [177Lu-DOTA ]-Tyr3-Octreotate (177Lu-DOTA TATE)

    • [18F]-L-dihydroxyphenylalanine (18F-L-DOPA)

    • [11C]-5-hydroxytryptophan (11C-5-HTP)

    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

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    SOMATOSTATIN

    Peptide regulatory

    CNS and peripheral tissues

    Hypothalamus

    Action:

    Neurotransmitter

    Hormonal effects:

    Inhibitory peptide

    GH

    Insuline

    Glucagon

    Gastrin

    Serotonin

    Calcitonin

    Other effects:

    Antiproliferative

    in tumors

    Specific regulation

    of immune responses

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    Somatostatin Receptor Scintigraphy

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    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

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    Mediated by membrane receptors

    Cloned : sstr1 – sstr5

    SOMATOSTATIN EFFECTS

    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

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    INTERNALIZATION

    Endosome

    (dephosphorylation)

    RECYCLED

    (resensitized)

    Lysosome

    In-111 DTPA D-Phe OC

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    SOMATOSTATIN RECEPTOR EXPRESSION

    Normal human tissues

    High incidence and density in human neoplasias

    Non-endocrine

    Non-neural cell tumors

    Lymphoma

    Breast cancer

    Renal-cell cancer

    Hepatocellular cancer

    Prostate cancer

    Sarcoma

    Gastric carcinoma

    Pituitary adenomas

    Pancreatic islet-cell tumors

    Gastroenteral NE tumors (carcinoids)

    Paragangliomas

    Pheochromocytomas

    SCLC

    Medullary thyroid cancer

    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

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    DOMINATING EXPRESSION OF sstr 2

    Simultaneous expression of multiple subtypes of sstr

    Prostate: sstr 1

    Non-functioning pituitary adenomas: sstr3

    Inhibitory, antiproliferative and apoptotic effects

    Basis for the clinical application of SA

    Human hypophysis ≠ sstr 4

    ~100% gastrinomas express sstr

    10%-50% insulinomas express sstr

    ¿Tumors with dominant sstr 4 expression?

    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

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    The expression of somatostatin receptors

    of tumor diseases

    Sarcoidosis: active granulomas

    Rheumatoid arthritis: synovial vessels

    Intestinal inflammatory disease: vascular

    Is not specific

    Tumoral or peritumoral

    Blood vessels

    Immune cells

    Contaminant normal cells

    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

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    Servicio de Medicina Nuclear – Instituto Nacional de Cancerología

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    Servicio de Medicina Nuclear – Instituto Nacional de Cancerología

  • Logo 23-03-06

    9-10-08

    Servicio de Medicina Nuclear – Instituto Nacional de Cancerología

  • Phe

    Trp

    Lys

    Tre

    Ala - Phe - Asn -

    Thr - Ser -

    H -

    Phe -

    Gly - Cys - Lys -

    Cys - OH -

    s

    s DTrp

    Somatostatin -14 Octreotide

    Half-life < 3 min Half-life: 6 h

    D Phe - Cys -

    Cys - Thr –

    (ol)

    s

    s

  • Phe

    DTrp

    Lys

    Thr

    D Phe - Cys -

    Cys - Thr –

    (ol)

    s

    s

    - DTPA - In-

    111

    ('"In-Pentetreotide) OctreoScan®; Mallinckrodt.

    10 µg of peptide; 222 MBq (6 mCi); 5 MBq/kg (0,14 mCi/kg) of Indium-111

    -diethylene triamine pentaacetic acid°-D-Phe1] octreotide ['"Indium

    No adverse effects < 50 µg

    Physical half-life: 2,83 days

  • Tyr

    DTrp

    Lys

    Thr

    D Phe - Cys -

    Cys - Thr –

    (ol)

    s

    s

    - DOTA - Ga-

    68

    68Ga-DOTA-Tyr3-OC

    Phe

    DTrp

    Lys

    Thr

    D Phe - Cys -

    Cys - Thr –

    (ol)

    s

    s

    - DTPA - In-

    111

    111In-DTPA-OC

    Tyr

    Thr -

    Lys

    Thr

    Cis -

    Cys -

    s

    s

    DPhe -

    DTrp

    Octreotate

    99mTc-HYNIC-TOC

    Tc-

    99m - HYNIC -

    Affinity 9 : 1

    Affinity for sstr2 (DTPA o DOTA):

    14- to 17-fold >octreotide

    8- to10-fold >TOC

    Affinity 3 : 1

    Higher affinity, higher rate of internalization, higher tumor uptake

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    99mTc- Hynic-Tyr3-Octreotide 111In-DTPAº-Phe1-Octreotide

    Nuclear Medicine Department – Instituto Nacional de Cancerología

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    Characteristics of a good scintigraphic scan

    • Dose: 222 MBq (6 mCi, adults), 5 MBq/Kg (0.14 mCi/Kg, children)

    • Spect should have enough counts per projection

    • 6-fold contrast enhancement

    • Separate overimposed structures

    • Enhanced diagnostic sensitivity

    • High-count static images are better than wholebody scanning

    • Special projections and delayed imaging to solve doubts

    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

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    Characteristics of a good scintigraphic scan

    • Dose: 222 MBq (6 mCi, adults), 5 MBq/Kg (0.14 mCi/Kg, children)

    • Spect should have enough counts per projection

    • 6-fold contrast enhancement

    • Separate overimposed structures

    • Enhanced diagnostic sensitivity

    • High-count static images are better than wholebody scanning

    • Special projections and delayed imaging to solve doubts SPECT/ CT

    NEUROENDOCRINE TUMORS

    Somatostatin Receptor Scintigraphy

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    Servicio de Medicina Nuclear – Instituto Nacional de Cancerología

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    Physiologic vs pathologic

    gastric uptake

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    Spect corporal total:

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    Servicio de Medicina Nuclear – Instituto Nacional de Cancerología

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    Servicio de Medicina Nuclear – Instituto Nacional de Cancerología

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    SPATIAL RESOLUTION vs MOLECULAR RESOLUTION

    CT/ MR Structural

    Molecular resolution in the range of 2 nm

    S en

    si tiv

    ity

    Spatial Resolution

    mmol

    mol

    pmol

    nmol

    1 mm 5 mm 10 mm

    PET/ SPECT Metabolism

    Sensitivity: capacity to detect a molecular marker Courtesy: Dr. Diana Páez

    MOLECULAR IMAGING

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    • Post surgical follow-up

    • Screen for recurrences when

    tumor markers are elevated

    • Differential diagnosis between

    NETs are space-occupying lesions

    • Radioguided surgery of small

    tumors/ confirmation of complete

    resection.

    • Search for primary tumor

    • Assess extent of disease

    • Assess treatment response.

    • Select patients for radionuclide

    treatment

    IN