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Differentiated Thyroid Cancer Old and Newer Therapies
Usha A. Joseph, M.D.University of Texas Medical School at
[email protected]
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Differentiated thyroid cancer (DTC) typesPapillary thyroid
Cancer (PTC) 80% Follicular thyroid cancer (FTC) 10-15% Combined
85%-98% recurrence rate of 20%. appropriate Rx long term survival
> 90%Massin- lower rate of lung metastasis in pts receiving post
op I-131 ablative Rx
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DTC mortality ratesLow risk : 2-5%; rec rate 10%. 33-50% death
rate in lobectomy only pts developing recurrence. Near total
thyroidectomy preferable.High risk: 40-50%; rec rate 45%. Rx near
total thyroidectomy, I 131 ablation, TSH suppression
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DTC risk factorsLow dose 10 rads- 1500 rads, risk thyd ca -13 %
>1500 rads, reduces ca risk from cell killing Thyd nodule + XRT
head /neck ->40% risk; 60% in nodule; 40% else where in gland
Females > males , ? hormonal/ reproductive factorsIncidence
Increase in thyroid deficient areas FTC, anaplastic more
commonHyper caloric diet increase risk; high fiber diet decrease
risk. Inc TSH- stim growth of cancer
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Prognostic factors in DTCPositive Family Hx assoc large tumor
size, multi-focal, invasion of local structures, more LN mets at
earlier stageAdvanced initial stage of tumor (III or IV)Extent of
surg resection (lobectomy or near total)Age: 59 higher risk of
recurrence/ cancer death
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Bad Molecular-genetic prognostic factors in aggressive DTC
aneuploid PTC, Hurthle Cell Cancer (HCC), decreased cAMP response
to TSH, inc epidermal growth factor binding, poor Iodine uptake,
N-ras and gsp or p53 mutations, inc expression of c-myc m RNA all
assoc poorly differentiated, aggressive cancer
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Negative I 131 WBSloss of Iodine uptake in 1/3 DTC from loss of
differentiated behavior, P-53 genetic mutations, 1.6% anaplastic
transformationMets- defect in iodine trapping mech, but retain
ability Tg synthesis Less responsive to traditional therapeutic
modalities.TSH directly stimulates Iodine trapping; iodine
deficiency less direct stim
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Factors affecting RAI uptakeSerum TSH levelNormal residual
thyroid tissue -normal thyroid conc 100 x more iodine than
DTCDegree of tumor differentiation, DTC typeStunning >sub-lethal
effects of beta rad on thyd cell from low dose I 131 used dxtic WBS
; high dose in Rx kills thyroid cells
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I 123 diagnostic WBS in DTC pure gamma , stunning unlikely.159
kev, high count rate 20 fold more and 6 fold > detectability
than equiv I 131-> better images. Dose 5-15 mci 24 hr I 123 WBS
highly comparable (98%) to I 131 post Rx scan Radiation to thyroid
is 1/5 or less than 2 mci of I 131. Disadv higher cost
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STUNNINGCourtesy Dr. Wan from MSKCC
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LN mets on I123 WBSI131 post RX WBS same findings
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FDG PET in DTC Progressive de-differentiation of DTC mets ->
loss of Iodine conc ability but increase metabolism from higher
growth rate- Flip-Flop or inverse relationship False Neg WBS: 20%
metastatic DTC, Hurthle Cell Cancer (HCC), aggressive and
anaplastic ca
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FDG PET in DTCFDG positive: 25% stage 2;60% stage 3 ; 84% in
stage 4always positive in Stg 4 with elev TG levels.stage 1 with
low Tg no FDG positive
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Neg WBS,+CXR and FDG scan, path anaplastic component
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FDG PET FDG,a glucose analogue, accumulates in cell with
increased glucose metabolism. DTC 6-17% mortality in 5 yrs more
recurrence with cerv LN involvement (32%) than without (14%)-
Harwood PET changed management in 51%. Low TG levels, FDG NPV of
93%Elev Tg, FDG +occult disease in 71%,PPV 92%.
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Thyrogen (rhTSH)Thyrogen exogenously stim TSH secretion,
increases uptake of I 131 and Tg secretion by neoplastic follicular
cells. Abnormal Tg level is > 2ng/ml. Tg value decreased by Tg
Antibody (Tg Ab ) Tg Ab in 15-25% pts, may indicate active
tumorThyrogen stim Tg +neck US high accuracy in persistent disease
( 96% vs 85% for Tg alone)
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Discordant Tg and WBSMost common: pos Tg/ neg WBSLess freq
discordant : pos WBS/ neg TgUndetectable Tg/ neg WBS = complete
remissionConcordant: detectable or elev Tg /+ WBS = local/distant
mets or resid thyd tissue
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Neg I 131 WBSloss of Iodine uptake in 1/3 DTC loss of
differentiated behavior, P-53 genetic mutations,1.6% anaplastic
transformationMets: defect in iodine trapping mech, but retain Tg
synthesizing capability,so less responsive to traditional I131 Rx
Iodine trapping directly stimulated by TSH; less directly by iodine
deficiency
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Pre I131 and FDG neg, Elev Tg-> empiric I131 Rx -230 mci, + I
131 post Rx WBS in mediastinum
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Octreoscan- Somatostatin receptor scan (SRS) Neuro endocrine
tumors or mets express somatostain receptors (SSTR) PTC high
expression of SSTR5 - SRS possible. Thyroxine withdrawal increases
yield of SRS 67% -> 85%. SRS guides therapy: surgery local Rx;
chemo extensive mets Sens for mets 74%. Higher uptake in mets
without iodine conc ability. Potential for Octreotride Rx
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Octreoscan uptake; Stokkel, MPM et al
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MetastasisLung mets better prog: Xray neg, younger age,
papillary tumor, positive I 131 uptake , absence of other distant
metsLung mets survival: CT neg (100%), micro-nodular mets (86%),
nodular mets (25%); 10 yr surv 87%.Lung most common distant met in
thyd ca- 4% Advanced Lung mets survive many yrs-I131 Rx Bone mets
10 yr surv 44%, Brain mets incid rare
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CT periph micro-nodules;I131 Rx bilat diffuse lung mets
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I 131 therapy in DTC Most empiric fixed dose Rx: location of
mets (Bierwaltes ). Max 300 mci/ time; yearly intervals, cumulative
life time dose of 800mci to decrease 2ary Leukemia. 100 mCi for
residual thyd tissue in neck; METS: 150-175 mCi for cervical LN
175-200 mCi lung; 200 mCi skeletal / brain
- I131 Rx in DTC indicationspost surg ablate residual thyd tiss
(
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WBS after 200mci I131RX-multiple metsDxtic WBS 4 mos later; some
mets imp, hip same, may need XRT to bone mets in left hip
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I-131 dosimetry in DTC maximize dose delivery to tumor, limit
whole body exposure, minimize risks/ complications (severe B M
depression, gram neg sepsis, 2ary leukemia . Benua criteria: blood
dose of no >200 rads; retained whole body activity of no >
120 mci; retained activity in diffuse lung mets of no > 80 mci
at 48 hr
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Complications of I131 RxEarly: radiation sickness,
sialo-adenitis, transient BM suppression, pain in mets, CNS
Symptoms from cerebral edema in Rx of brain metsLate: Infertility,
chromosomal aberration a concern; 2 ary leukemiaAnaplastic
transformation same +/- 131 Rx
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New agent development in progressive thyroid cancer (TC) target
intracellular molecules causing genetic alterations / dys-regulated
growthnot tumor specific ( normal/ malig cells) but tumor
selective- cancer more pathway activation, affected lower
conc)Signific toxicity from effect on normal cells
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New agent developmentBased : mech of action, freq of pathway
abnormal in thyroid ca Over expression/ uncontrolled activation of
receptor tyrosine kinase (RTK) or down stream signaling molecules
in Ras pathwayinhibition of programmed cell death-apoptosis
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Ras Pathway Ras main pathway in thyd ca; affects cell growth,
apoptosis, angiogenesisMutations of genes encoding Ras, or
activation of upstream regulatorsRas small GTP binding protein
involved in cell proliferation, differentiation, survival.Regularly
expressed in normal thyroid tiss
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Ras pathway activationactivated receptor K interacts with GRB2
(adaptor protein), then binds ptn, Son of sevenless RAS is
activated by exchanging GDP for GTPGTP Ras phosphorylates targets
with cascade of events cellular proliferation. Ras inactivated by
hydrolysing GTP-> new GDP available for another cycle
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Drugs targeting intracellular signaling-RAF inhibition Many RAS
activation effects via down stream effector -Raf Activated (GTP
bound) Ras localizes Raf to membrane.Raf phosphorylates MAPK kinase
(MEK)--> a cascade of events -> cell growth and reduced cell
death.MEK1 and MEK 2
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Drugs targeting intracellular signaling antisense compd: small
synth DNA seq to particular targeted mRNA. On binding to mRNA
prevent translation Ribonuclease H cleaves mRNA strand but not
anti-sense compound, thus transcription / translation
preventedInterferes with ribosomal assembly, blocks gene
expression, inhibit protein synthesis
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Anti sense compd
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Drugs targeting intracellular signalingPhenyl acetate: inhibit
cell growth via effect on post translational processing of
Ras.Decrease TSH /non TSH induced cell growth, inc iodine uptake,
inc Tg secretion.
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Drugs targeting intracellular signalingFarnesyl transferase
inhibitors (FTI): post transational modification is required for
trans-location of activated Ras to cytoplasmic membrane inhibition
of enzyme farnesyl transferase, inhibits membrane accumulation of
Ras Four FTI s
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Receptor tyrokinase (RTK) over activation Over activation of
RTK- EGFR, VEGR with enhanced signaling by many ligands EGF(
epidermal growth factor) or VEGF( Vascular endothelial growth
factor) Freq mutations result in constitutive activation. Most
common over-expressed receptor in thyroid ca.
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Drugs targeting receptor tyrosine kinase- VEGFVEGF: stim vasc
proliferation & permeability, induces metastasis, and apoptotic
protector for new vesselsIncreased in differentiated thyroid ca and
mets ;carries poorer prognosisAnti VEGF antibody neutralizes
VEGF-> reduces angiogenesis
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Drugs targeting receptor tyrosine kinase -EGFREGFR homo- or
hetero-dimerized on binding to ligands-> phosphorylation of
Tyrosine residues -> Ras and P13 k-> PKC & AKT->
cancer progression Her2/neu preferred hetero-dimerization partner
of EGFR, over expressed in PTCHer2/neu/ EGFR implicated in Thyroid
cancer progression
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Drugs targeting receptor tyrosine kinase Gene amplification of
Her2/neu assoc with poor prognosis. Over expression of Her2/neu
acts as potent oncogene Herceptin, humanized monoclonal antibody
binds to HER2/neu receptor
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Drugs targeting receptor tyrosine kinaseEGFR expressed in DTC;
over expression worse prognosis.EGFR blocking -> cell cycle
arrest in G1 apoptosis, anti-angiogenesis, down regulation of
metallo-proteins, decrease incidence of metastasisAnti EGFR
antibody reduces availability of receptor by internalization
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Drugs targeting receptor tyrosine kinaseover expressed Her2/neu
can be activated without ligand. Her2/neu up regulated in papillary
thyd caReceptor activation interrupted by monoclonal antibody,
Trastuzumab, OR blocking receptors with small molecules or anti
sense compounds
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Drugs targeting angiogenesis by alternative pathwaysThalidomide,
sedative drug; anti neoplastic in animal models; promising anti-
angiogenenis properties Phase II trials- metastatic FTC,PTC,
medullary cancerCombrestatin, tubulin binding protein - African
willow, unique vascular targeting props, active against endothelial
cells/ angiogenesis
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Drugs target Akt/ mammalian target of rapamycin (MTOR)
mTOR activation increases cell cycle progression /cell growth by
dys regulation of targets . mTOR directly controlled by kinase, Akt
- elevated in thyd ca targets of mTOR dys-regulation, over
expressed in thyroid cancer like cell cycle stimulators: C-Myc,
cyclin D1.Level directly correlate with aggressive ca.
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Targets of PI3 kinase signaling dys-regulation
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Drugs targeting mammalian target of rapamycin (MTOR)
Rapamycin a macrolide antibiotic with immuno- suppressive
properties (used to prevent allograft rejection in organ
transplant); anti tumor propsPhase I study in advanced solid tumors
including thyroid cancer
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Drugs targeting apoptotic pathwaysThyroid cancer reduced
sensitivity to cell death, can sustain genetic alterations &
keep growingApoptosis: orderly process leading to cell death via
specific signaling pathways Apoptosis initiated by
intra/extracellular stimuliRecombinant TRAIL induces apoptosis in
presence of protein inhibitor, cycloheximide
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TRAILTumor Necrosis Factor related apoptysis inducing ligand
(TRAIL) - benign and malignant tissue. Cancer cells more sensitive
to TRAIL Reduces cell growth by inducing apoptosis via caspase
pathway
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TRAIL TRM-1 human monoclonal antibody, high affinity binding to
TRAIL-R1 receptor to induce apoptysis. Inhibition of Bcl-2 by
phosphorylation-> resistance to apoptosis.Over expression Bcl-2
->cell proliferation in thyd ca.Bcl-2 antisense compd used for
Rx
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Cox-2 inhibitorsCox 2 key enzyme in synth of prosta-glandin ;
occurs freq in thyroid / other ca. Over expression/ over activation
of Cox 2 inhibits apoptosis, enhances angiogenesisCox-2 inhibitor
(celecoxib) potent therapeutic agent alone or with chemo in
malignancies including thyroid ca
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90-kDa Heat shock proteininhibitor (Hsp 90)Hsp 90 chaperone
molecule for activation/ stabilization of proteins in signal
transduction pathways. Serine /threonine kinase ,Raf1 and Akt, need
Hsp90Geldanamycin Blocks Hsp-90 -> enhanced degradation and
decrease activation of signaling molecules, Akt, Raf involved in
thyroid ca, thyroid cell growth
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Demethylating agents DNA Hyper methylation in promoter regions
of gene -> altered binding of co- factors altered/reduced gene
expression reduced binding of transcription factors Blocking
induces re-expression of tumor suppressor genes, reduces cell
growth or inc expression of genes facilitating therapy
5-Azacytidine and 5-Aza-2deoxycitidine.
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Histone deacetylase inhibitors Histones: small positively
charged major protein of chromosome. Binds tightly to negatively
charged DNA to form condensed Protein-DNA complex. Bond relaxation
by enzyme modification enables transcription of DNA into mRNA. Bond
disruption induces cell cycle arrest, differentiation, and aptosis
in cancer cell lines. In vitro work - anaplastic/ FTC is promising
(increase TG and Iodine conc).
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Lithium Lithium occasional adjunct to improve uptake in de-
differentiated tumors that concentrate Iodine poorly or none at
allReduces release of iodine and increase I131 effective half life
in thyroid tissue
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Proteasome inhibitors26s proteasome involved in elimination of
damaged proteins,apoptosis and cell cycle progression. PS-341 a
selective inhibitor of 26 s proteasome -> growth arrest,
inhibition of angiogenesis, enhanced radio and chemo sensitivity.
Clin trials planned in thyd ca
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Gene therapy induce expression of genes not normally expressed
in particular cells induce re-expression of silenced genes inhibit
expression of abnormal genesenhance therapeutic effect of other
agents
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Gene therapyIntra-tumoral gene delivery via direct injection of
c DNA encoding gene of interest or of viral vectors Systemic Rx of
mets more difficult due to host of immune response to vector and
first pass through liver
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Gene Therapy -p53 critical regulator of cell cycle progression
p53 protein activation allows for repair of DNA mismatches from
external events like radiation or aging. With enough damage, p53
activates a cascade of events resulting in apoptosis.
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Gene therapy-p53 Heterozygous mutation-> reduced function of
normal p53 or direct inhibition of p53 activity (dominant negative
effect)Homozygous missense mutation in coding region of both
alleles of p53 -> reduced or absent activityInhibition of normal
P53 activity -> rapid cell cycle progression and growth without
allowing for appropriate DNA repair or apoptosis
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Gene therapy-p53Inactivating mutations of p53 most common in
poorly differentiated solid malignancy including anaplastic thyroid
ca Malignant cells bearing wild- type p53 more susceptible to
chemotherapy agents compared to mutant p 53
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Gene therapy application -NISRestore iodine uptake in thyroid ca
by re-expression of NIS protein function . NIS important for iodine
conc in thyroid cellDefective iodine uptake: hyper methylation of
NIS gene promoter, altered sub cellular localization of NIS protein
or reduced NIS gene expression by other mechanisms
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Gene therapySuccessful induction of NIS re-expression by gene Rx
in malignant cell lines including FTC Suicide gene therapy goal
-induce expression of proteins in cancer cells which are directly
toxic to cancer cell OR induce sensitivity of cancer cells
selectively to particular medication
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Suicide gene therapyInduce expression of viral enzyme TK in
target cells so gene encoding TK is controlled by a type specific
TG promoter with expression of TK in cancer cell only. Promise-
future Expression of TK increases sensitivity to antiviral drug,
ganciclovir with DNA strand break and subseq cancer specific cell
death only. Enhances efficacy of y-radiation.TK not normally
expressed in mammalian cells
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New therapies in futuredevelop compounds targeting intracellular
molecules involved in: dys-regulated growth, or in pathways of cell
growth, apoptosis, or angiogenesis Ras directed Rx, drugs targeting
receptor tyrosine kinase (RTK), angiogenesisGene therapy, suicide
gene therapy, re-differentiation of tumors Rx ; Clinical trials
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Newer Current TherapiesMeantime, new ways I 131 Rx: more
effective dose to tumor using dosimetry-> enhanced cell kill and
responseOut patient Rx vs inpatient Rx- pt convenienceRh TSH stim
dxtic WBS avoids hypothydism pt friendly. Future- thyrogen stim pre
I 131 RX I 123 Dxtic WBS avoid stunning-> more effective I131
Rx. FDG PET-non iodine conc thyd ca->surg or XRT. Empiric I 131
Rx in Tg +/ WBS as needed
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DTC ReferencesBraga- Brasaria, M: 2003. J of Endocrinololy and
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.2000. World J of Surg24,942-951Pacini, F. 2002. Eur J Nuc
Med,29,Suppl 2, Aug 2002Mazzaferri, EL. 2003.J Clin Endocrinology
and Metab. 88:4;1433-1441
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DTC ReferencesToubeau,M.2004 J Nuc Med 45: 6; 988-994Ma, C.
2005. J Nuc Med 46: 9,1473-1480Jarzab, B. 2003. Eur J Nucl Med Mol
Imaging. 30: 1077-1086Lippi,F.2001.Eur J of Endocrinol 144: 5-11
Lupoli,GA.2005.Med Sci Monit 11(12)RA 368-73 Alzaharani, AS. 2001.
J Clin Endocrinology and Metabolism 86:11:5294-5300Stokkel, MPM.
2004; July 31(7); 950-957
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DTC ReferencesWang,W.1999.J Clin Endocrinology and Metabolism.
84: 7: 2291-2302Cushing SL.2004. Laryngoscope.114: 2110-
2115Pacini, F. 2003. J Clin Endocrinol Metab 88: 8:
3668-3673Verburg, F.2005.Eur J Endocrinol152;33-7Datz, FL.1986. J
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