contributions of nuclear isotopes in medicine, a perspective · 21-02-2012  · contributions of...

Contributions of Nuclear Isotopes in Medicine, a Perspective

February 21, 2012at

American Nuclear Society, CT Section

David W. Cheng, MD, PhDAssociate Professor of Diagnostic Radiology

Chief of Nuclear MedicineMedical Director of Yale PET Center

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Basic Principles

• Basic physics in Nuclear Medicine – how are the signals generated (-rays and characteristic x-rays)

• Radiation detection and instrumentation – probe (for counting) and scanners for imaging

• Nuclear pharmacy – radio-pharmaceutical production (sterile, pyrogen-free, purity)

• Biodistribution and pathophysiology – chemical property dictates the pattern of uptake

Properties of an atom

XA

Z

X = name of elementA = atomic massZ = atomic number

Physical constants

• Charge = 1.602 x 10-19 coulomb• Rest mass of proton = 1.67 x 10-24 grams• Rest mass of electron = 9 11 x 10-28 grams• Rest mass of electron = 9.11 x 10 28 grams• 1 electron volt (eV) = 1.602 x 10-12 erg• 1 calorie (cal) = 4.18 x 107 erg• 1 angstrom (A) = 10-10 meter• 1 Curie = 3.7 x 1010 Bq (or dps)

Mass-Energy Equivalence

Particle Mass (A.U.) Energy (MeV)

electron 5 4 x 10-4 0 511electron 5.4 x 10 0.511proton 1.0073 938.20neutron 1.0087 939.5

Concept of Half-life (t1/2)• physical t1/2 = time required for the number

of radioactive atoms in a sample to decrease by 50%

• biological t1/2 = biological clearance of di lid f i l iradionuclide from a particular tissue or

organ by 50%• effective t1/2 = actual half-life of the entire

biological system:1 1 1

= +t1/2eff t1/2p t1/2b

Schematic of Anger Camera (Hal Anger, 1957)

Multichannel Analysis

10

8

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0 0 0

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0 0 0

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0 0 0 00

1

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0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150Photon Energy (keV)

Comparative Spectrums of Tc-99m & Co-57

0.6000

0.7000

0.8000

0.9000

1.0000

1.1000122-136 keV 140 keV

0.0000

0.1000

0.2000

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0.4000

0.5000

0 100 200 300 400 500 600 700 800 900 1000Channel Number

Co-57 Tc-99m

Cardiovascular Scintigraphy

• Common radiopharmaceutical– Thallium-201 chloride (Tl-201)

• t1/2p = 73 hours, photopeak = 69-83 keV (95%)• First pass extraction = 88% under normal flowp %• Redistribution

– Tc-99m Sestamibi (isonitrile, mono-cation)• t1/2p = 6 hours, photopeak = 140 keV (89%)• First pass extraction = half of Tl-201• t1/2eff > 5 hours in myocardium, no redistribution

– Tc-99m tetrafosmin– MUGA with Tc-99m RBC

Skeletal System

• Tc-99m MDP: bone metastases, acute fractures, osteomyelitis, osteonecrosis (AVN), Paget’s disease, prosthesis evaluation

• Tc 99m sulfur colloid: bone marrow portal• Tc-99m sulfur colloid: bone marrow, portal hypertension, hypersplenism

• In-111 or Tc-99m WBC: osteomyelitis versus cellulitis, fever of unknown origin

• Ga-67 citrate: osteomyelitis, fever of unknown origin, sarcoidosis, tumors

Characteristics of Gallium

• Group III element and serves as an iron analog (Fe3+)

• Circulates in the blood bound to transferrin• Accumulates due to increased blood flow

and vascular permeability• Lactoferrin is released by leukocytes

(mostly by neutrophils) at inflammtory site, which outcompetes transferrin for Ga3+

Biodistribution of Gallium

• Firmly binds to infection site by 12-24 hours• Renal excretion = 15-25%• Colon excretion is the major routeColon excretion is the major route• Biologic t1/2 = 25 days, Physical t1/21/2=78 h

(Ga-67)• Pattern can be altered by high iron pool, e.g.

multiple blood transfusions and recent gadolinium exposure (from MRI)

Applications of Gallium Scans

• Inflammation or infection in soft tissue and skeleton

• Sarcoidosis Sjogren’s syndromeSarcoidosis, Sjogren s syndrome• Tumor imaging

– More sensitive above the diaphragm– Has been largely replaced by FDG-PET

scanning

In-111 Leukocyte Scan

• Mechanisms of action – chemotaxis (attractant) and diapedesis (phagocytosis)– Inhibited by corticosteroid useInhibited by corticosteroid use

• Normal CBC contains 55-65% neutrophils and 25-35% lymphocytes– Neutrophils circulate for 5-9 hours (only 2-3%

reside in circulating blood)– Lymphocytes accumulate during chronic phase

Optimal labeling criteria

• Leukocyte count >5000/mm3 with minimum being 3000/mm3

• 50 cc is drawn to ensure sufficient number of leukocytes (20-30 cc for children)

• In vitro labeling takes 2 hours• In-111 binds to nuclear and cytoplasmic

proteins• Labeling efficiency is 75-90%

Biodistribution of labeled WBC

• Initially, it is seen in the lungs due to cellular activation from the process

• At 4 hours after re-infusion, lung activity g yand blood pool should decrease

• At 24 hours, spleen > liver > bone marrow• The critical organ is the spleen (20 rad/500

uCi) for In-111• Large intestine for Tc-99m (3.6 rad/10 mCi)

Tc-99m Leukocyte

In-111 WBC with colitis on CT

Pulmonary System

• Ventilation agents:– Xe-133 (t1/2p=5.2 days, 81 keV, 36.5%) – Xe-127 (t1/2p=36.4 days, 172, 203, 375 keV)– Rb-81/Kr-81m (t1/2p= 13 seconds, 190 keV), generator

is good only for 1 day– Tc-99m DTPA aerosol particulate (0.1-0.5 m in size)Perfusion agents:

Tc-99m MAA (10-50 m in size, 60-400k particles or <1% of normal vascular bed)

V/Q Scan

Hepatobiliary System

• HIDA scan (iminodiacetic acid) for acute and chronic cholecystitis, biliary atresia– Lidofenin (dimethyl IDA) - 84% hepatic uptake– Disofenin (disopropyl IDA) - 88% uptake

• competes well up to 10 mg/dl bilirubin

– Mebrofenin (bromotriethyl IDA) - 98% uptake• competes well up to 28 mg/dl bilirubin

• Tc-99m sulfur colloid for liver-spleen imaging• Tc-99m RBC for hemangioma versus tumor

HIDA Scan

Quantitative HIDA Scan

Gastrointestinal System• Gastrointestinal bleeding - Tc-99m RBC

– can detect slow bleed at 0.05-0.1 ml/min• Gastric emptying - Tc-99m sulfur colloid mixed

with standardized diet• Ectopic gastric mucosa - Tc-99m TcO4

-

– Meckel’s diverticulum• Cimetidine - inhibits release• Glucagon - antiperistaltic effect delays washout• Pentagastrin - increases uptake and duration of uptake

• Helicobacter Pylori - C-14 urea breath test• Malabsorption -

– Co-57/Co-60 cobalamin Schilling test – Tc-99m human serum albumin for protein losing

enteropathy

Endocrine System

• Thyroid benign– I-123 (t1/2p=13.2 hrs, 159 keV, 83.4%) for

uptake and imagingp g g– Tc-99m for imaging only (symporter without

organification information)– I-131 (t1/2p=8.1 days, 364 keV, 81%) for uptake

and imaging

Cold thyroid nodule

Graves’ Disease

Multinodular Goiter

Endocrine System (cont’d)

• Papillary carcinoma - 60-70% of well-differentiated thyroid cancers, metastasizes mostly via lymphatic system but also via hematogenous to lungsto lungs

• Follicular carcinoma - 20-30% of well-differentiated thyroid cancers, metastasizes via hematogenously to skeleton – Hurthle cell - a variant of follicular carcinoma

• Medullary - parafollicular “C” cells

29 y.o. female with papillary CA

52 y.o. female with BRAF(+) follicular variant papillary CA

41 y.o. male with 3 cm papillary CA

Parathyroid Imaging

• Subtraction imaging with Tl-201 chloride/Tc-99m pertechnetate– Sensitivity reported to be 85-95% for larger primary

adenomas (300 mg)adenomas (300 mg)• Tc-99m Sestamibi/I-123 subtraction imaging

– 2 day protocol with I-123 given the first day• Tc-99m Sestamibi only

– Planar and SPECT imaging at 15 and 120 minutes post-injection

– Sensitivity at Yale has been 75-80%

PET/CTDiscovery LS16 Discovery ST4

Fixed &Mobile

Positron Emission Tomography

• Positron = anti-matter of an electron• Conservation of mass law (E=mc2) yields

511 keV x 2 photons diametrically (at 180o511 keV x 2 photons diametrically (at 180apart—coincidence photons)

• Detector material has to be more dense to increase the capture ratio (e.g. BGO, LSO, GSO, LySO crystal)

• Positron Emitter - nuclear decay produces a positron

• Positron travels short distance and annihilates with electron

• Annihilation process produces two photons • Each at 511KeV

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PET Training

Each at 511KeV• Photons emitted 180o apart

• Simultaneous detection of the two 511KeV photons produces a coincidence pair.

• Count of each coincidence pair stored as Sinogram (Raw Data)

• Sinogram reconstructed to produce activity based transaxial slice

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Coincidence Detection

Common PET Radiopharmaceuticals

• Rb-82m (t1/2p=75 sec, Emax=3.35 MeV): eluted from a portable Sr82Cl(t1/2p=25.5 days)/Rb82Cl/Kr82Cl generator

• O-15 (t1/2p=2.07 min, 99.9%, Emax=1.72 MeV, rangemax=8.2 mm H2O): H2O15

• N-13 (t1/2p=9.96 min, 100%, Emax=1.19 MeV, rangemax=5.39 mm H2O): N13H3

• C-11 (t1/2p=20.4 min, 99+%, Emax=0.96 MeV, rangemax=4.108 mm H2O): C11-neuroreceptors

• F-18 (t1/2p=109.7 min, 97%, Emax=0.635 MeV, rangemax=2.39 mm H2O): F18DG

• Positron Emitter - nuclear decay produces a positron

• Positron travels short distance and annihilates with electron

• Annihilation process produces two photons • Each at 511KeV

P������� A�����������

Detector Ring

511K�V

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PET Training

Each at 511KeV• Photons emitted 180o apart

• Simultaneous detection of the two 511KeV photons produces a coincidence pair.

• Count of each coincidence pair stored as Sinogram (Raw Data)

• Sinogram reconstructed to produce activity based transaxial slice

511K�V

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2

2-Fluoro-2-DeoxyGlucose

• F-18 FDG is taken up like glucose by tissues at a rate proportional to demand for glucose

• Phosphorylated and then trapped intracellular• Radionuclide (F-18) releases a positron whose

annihilation photons can be detected• Coincidence detection will lower interference

from random photons in the vicinity

FDG accumulation

• other characteristics of tumor cells– increased level of hexokinase– decreased level of glucose-6-phosphatasedecreased level of glucose 6 phosphatase

• in combination with increased transport capacity, FDG retention has a more favorable environment within a tumor cell (Smith, TA. Nucl Med Commun 19:97-105, 1998)

[glucose]plasma [glucose]intracellular

hexokinase

phosphatase[glucose-6-P]

glycolysis

Intravascular Tissue

[FDG]plasma [FDG]intracellular

hexokinase

phosphatase[FDG-6-P]

FDG-PET Imaging

Lung Cancer Staging

• FDG PETSensitivity: 83%

• CTSensitivity: 57-64%Sensitivity: 83%

Specificity: 92%

J Nucl Med 2001;42:1S-93S

Sensitivity: 57 64%Specificity: 74-85%

Non Small Cell Lung Cancer

Lymphoma Staging

• FDG PET • CTSensitivity: 87%Specificity: 93%

J Nucl Med 2001;42:1S-93S

Sensitivity: 92%Specificity: 10%

Lymphoma

Head & Neck Cancer Staging

• FDG PET • CTSensitivity: 84-87%Specificity: 89-95%

J Nucl Med 2001;42:1S-93S

Sensitivity: 62-77%Specificity: 73-87%

Squamous Cell CA of Tongue and NSCLC

Colorectal Cancer Recurrence

• FDG PETS iti it 93%

• CTS iti it 79%Sensitivity: 93%

Specificity: 87%

J Nucl Med 2001;42:1S-93S

Sensitivity: 79%Specificity: 73%

Rectal CA

Breast Cancer Staging

• FDG PETS iti it 91 95%

• CTS iti it 63%Sensitivity: 91-95%

Specificity: 88%

J Nucl Med 2001;42:1S-93S

Sensitivity: 63%Specificity: 96%

Internal Mammary Lymph Node

Acetabular MET: Breast CA

Melanoma Staging

• FDG PETS iti it 83%

• CTS iti it 88%Sensitivity: 83%

Specificity: 91%

J Nucl Med 2001;42:1S-93S

Sensitivity: 88%Specificity: 75%

Melanoma

SUV= standard uptake valueMRglc = {([glc]/100) C(t)/(dose/body weight)}

LC (b/100)

MRglc = glucose utilization rate in tissue

[glc] = glucose concentration in arterial plasma (mg/dL)

C(t)* = radioactivity concentration in tissue

dose = dose injected

LC = lump constant

b = assumed to be a constant

* Works better if t > 45 minutes post-injection

Therapy: bone pain palliation

• [Sr-89]Cl (t1/2p = 50.5 days, t1/2b = 14 days)– Bioavailability = 50% of injected dose =1.46 MeV (max. range = 8 mm in tissue)max 1.46 MeV (max. range 8 mm in tissue)

– Typical dosing 16 Ci/kg to 10.8 mCi/kg or empiric total dose of 4-5 mCi for adults

– Blood count nadir = 4-8 weeks– Recommend platelet >60k and WBC >2.4k

before therapy

Therapy: bone pain palliation• [Sm-153] Ethylene Diamine

Tetramethylene Phosphonate (EDTMP) or Quadramet– t1/2p = 47 hours (1.93 days)1/2p ( y )– Typical dosing: 0.5 mCi/kg to 2 mCi/kg-emission: 103 keV (29%)-emissions: 640 keV (30%), 710 keV (50%), and 810 keV (20%)

• Maximum range = 3.0 mm in tissue• Average range = 0.5 mm in tissue

Radioimmunotherapy: Bexxar

• [I-131] Tositumomab (MW 150 kD, t1/2p = 8 days) – murine IgG2a anti-CD20 antibody

-emission: 364 keV (82%) emission: 606 keV maximum (89%) with-emission: 606 keV maximum (89%) with range = 2 mm in tissue

– Covalently linked• Dosing: maximum 88 cGy total body

– Typically at 75 cGy if platelet >150k– Reduced to 65 cGy if 100k> platelet <150k

Radioimmunotherapy: Zevalin

• [Y-90] Ibritumomab tiuxetan- murine IgG1anti-CD20 antibody (t1/2p = 64 hours)

-emission only: 2.274 MeV• Range = 11 mm (max) and 2.5 mm (avg) in tissue

– Chelation of yttrium-90• Dosing: 0.4 mCi/kg if platelet >150k

– 0.3 mCi/kg if 100k> platelet <150k– up to 32 mCi maximum

Therapy: Sirtex Sphere

• [Y-90]Microspheres to be administered directly into hepatic circulation for treatment of hepatocellular carcinoma or hepatic metastatic lesions– 20-40 m / 22k-73k particles

• Dosimetry is estimated using Tc-99m macroalbumin aggregate mapping and dedicated software

• Dosing: 100-150 Gy to the liver