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and young adults with differentiated thyroid cancer. Cancer 1993;71 :1348 —1352. 2. Vassilopoulou-Sellin R, Libshitz HI, Haynie TP. Papillary thyroid cancer with
pulmonary metastases beginning in childhood. Clinical course over three decades. Med PediatrOncol 1995;24:l19—122.
3. Hamess JK, Thompson NW, McLeod MK. Pasieka JL, Fukuuchi A. Differentiated thyroid carcinoma in children and adolescents. World J Surg 1992;16:547—554.
4. WithersEH,RosenfeldL. O'NeilJ,LynchJB,HolcombH. Long-termexperiencewith childhood thyroid carcinoma. i Pediatr Surg 1979,14:332—335.
5. BuckwalterJA, Gurll NJ, ThomasCG. Cancerof the thyroid in youth. WorldJ Surg 198l;5:15—25.
6. Dc KeyserLFM, VanHerleAJ.Differentiatedthyroidcancerinchildren.HeadNeck l985;8:lOO—l14.
7. Tallroth E, Backdahl M, Einhorn J, Lundell G, Lowhagen T, Silfversward C. Thyroid carcinoma in children and adolescents. Cancer l986;58:2329—2332.
8. La Quaglia MP, Corbally MT. Heller G, Exelby PR. Brennan MF. Recurrence and morbidity in differentiated thyroid carcinoma in children. Surgen' 1988;104:1 149— I156.
9. Lamberg BA, Karkinen-Jaaskelainen M, Franssilla KO. Differentiated follicular derived thyroid carcinoma in children. Ada Paediatr 1989;78:4l9—425.
10. McConahey WM, Hay ID, Woolner LB. van Heerden JA, Taylor WF. Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy and outcome. Mayo Clin Proc 1986;6l :978—996.
I I. Bonte FJ. Radioiodine and the child with thyroid cancer. AiR 1965;96: I—24. 12. DeGrootLi, KaplanEL. McCormickM, StrausFH.Naturalhistory,treatmentand
course of papillary thyroid carcinoma. J Clin Endocrinol Mezab 1990;7l:414—424. I3. Clark OH, Duh QY. Thyroid cancer. Med C/in North Am I99 1;75:2 I 1—234. 14. Katoch DS, Mehta Di, Somasundaram S. Role of shadow shield whole body counter
in clinical studies. In: Das KR, Gopalkrishnan AK, eds. Proceedings of National Seminar on Radiation Protection. Bombay: India: 1976:208 —213.
Is. KnudsonRi, SlakinRC, LebowitzMD, BurrowsB. The maximalexpiratoryflow volume curve. Normal standards, variability and effects of age. Am Ret' Respir Dis 1976;I13:587—600.
16. SamuelAM,UnnikrishnanTP, BaghelNS, RajashekharraoB. Effectof radioiodine therapy on pulmonary alveolar-capillary membrane integrity. J Nuc/ Med 1995:36: 783—787.
I7. lain SC, Mehta SC, Kumar B, Reddy AR, Nagaratnam A. Formulation ofthe reference Indian adult:anatomic and physiologic data. Health Phvs 1995:68:509—522.
18. Loevinger R, Berman M. A schema for absorbed dose calculation for biologically distributed radionuclides. MIRD pamphlet no. I. J Nucl Med 1968;9(suppl l):7—l4.
19. CrileG. Carcinomaofthe thyroidin children.AnnSurg 1959;150:959—964. 20. Winship T. Rosvoll RV. Thyroid carcinoma in childhood: final report on a 20 year
study. C/in Proc Child Hosp Wash DC 1970;26:327—347. 2 1. Goepfert H, Dichtel Wi, Samaan NA. Thyroid cancer in children and teenagers. Arch
Otolarvngol Head Neck Surg 1984:1 10:72—75. 22. Samaan NA, Maheshwari YK, Nader 5, Hill CS, Schultz PN, Haynie TP. Impact of
therapy of differentiated carcinoma of the thyroid: an analysis of 706 cases. J C/in EndocrinolMetab 1983:56:1131—1138.
23. Massin JP, Savoie IC, Gamier H, Guiraudon G, Leger FA, Bacourt F. Pulmonary metastases in differentiated thyroid carcinoma: study of58 cases with implications for the primary tumor treatment. Cancer 1984;53:983—992.
24. Samaan NA, Schultz PN, Haynie TP, Ordonez NG. Pulmonary metastases of differentiated thyroid carcinoma: treatment results in 101 patients. J Clin Endocrinol Metab I985;60:376—380.
25. SchlumbergerM,TubianaM,DcVathaireF,et al. Longtermresultsof treatmentof 283 patients with lung and bone metastases from differentiated thyroid carcinoma. J C/in Endocrinol Metab I986;63:960—967.
26. Mazzafem EL. Papillary thyroid carcinoma: factors affecting prognosis and current therapy.SeminOncol 1987:14:315—332.
27. SissonJC, GiordanoTi, iamadarDA,et al. Iodine-l3l treatmentof micronodular pulmonary metastases from papillary thyroid carcinoma. Cancer 1996;78:2 184 —2192.
patient-by-patient basis and of 91 % (78%—100%)on lesion-by lesion basis for 18F-FDG.The sensitivity of se@@@Tc@furffosminappears to be poor,evenforcervicaland mediastinaltumormanifestations where the value of 20111-chlorideis established.
Key Words technetium-99m-furifosmin; differentiated thyroid car cinoma; fluorine-i 8-fluorodeoxyglucose; PET
J NucI Med 1998; 39:1536-1541
Tec@metium-99m-t'urifosminis a newtechnetium-labeled agent for myocardial perfusion imaging (1—5).It is composed ofan equatorial Schiffbase ligand and two transaxial phosphine ligands (l,2-bis(dihydro-2,2,5,5-tetramethyl-3(2H)-furanone-4- methyleneamino)ethane and tris(3-methoxy-propyl))phosphine. It is a lipophilic cationic agent (4 ). Rosetti et al. (2 ) described good heart uptake without significant washout up to 5 hr.
There is a variety of cardiac perfusion agents with a@glica tions in oncolo@ical imaging, such as, 201Tl-chloride, mTc.. sestamibi and 9@'°'Tc-tetrofosmin(6). The myocardial kinetics of 201T1-chloride, 99mTc@sestamibi, 99mTc..tetrofosmin and 99mTcffirifosmin are different (5). In the literature, 201T1- chloride imaging in metastases of differentiated thyroid carci noma (DTC) is an established method (7—14). Because of superior physical charcteristics of 99mTc and reduced radiation exposure there is a trend to prefer technetium-labeled agents (14—20). None of the approved radiopharmaceuticals has per fect diagnostic accuracy. Therefore, the investigation ofthe new agent 99mTc4.@rifosmin for thyroid cancer imaging seems to be justified. The uptake-mechanism of99mTc@furifosmin in normal
Tumor scintigraphy with flow tracers, such as 20111-chloride,has an established role in the follow-up of differentiated thyroid cancer. We investigated a new tracer, @‘Tc-furifosmin(Technescan Q12, Mallinckrodt Diagnostika, Hennef, Germany), in patients with ele vated thyroglobulin levels or sonographic suspicion of lymph node metastases or recurrent disease. Methods: In a prospective study, we examined 20 patients with @Tc-furffosmin.Allpatients under went a 18F-fluorodeoxyglucose (FDG) PET scan of the neck and chest Positive se@@Tc@furffosminfindings were validated by biopsy, 1311 scan, CT or 18F-FDG PET examinations. Results: In three patients with cervical lymph node metastases detected on a planar
@°Tc-furifosminscan, we found a rapid tracer accumulation in the tumor (maximum < 2 mm) and a significant washout in 2 of 3 patients after 4 hr. The visual contrast and the tumor-to-nontumor ratio was rather poor (average 1.2:1). In 3 additional patients, 3 pulmonary and 2 mediastinal lymph node metastases were de tected by the @“Tc-furifosminSPECT scan. Two patients were true-negative, and in 13 of 18 patients, the tumor could be localized by ‘8F-FDGPET (10 cervical, 6 mediastinal, 4 pulmonary metasta ses, 1 bone metastasis); 5 patients were false-negative. In3 of these false-negative cases we could not localize the tumor with other diagnostic methods. Two patients had a true-negative PET exami nation. Conclusion: The statistical analysis of our data on furifosmin reveals that the sensitivity and 95% confidence interval of 33% (11%—56%)on a patient-by-patient basis and of 34% (17%— 57%) for the lesion-by-lesion analysis is significantly lower than the sensitivity and 95% confidence interval of 72% (50%—89%)on a
Received Jul. 21, 1997; revision accepted Dec. 19, 1997. Forcorrespondence or reprints contact: K Brandt-Mwnz, MD,Klinikund Poliklinikfür
Nuk1earmed@in,UniversitätsldinikumEssen, HUfelandtr.55, D-45122 Essen, Germany.
1536 THE JOURNALOFNUCLEARMEDICINE•Vol. 39 •No. 9 •September 1998
Technetium-99m-Furifosmin in the Follow-Up of Differentiated Thyroid Carcinoma K. Brandt-Mainz, S.P. MUller, W. Sonnenschein and A. Bockisch Klinik und Po!ik!inikflir Nuklearmedizin, Universitätsk!inikum Essen, Essen, Germany
.PatienthlgTumorno. HistokgyNM location 1311 Hlatokgy Sono CT Supp Stim
1 Pap T2NOMO Pos
13 62Cet@tNegnaPosMedNegnaNegPulmNegnaNeg2EosinT3NOMOCervnaPosPosPosMednaPosPosPuImnanaPos3PapT4aN1aMOCerv
na na
NagNag
NagEosinT2aNOMOCan,
Pap
Pap
PapT4bN1bM1
T4aNOMO
T2bN1aMO
T4aN1aMOCerv
Med PuIm Cerv Med PuIm Cerv Med PuIm Cent Med PulmNag
Nag Nag Nag Nag Nag Nag Nag Nag Nag Nag Nagna
na na
Pos
Nag
NagNag
Nag Pos
TECHNETIUM-99M-FURIFOSMIN IN THYROID CANCER •Brandt-Mainz et al. 1537
FiGURE1. Patient with proven cervk@al lymph node metastasis and @Tc-fun fosmin accumulation in middle neck 1.5 hr after injection(left).Four hours later (right), there is significant washout.
3—5days after oral administrationof 1—6GBq ‘@‘Iunder hypo thyroid conditions (TSH > 30 mU/ml). In 4 patients with marked elevations of hTg ( 11, 62, 344, 365 ng/ml), there were only small mediastinal foci on the therapeutic 1311scan that were not consid ered to represent an adequately large tumor mass to explain the hTg-level. Because ofthe flip-flop phenomenon described by Feine et al. (22), an ‘8F-FDGstudy was performed to find metastases without the ability to accumulate 1311. This ‘8F-FDGuptake correlates with poorly differentiated tumors and possibly with higher malignancy. Ten of these patients had sonographic abnor malities in the neck and four had eosinophilic thyroid carcinomas. Furthermore, we included two patients with sonographic abnormal ities in the neck but with normal hTg-levels.
We injected 450 MBq o9mTcffirifosmin During injection we initiated a dynamic study of the neck and chest for 1 hr with a large-field-of-view camera (Siemens ZLC, Body Scan, Multi SPECT 3; Hoffman Estates, IL) with a frame rate of 1/mm using a high-resolution collimator. After 1 hr, the SPECT examination of the neck and chest was performed using the Mu1tiSPECT 3 and a
FiGURE 2. Patient with mediastinal lymph node and solitary pulmonary me tastases (validatedby CT)with negative planar @c-furifosminscan.
FIGURE3. Metastases are detected only by the followingSPECTexamination.
1538 THE JOURNALOF NUCLEARMEDICINE•Vol. 39 •No. 9 . September 1998
. ... @*‘
and tumor cells is unclear. One group could show 99mTc@ furifosmin uptake in cell lines of breast, pancreatic and gastric carcinoma (21 ). In this prospective study, we examined the uptake of 99mTcf.@rifoSmin in DTC in vivo. All patients had additional I8F-fluorodeoxyglucose (FDG) PET scanning, which has been shown to have good diagnostic accuracy in the follow-up of thyroid carcinoma in tumors without adequate ‘311-uptake(22).
MATERIALS AND METhODS We performed a prospective study in 20 patients (1 1 women, 9
men). Table I lists the clinical, laboratory and imaging data of all patients. All patients had histologically proven DTC ( 15 papillary, 1 follicular and 4 eosinophilic carcinomas) and had undergone our standard treatment protocol of thyroidectomy, radioiodine resec tion of the thyroid remnant, and suppressive levothyroxine replace ment therapy. We used a DYNOtest Tg (Henning, Berlin, Ger many) for thyroglobulin (hTg) measurement (immunoradiometric assay, lower detection level 1.0 ng/ml). Eighteen patients had elevated hTg-levels with no or inadequate uptake in an iodine scan
.4. - ,.
a'
@ :@ @i
TABLE 2 Comparison Between Technetium-99m-Furifosmin Planar and SPECT to fluorine-i 8-FDG Using a Lesion-by-Lesion Analysishigh-resolution
collimator. Data were acquired in I83 projections over 360°,30 sec/projection/image in a 128 X 128 matrix. The transverse images were reconstructed by filtered backprojection with a Shepp-Logan-Hanning filter with a cutoff of 0.5 pix I@ After 1.5 and 4 hr postinjection all patients had a whole-body scan
. using a dual-head gamma camera (Siemens Body Scan) with a high-resolution collimator. The scan speed was 10 cm per mm.
All patients had a PET examination with ‘8F-FDGafter over night fasting (Siemens/CTI ECAT 953/15); none of our patients were diabetic. After a transmission scan (8—12mm/bed position), 350 MBq ‘8F-FDGwere injected intravenously and 30 mm postinjection scans of the neck and chest were acquired in 6 bed positions because of the limited field of view of our PET scanner (5.4 cm). Images were reconstructed by filtered backprojection with a Hanning filter (cutoff 0.5 pix I)•In most cases,thePatient
Tumor Furifosmin Furifosmin no. location planar SPECTFDG1
Cerv Nag Nag Pos Med Nag Nag Nag Pulm Nag Nag Nag
2 Cerv Pos Pos Pos Med Nag Nag Pos Pulm Nag Nag Nag
3 Cars, Nag Nag Nag Med Nag Nag Nag PuIm Nag Nag Nag
4 Can, Nag NagPosMed Nag Nag Nag99mTc-furifosmin scan and the@ 8F-FDG PET study wereperformedPuIm Nag Pos Pos
5 Cerv Nag Nag Pos Med Nag Nag Nag PuIm Nag Nag Nag
6 Cervi Pos Pos Pos Cerv2 Nag Nag Med Nag Nag Nag PuIm Nag Nag Nag
7 Cerv Nag Nag Poswithin
1 wk. Four weeks was the longest interval between the two studies and occurred in one patient.
All 99mTc@furifosminand@ 8F-FDG PET scans were read mdc pendently by two experienced observers blinded to the clinical data. All scans were interpreted visually for focal or diffuse anomalities. The positive findings were validated by surgery in 7 of 13 cases (5 cervical lymph node mctastases, 1 mediastinal lymph node metastasis and 1 pulmonary metastasis). In the other 6casesMed
Nag Nag Posthe presence of tumor was confirmed by CT examination withaPulm Nag Nag Naghigh-resolution technique of the neck and thechest.8
Cerv Nag Nag Nag Med Nag Pos Pos Pulml Nag Pos Pos Pulm2 Nag Pos Pos
9 Cerv Nag Nag Nag Med Nag Pos Nag Pulm Nag Nag Nag
10 Cerv Pos Pos PosWe
calculated the sensitivity for 99mTc@furifosminin planar and SPECT technique and for the ‘8F-FDGPET examinations on a patient-by-patient basis and on a lesion-by-lesion basis. We calcu lated 95% confidence intervals for the sensitivities from the binomial distribution and compared the sensitivity of 99mTc@ furifosmin and 18F-FDG PET with each other and with values reported in theliterature.Med
Nag NagNagPulm Nag NagNag1
PuIm Nag Nag Nag 12 Ceoi Nag Nag Nag
Med Nag Nag Nag PuIm Nag Nag Nag
13 Cerv Nag Nag Nag Med Nag Nag Nag PuIm Nag Nag Nag Bone Nag Nag PosIn
the dynamic scans, we found a rapid tracer accumulation in the tumor (peak < 2 mm); over 4 hr there was a noticeable washout in 2 of 3 patients (Fig. I).
In three patients the planar 99mTc..furifosmin scan showed lymph node metastases, which were validated by surgery; 1 patient had eosinophilic and 2 patients papillary carcinomas. From the positive patients, 2 had hTg-levels under the detection limit and 1 had an elevated hTg of 22 ng/ml under TSH
14 Cerv Nag Nag Nagsuppressive levothyroxine medication. In the SPECT examina Med Nag Nag Nag Pulm Nag Nag Nag
15 Cent Nag Nag Nag Med Nag Nag Nag Pulm Nag Nag Nag
16 Cer@, Nag Nag Pos Med Nag Nag Nag PuIm Nag Nag Nag
17 Cerv Nag Nag Pos Med Nag Nag Postion
we found tumors (2 eosinophilic and I papillary carci noma) in 3 additional patients, I with a mediastinal lymph node and nodular pulmonary metastases (Figs. 2 and 3), 1 with mediastinal lymph node and 1 patient also with a nodular pulmonary metastasis. One of these patients was validated by surgery and the other two by CT. Two patients had a true negative Tc-fL@rifosminscan.
In 13 patients the I8FFDG scan was positive with the following tumor locations. We found 10 cervical lymphnodePuIm
Nag Nag Nagmetastases, 6 mediastinal metastases, 4 pulmonarymetastases18 Can, Nag Nag Nag Med Nag Nag Nag Pulm Nag Nag Nag
19 Cerv Nag Nag Nag Med Nag Nag Pos Pulm Nag Nag Pos
20 Ceni Nag Nag Nag Med Nag Nag Pos PuIm Nag Nag Nagand
I bone metastasis. Six cervical lymph node metastases and 1 pulmonary metastasis were validated by surgery, the other patients by CT with high-resolution technique. In 2 patients
@thonly stimulated elevated hTG-levels both the 18F-FDG PET and the @°@Tc-furifosminexamination were true negative.
In 5 of 18 patients the PET scans were false-negative. All patients had elevated hTg-levels (stimulated hTg 11—117 ng/ ml). In 3 of these 5 false-negative patients no other diagnostic modality was able to locate a tumor. In one false-negative patient we found a mediastinal lymph node metastasis and in
TECHNETIUM-99M-FURIFOSMININ THYROIDCANCER •Brandt-Mainz et al. 1539
,r@4
@v,y@,
FIGURE 4. Patient wfth histokgIcally proven cervical lymph node metastasis and completely negative @Tc-furifos mm examination. Shown are coronal slices (6.3 mm) of SPECT examination fromdorsal to ventral.
another one disseminated lung metastases by CT. The medias tinal metastasis could be seen in the 13‘I-scan.
In addition, the 9@Tc-furifosmin examination gave an over all sensitivity of33% (95% confidence interval 1l%@56%).The sensitivity of the ‘8F-FDGexamination was 72% (95% confi dence interval 5O%—89%) in our patient group.
Analyzing lesion by lesion, we found 3 of 23 tumors in the planar 99mTc$.@rifosmin examination (all histologically proven cervical lymph node metastases 3/10), 8 positive lesions in the 9@Tc-furifosmin SPECT (3/10 cervical, 2/7 mediastinal and 3/5 pulmonary lesions). In the ‘8F-FDGPET scan we could see 2 1 of23 lesions ( 10/10 cervical, 6/7 mediastinal, 4/5 pulmonary and 1/1 bone lesion). Table 2 shows the results for 9@°'Tc furifosmin planar imaging, SPECT and ‘8F-FDG in all patients and lesions.
In seven patients we saw unknown tumor lesions (3 cervical, 2 mediastinal and 2 pulmonary metastases) based on ‘8F-FDG. In these patients we changed therapeutic management because of the ‘8F-FDGfindings. In one patient we saw a mediastinal lymph node metastasis in the 9@Tc-furifosmin SPECT. In this patient the ‘8F-FDG PET was false-negative. Figures 4 and 5 show the same patient with a negative @Tc-furifosminexam ination and a positive ‘8F-FDGscan.
FIGURE 5@Patient showed focal @F FDG accumulation in PET.
DISCUSSION The statistical analysis of our data on 99mTc..f.@rifosmin
reveals that the sensitivity and 95% confidence interval of 33% (1 1%—56%)on a patient-by-patient basis and of 34% (l7%— 57%) for the lesion-by-lesionanalysis is significantly lower than the sensitivities reported in a recent review article for either 201Tl-chloride (68%), and 99mTc..MIBI (73%) (23). The data on 201Tl-chloride from this review are in agreement with our own ROC study in 162 patients where a high sensitivity (75%; confidence interval 65%—84%) and a good specificity (90%) was observed (13).
We localized tumor manifestations on planar imaging in only 3 of 18 patients with 9@Tc-furifosmin. A reason for this disappointing result may be the different uptake mechanism for 99mTcf..@fosmin compared to other heart perfusion agents. Arbab et al. (24) compared the different uptake mechanism of 99mTc..tetrofosmin @°@Tc-MIBIand 201T1-chloride in tumor cell lines.
Thallium-20l-chloride uptake depends on the Na@,K@-AT Pase activity and the membrane potential. Technetium-99m- MIBI accumulates in the mitochondria because of a negative mitochondrial potential. Technetium-99m-tetrofosmin uptake depends on both the cell membrane and mitochondrial potential
. @‘.
1540 THE JOURNALOFNUCLEARMEDICINEâ€Vol. 39 •No. 9 . September 1998
‘,
..
(24). Wolf et al. (21 ) observed uptake of 99mTc@MIBI, 99mTc.. tetrofosmin and 99mTc@furifosmin in a tumor cell study. The uptake of99mTc@MIBI was found to be the highest. Technetium 99m-furifosmin uptake is also reported in a mouse model (25).
In the SPECT examination we could detect mediastinal lymph node and pulmonary metastases in three additional patients. We found a higher sensitivity of SPECT compared to planar images. This agrees with studies that show increased sensitivities for SPECT examination. Charkes et al. (7) suggest an increase of sensitivity of 25% in thyroid cancer metastases using 201Tl-chloride SPECT. In their 201Tl-chloride SPECT examination foci of I cm in the neck and of 1.5 cm in the lungs were seen. Disseminated lung metastases are better detected with CT (26). Muller et al. (18) compared planar to SPECT examinations using 99mTcMIBI in patients with lung cancer by ROC analysis and also found increased sensitivities using SPECT.
Other studies deal with the multidrug resistance behavior of these agents. Both 99mTc@tetrofosmin and 99mTc..MIBI are useful for imaging p-glycoprotein-status of tumor (27). Thalli um-201-chloride is not a substrate for p-glycoprotein.
The sensitivity in our highly selected patient group of I8F-FDG PET of 72% with a 95% confidence interval of
50%_ 89% on a patient-by-patient basis, and of 91% with 95% confidence interval of 78%—100%on a lesion-by-lesion basis is far superior to 99mTc$.@rifoSmin and agrees with the reported sensitivity of 83% in the literature (23 ). Despite having per formed only PET studies of neck and thorax, our sensitivity agrees with other studies performed on larger numbers of patients with whole-body scans (22). Similar to other studies, ‘8F-FDGPET proved to be a valuable diagnostic method in the follow-up of thyroid cancer, especially in tumors that do not accumulate 1311and patients with elevated hTg-levels (22).
CONCLUSION Technetium-99m-funfosmin is not likely to be a competitive
radiopharmaceutical compared to established tracers for use with SPECT and PET. Although 99mTc@furifosmin has better physical imaging characteristics, its diagnostic sensitivity is significantly inferior to 201Tl-chloride. The study also confirms the value of the ‘8F-FDG PET. Although we did not perform whole-body scans, we achieved similar sensitivities in agree ment with other studies using whole-body imaging.
We conclude that in our patients with DTC the scintigraphy with 99mTcffirifosmin is not useful, even for cervical and mediastinal lymph node metastases where the value of 201T1- chloride is established (12,13).
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TECHNETIUM-99M-FURIFOSMIN IN THYROID CANCER •Brandt-Mainz et al. 1541