9. Maxon HR III, Deutch EA, Thomas SR. et al. Rhenium-l86(Sn)HEDP for treatmentof multiple metastatic foci in bone: human distribution and dosimetric studies.Radiology1988;166:501—507.

10. de Klerk JMH, van Rijk, van het Schip AD, et al. Pharmacokinetics of rhenium-I86after administration of rhenium-186-HEDP to patients with bone metastasis. J NuciMed I992;33:646—651.

I I. Singh A, Holmes RA, Farhangi M, et al. Human pharmacokinetics of samarium-153-EDTMPin metastaticcancer.J NuciMed1989;30:I814—1818.

12. Eary iF, Collins C, Stabin M, Ct al. Samarium-153-EDTMP biodistribution anddosimetry estimation. J Nuc! Med 1993;34:lO3l—1036.

13. Maxon III HR. Schroder LE, Hertzberg VS, et al. Rhenium-I86(Sn)HEDP fortreatment ofpainful osseous metastasis: results ofa double-blind crossover comparisonwith placebo. J Nuc! Med 1991;32: 1877—1881.

14. Farhangi M. Holmes RA, Volkert WA, et al. Samarium-I53-EDTMP: pharmacokinetics, toxicity and pain response using an escalating dose schedule in treatment ofmetastatic bone cancer. J Nuci Med I992;33:1451—l458.

15. Srivastava SC, Meinken GE, Richards P. et al. The development and in vivo behaviorof tin-containing radiopharmaceuticals: I. Chemistry, preparation and distribution insmall animals. ml J NucI Med Biol 1985;12:l67—l74.

16. Oster ZH, Som P. Srivastava SC, et al. The development and in vivo behavior oftin-containing radiopharmaceuticals: II. Autoradiographic and scintigraphic studies innormal animals and animal model of bone disease. ml i Nuci Med Biol 1985;l2: 175—184.

17. Atkins HL, Mausner LF, Srivastava SC, et al. Biodistribution of Sn-lI7m(4+)DTPAfor palliation therapy of painful osseous metastases. Radiology l993;186:279—283.

18. Atkins HL, Mausner LF, Srivastava SC, et al. Sn-I 17m(4+)DTPA for palliation ofpainful osseous metastases: a pilot study. J Nuci Med l995;36:725—729.

19. Albert SN. Blood volume. In: Blahd WH, ed. Nuclear medicine. New York:McGraw-Hill; 1971:593—619.

20. Simpson L, Morey i, Kreis J, et al. Imaging protocol for quantification of total-bodyretention of Sn-I 17m(4+)DTPA in patients with bone metastasis [Abstracti. J NuciMed Technol1995;23:I16.

21. Blake GM, Zivanovic MA. McEwan AJB, Ackery DM. Strontium-89 therapy:strontium kinetics in disseminated carcinoma of the prostate. Eur J NucI MedI996; 12:447—454.

22. Marshall JH, Lloyd EL, Rundo J, et al. Alkaline earth metabolism in adult man. HealthPh@vsI973;24:I25—221.

23. Atkins HL, Krishnamurthy GT, Srivastava SC, et al. A dose escalation trial ofSn- I I7m(4+)DTPA for bone pain palliation [Abstract]. J NucI Med 1995;36:3 1P.

24. Subramanian G, McAfee JG, Blair Ri, et al. Technetium-99m-methylene diphosphonates—a superior agent for skeletal imaging: comparison with other technetiumcomplexes. J Nucl Med I975;16:744—755.

25. Srivastava SC, Meinken GE, Mausner LF, et al. Nuclear, chemical and mechanisticconsiderations in the use of Sn-I l7m(4+)DTPA relative to Re-186-HEDP and otheragents for bone pain therapy. In: Nicolini M, Bandoli G, Mazzi U, eds. Technetium andrhenium in chemistrt and nuclear medicine. Padova: 1994:287—292.

of 36 patients studied at VAMC and BNL (23). We anticipate thetotal therapeutic dose to be between 10—20mCi (370—740MBq)for a 70-kg patient. Favorable biokinetic, nuclear physical andchemical characteristics combined with our preliminary pain palliation results suggest that ‘l7mSn(4+)DTPA meets most of therequirements for an ideal bone pain palliation agent (Table 3).Double-blind studies comparing the results with a placebo or theFDA-approved 89Sr-chloride are required before final judgmentsare made on this new agent. An application to the FDA to beginPhase III clinical trials is under preparation.

ACKNOWLEDGMENTSWe thank Ms. Michelle Reagan for preparing and Ms. Pattie K.

Hurt for critical review of this manuscript. Supported in part byDepartment of Veterans Affairs, Brookhaven National Laboratoryand Diatide Inc., Londonderry, NH.

REFERENCESI . American cancer society. A cancer journal for clinicians. Cancer I996;46: 1—28.2. Nielsen OS, Munro AJ, Tannock IF. Bone metastasis. Pathology and management

policy.J ClinOncol1991;9:509—524.3. CleelandCS,GoninR, HatfieldAK,et al. Painand its treatmentin outpatientswith

metastatic cancer. N Engi J Med 1994;330:592—596.4. Joshi DP. Seery WH, Goldberg LG. Goldman L. Evaluation of phosphorus-32 for

intractable pain secondary to prostatic carcinoma metastases. JAMA 1965;193:151—153.

5. LawrenceJH, Tobias A. Radioactiveisotopesand nuclearradiationin the treatmentofcancer. CancerRes I956;16:185—I93.

6. Firusian N, Mellin P, Schmidt CG. Results of strontium-89 therapy in patients withcarcinoma of the prostate and incurable pain from bone metastasis: a preliminaryreport. J Uro! l976;I 16:764—768.

7. Robinson RG, Blake GM. Preston DF, et al. Strontium-89 treatment results andkinetics in patients with painful metastatic prostate and breast cancer in bone.Radiographics I989;9:27 I—281.

8. Porter AJ, McEwan AJB, Powe JE, et al. Results of a randomized phase III trial toevaluate the efficacy of strontium-89 adjuvant to local field external beam irradiationin the management of endocrine resistant metastatic prostate cancer. In: J Onco! BiolPkvs I993;25:805—813.

techniques were incompletalysuccessful and disappearance onseven occasions when success was achieved (three occasions afterthe first TAE and one occasion after the second TAE).Of the sevenoccasions when TAE was unsuccessful, four patients received thesecond or third TAE to resutt in complete destruction of the aldosteronoma; three patients underwent unilateral adrenalectomy.Conclusion: Adrenocortical scintigraphy can correctly predict theeffect of TAE on aldosteronomas and is a valuable indicator fordecisions on the necessity of repeated TAE or adrenalectomy.

Key Words adrenal gland; primary aldosteronism; transcatheterarterial embolization; absolute ethanol

J Nuci Med 1997;3&237—24I

Primaryaldosteronismisoneofthecausesofsecondaryhypertension. Its incidence is assumed to be

Patient AgeSexBlood pressureSerum KPlasma

levelsLesionAldosterone@Renin

activity@Sizeonno.(yt)(mmHg)(mEq/l)(ng/dl)(ng/ml . ha)SideXCT(mm)1

44F190/1202.834

Patientno.Numberof TAEPlasmaaldosterone

leveis(ng/dl)

14—21days S (days)Scintigraphic

findings

F (mo) Before After TAEBlood

pressureBefore

(days)After

TAES

F1day7 days

days = days after the last measurement after the previousTAE,S (days)= days of 1311NCL-6imagingafterTAE,F (mo)= months of the finalfollow-upafter the last TAE,S = around the day of 1311NCL-6imaging,F = on the day of finalfollow-up,H = hot nodule;W = warm nodule;0 = disappearance ofhot nodule R = residualhot nodule (C = concordant uptake (D = disconcordant uptake (S = symmetricaluptake.

TABLE 2Plasma Aldosterone Levels and Adrenocortical Scintigraphic Findings before and after TAE and BlOOdPressure after TAE in Ten

Patients with Unilateral Aidosteronoma

1 1 342 1 1953 1 644 1 66

2 60(0)5 1 60

2 51(0)6 1 43

2 56(0)7 1 66

2 60(8)3 68(0)

8 1 649 1 44

2 34(4)10 1 61

2 35(22)

161 1 (29)1 1 (31)H (C)D(D)130/90124/8431010(24)1 1 (17)H (C)D (D)148/110124/72144(17)10 (2)H (C)D(D)150,90150/90536060(22)H (C)A(C)180/110145(52)3 (30)0(0)160/100140/80374051(22)H (C)A(C)160/110—69(37)13(21)0(D)170/120136/1063056-H(C)-365

(29)1 1 (15)D(D)154/90130/85394343(15)H (C)H(C)160/1106068---253

(18)4 (18)D(S)120/80120/8032——(24)W (S)W(S)180/100(Adrenalectomy)132727(21)H (C)A(S)150/901

123——170/90(Adrenalectomy)182323(22)H (C)A(C)180/120271762(43)H (S)180/130(Adrenalectomy)

83

203

134

1346

104

1568

nal tissue and a warm nodule when it showed the same intenseactivity as the extranodular activity (15). The scintigraphic appearance of the nodule after therapy was compared with that beforetherapy. The hot nodule with less avid activity than the one beforetherapy was termed a residual hot nodule. The relative activitybetween both adrenal glands was classified as a concordant uptake(the uptake is higher in the adenoma-bearing gland than theopposite gland), disconcordant uptake (the uptake is lower in theadenoma-bearing gland than the opposite gland) and symmetricaluptake (14). Follow-up studies including measurements of bloodpressure, levels of plasma aldosterone, renin activity and serumelectrolytes were periodically made over 15 mo in six patients andfor 2 mo in one patient who was lost to follow-up thereafter. Theremaining three patients underwent adrenalectomy to achievenormalization of the levels of plasma aldosterone.

RESULTSTable 2 shows the plasma aldosterone levels and adrenocor

tical scintigraphic findings before and after TAE, and bloodpressure after TAE in the 10 patients with unilateral aldosteronoma. Successful and complete destruction of the aldosteronoma was achieved in three patients after the first TAE, threepatients after the second TAE and one patient after the thirdTAE: No hypersecretion of aldosterone was observed duringthe period from 15 to 3 1 mo post-TAE in six patients and in onepatient for 2 mo who was then lost to follow-up. The remainingthree patients who failed to respond to TAE underwent unilatera! adrenalectomy.

On the day after TAE, plasma aldosterone levels were allwithin normal limits in the six completely and eight incompletely successful procedures. On the seventh day after TAE,the levels were within normal limits in the six completely andthree incompletely successful procedures and high in sevenincompletely successful occasions, and on the 14—21stdaywere within normal limits in seven completely and threeincompletely successful procedures and high in six incom

plete!y successful procedures. The levels of plasma aldosteronearound the day of ‘31-NCL-6 imaging were within normallimits for the seven occasions of complete success and oneoccasion of incomplete success and high in five occasions withincompletely successful procedures. Thus, the levels of plasmaaldosterone obtained after the TAE could not predict incomplete therapeutic success for aldosteronomas on all of eightoccasions on the day after TAE, in three of ten occasions by theseventh day, and three of nine occasions by the 14—21st day.

For the seven completely successful TAEs, the levels ofplasma renin activity remained suppressed in all of the sixpatients (not measured in one) on the day after TAE, returned tothe normal range in three patients by the seventh day and in theother three by the fourteenth day, and remained suppressed inanother patient until the last follow-up day. Hypokalemia wasalso noted in the same six patients on the day after TAE. Thenthe serum potassium levels improved to the normal range in twopatients by the seventh day, in the other four by the fourteenthday and in another patient by the sixteenth day. Finally, thelevels of plasma aldosterone, renin activity and serum potassium showed to be all within normal limits on the last follow-upday, except for a low level of plasma renin activity in Patient 6,in the seven completely successful TAE patients. In the case of10 incompletely successful TAEs, the levels of plasma reninactivity remained suppressed in five patients, increased slightlyin two patients and definitely in one patient (not measured intwo) on the day after TAE, remained suppressed in four,increased slightly in three and definitely in three on the seventhday. However, they returned to the suppressed state in nine (notmeasured in one) on the fourteenth day. Hypokalemia wasnoted in all of the eight patients (not measured in two) on theday after TAE. The levels of serum potassium remained in thehypokalemic range in seven patients and were within normallimits in two (not measured in one) on the seventh day. On thefourteenth day, the serum potassium levels were in the hy

ADRENAL SCINTIGRAPHY FOR TAE TREATED ALDOSTERONOMA •Nakajo et al. 239

240 THEJOURNALOFNUCLEARMEDICINE•Vol. 38 •No. 2 •February1997

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FIGURE 1. Adrenocortical images of Patient 1 with right aldosteronomabeforeand after the firstsuccessful TAE.The hot nodule(arrowhead)at theinferiorportion of the nght adrenal before the TAE(A@disappeared after theTAE(B).

pokalemic range in six and within normal limits in three (notmeasured in one).

The scintigraphic results were as follows: The aldosteronomawas visualized as a hot nodule in nine patients who also showedconcordant uptake, and a warm nodule in one patient withsymmetrical uptake before the first TAE. A hot, warm orresidual hot nodule was observed on seven occasions whensuccess ofTAE ofaldosteronomas was incomplete. Concordantuptake was preserved on four occasions while symmetricaluptake was observed on the remaining three occasions. A hotnodule disappeared on seven occasions when TAE of thealdosteronoma was completely successful and the pretherapeutic pattern of concordant uptake changed into one of disconcordant uptake in six patients and symmetrical uptake in onepatient. Figures 1 and 2 show the scintigraphic changes in twopatients whose aldosteronomas were completely cured by thefirst TAE. Figure 3 shows the scintigraphic changes in a patientwhose aldosteronoma was incompletely responsive to the firsttherapy and completely cured by the second therapy. Figure 4shows the scintigraphic changes in a patient whose aldosteronoma was not completely responsive to therapy even with thesecond TAE.

The scintigraphic findings after TAE agreed with the levelsof plasma aldosterone measured around the day of ‘311-NCL-6imaging on 12 occasions. However, the plasma aldosteronelevel was within normal limits when a residual hot nodule wasdemonstrated on one occasion.

Blood pressure remained in hypertensive range around theday of 13‘INCL6 imaging or just before adrenalectomy on 13occasions and was in the normotensive range on two occasions.On the final day offollow-up, blood pressure was normal in fivepatients with completely successful TAE ofaldosteronomas andreduction in severity of hypertension was observed in theremaining two patients.

DISCUSSIONThe TAE of aldosteronoma is less invasive than adrenalec

tomy and can provide a long-term cure, which has beendemonstrated in this study. However, completely successfultherapeutic responses of aldosteronomas were achieved by thefirst TAE in only 3 of 10 patients. A second or third TAE wasrequired to abolish the function of aldosteronoma in four otherpatients, while the remaining three patients required adrenalectomy.

We used AE as an embolic agent. The embolic effects of AEare related to its protein denaturant and hygroscopic propertieswhich would be expected to result in tissue damage andnecrosis. Its major effects on blood vessels may be due todamage to the vascular endothelium with activation of the

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FIGURE2. Adrenocorticalimages of Patient 2 @thleft aldosteronomabeforeand after the firstsuccessful TAEThe hot nodule(arrowhead)of theleftadrenal before the TAE(A)disappeared after the TAE(B).

coagulation systems and a direct irritant effect, causing vascularspasm, which in turn slows blood flow and contributes tothrombosis (3,4). When AE was infused into the renal artery indogs, it produced renal infarction with thrombi in the renalarterial branches and complete coagulation necrosis ofthe renalcortex (3). Therefore, if AE is adequately infused into thealdosteronoma, it should become to be necrotic and secondarilyinactive. However, it is difficult to judge whether AE perfusesthe entire adenoma during therapeutic infusion ofAE because itis radiolucent. The most sensitive method to assess the emboliceffect on aldosteronomas may be the measurement of the levelsofplasma aldosterone. Nevertheless, in our series, the levels onthe day after TAE were invariably within normal range in allpatients regardless of whether the TAE was incompletely orcompletely successful.

Therefore, the next day values could not predict complete orincomplete therapeutic success. The reasons why the falselynormal levels of plasma aldosterone were obtained on the dayafter TAE in case of incompletely successful TAE are unknown. However, the transient blockade ofblood supply for theadenoma by the interventional prosedures such as insertion ofthe outer and microcatheters into the adrenal artery and itsbranches feeding the adenoma, injection ofthe contrast mediuminto these branches, and the true but partial necrotic effect ofAE on the adenoma might all reduce the aldosterone-producingcell function of the adenoma to result in the falsely normalvalues. Although the levels of plasma aldosterone remainedwithin normal range after all completely successful TAEs, thevalues in the normal range were shown in 3 of 10 eventuallyunsuccessful TAE procedures on the seventh day and in three ofnine unsuccessful TAE procedures on Days 14—21. Thereforeabout 30% of unsuccessful TAEs could not be predicted bymeasurements of the levels of plasma aldosterone performedeven a 7—21stday after TAE. Such delay to show the increasein the levels of plasma aldosterone in some incompletelyresponsive cases is a problem for patient management. Ifincomplete therapeutic responses can be predicted as soon aspossible, the management plan can also be modified earlier.

Iodine- 13 1-NCL-6 is an analog of cholesterol which is theprecursor for steroid hormone biosynthesis and is accumulatedby and esterified in adrenocortical cells of the normal orhyperplastic adrenal cortex, aldosteronomas, cortisol-producingadenomas, sex hormone-producing adenomas and nonhyperfunctioning (silent) adenomas (10—15).Therefore, the adrenalcells must be viable to take up this tracer. Adrenocorticalscintigraphy with this agent correctly visualized the state ofaldosteronomas after TAE: a hot or warm nodule in case ofunsuccessful TAE, a residual hot nodule in case of partially

FiGURE 3@Adrenocortical images of Pabent 4 with right aldosteronoma beforeand after the firstunsuccessful and seeond successful TAEs. The hot nodule(arrowhead)of the ñghtadrenal beforethe TAE @A)decreased in activitybut stilldemonstrated residual activity after thefirst TAE (B). Disappearance after thesecond successful TAE(C).

FIGURE4, Adrenocorticalimages of Pabent 10 with left aldosteronoma beforeand afterthe firstand second unsuccessfulTAEs.The hot nodule (arrowhead)ofthe left adrenal before the TAE(A@decreased in activityafter the firstTAE(B).The nodule persisted and increased intracer uptake after the second TAE(C),suggesting unsuccessful therapeutic int@vention.

4. Ellman BA, Green CE, Eigcnbrodt E, Garriott JC, Curry TS. Renal infarction withabsolute ethanol. Invest Radiol 1980;15:318—322.

5. Ekelund L, Jonsson N, Treugut H. Transcathater obliteration of the renal artery byethanol injection: experimental results. Cardiovasc Intervent Radiol 198 I;4: 1—7.

6. Ekelund L, EK A, Forsberg L, et aI. Occlusion of renal arterial tumor supply withabsolute ethanol experience with 20 cases. Acta Radial Diagn l984;25:195—201.

7. O'keeffe FN, CarrascoCl-I,ChansangavejC, Richei WR, Wallace S. Arterialembolization of adrenal tumor: result in nine cases. AJR l988;l51 :819 —822.

8. Kojima M, Maeda M, Ogawa H, Nifta K, Ito 1. New adrenal scanning agent. J NucIMed 1975;16:666—668.

9. Sarkar SD, Beierwaltes WH, Ice RD. et al. A new and superior adrenal scanning agent,NP-59. J NucI Med I975;16:l038—l042.

10. Gross M, Valk T, Freitas JE, Swanson DP, Schteingart DP, Beierwaltes WH. Therelationship of adrenal iodomethylnorcholesterol uptake to indices of adrenal corticalfunction in Cushing's syndrome. J Cliii Endocrinol Melab 1981 ;52: 1062—1066.

I I. Gross MD, Shapiro B, Grekin Ri, Meyers L, Swanson DP, Beierwaltes WH. Therelationship of iodomethylnorcholesterol adrenal gland uptake to zona glomerulosafunction in primary aldosteronism. J Clin Endocrinol Metab l983;57:477—481.

12. Shapiro B, Gross MD, Sandier MD. The adrenal scan revisited: a current status reporton radiotracers, clinical utility and correlative imaging. In: Freeman LM, Weisman HS,eds. Nuclear medicine annual. New York: Raven Press; 1987:193—232.

13. Beierwaltes WU. Endocrine imaging: parathyroid, adrenal cortex and medulla, andother endocrine tumors. Part 2. J NucI Med 1991;32:l627—1639.

14. GrossMD,ShapiroB. FrancisIR,et al. Scintigraphicevaluationof clinicallysilentadrenal masses. J Nucl Med l994;35:1 145—1152.

15. Nakajo M, Nakabeppu Y, Yonekura R, Iwashita S. Goto 1. The role of adrenocorticalscintigraphy in the evaluation of unilateral incidentally discovered adrenal andjuxtaadrenai masses. Ann NucI Med l993;7:157—166.

A

successful TAE and disappearance of a hot nodule in case ofcompletely successful TAE. This suggests that adrenocorticalscintigraphy is a sensitive indicator to assess the effects of TAEwith AE on aldosteronomas. The use of this scintigraphicmethod by injection I311-NCL-6 within one week after TAE,in combination with measurements ofplasma aldosterone levelsmay allow for more precise assessment of the complete orincomplete success of the TAE of aldosteronomas within 2 wkand provide earlier information on the decision for a next stepsmanagement such as no further therapy, repeated TAE orsurgical operation than only the measurement of the levels ofplasma aldosterone.

I n a recent editorial in JNM, Peter Valkof the Northern California PET Imag

ing Center (1 ) described problems indetermining the specificity of [‘8F]fluorodeoxyglucose (FDG) studies in thecare of patients with cancer. As an exampie, Valk considered the validation ofFDG imaging for detection of hepatic

Received Sept. 4, 1996; accepted Sept. 25, 1996.For correspondence or reprints contact: Johns Hop

kinsMed@ Institution,DivisionofNuclearMedicineandRadiationHealth,615 North WolfeSt., Baltimore,MD21205-2179.

metastases. Even if all patients undergosubsequent surgery, lesions can only bedetected if they are superficial or largeenough to be palpated in the accessibleportions of the liver. Small or deeperlesions will remain unconfirmed, andsensitivity of the FDG imaging will possibly be over estimated.

While measurement of sensitivity andspecificity of diagnostic procedures, suchas [‘8F]FDGstudies, whether performedby dedicated PET instruments or by recently developed dual-detector coinci

dence detections (SPECT) systems, arehelpful, such parameters are not sufficient and often not knowable. Of increasing importance is the establishment of thevalue of the tests in meeting patients'needs reliably and consistently and in acost-effective manner.

Assessment ofthe incremental value ofdiagnostic tests is an idea whose time hascome. In modern medicine we try to beas scientific as possible. We try to makeour tests as precise and as accurate aspossible. Precision is a measure of the

THE INCREMENTALVALUESOF DIAGNOSTICTESTS •Wagner 241

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REFERENCESI. Baxter JD. Mineralocorticoid excess states. In: Wyngaarden JB, Smith LH Jr, Bennett

JC,eds.Ceciltexthookofmedicine,19thed.Philadelphia:W.B. Saunders;1992:1288—I291.

2. Inouc H, Nakajo M, Miyazono N, et al. Successful therapeutic embolization ofaldosteronoma using absolute ethanol. Radiat Med 1993;l I:256 —259.

3. InoueH,NakajoM,MiyazonoN,et al. Treatmentof aldosteronomawithsuperselective intraarterial injection of absolute ethanol. Nippon Ada Radiology l994;54:l54—I62.

The IncrementalValueof DiagnosticTests