Lymphoscintigraphywith Tc-99m-LabeledDextran

8
Lymphoscintigraphy withTc-99m-LabeledDextran E.Henze,H.R.Schelbert,J. D.Collins,A. Najafi,J. R.Barrio,andL. A. Bennett UCLA School of Medicine, University of California at Los Angeles, Los Angeles, California Currentagentsfor lymphosclntlgraphyhave limitationsbecauseof slowmigra tlonof the colloidaltracersfromthe Injectionsite andthe unknowneffect of phago cytosis on the removal of the labeled particles. The usefulness of Tc-99m dextran (TcDx) with a molecular weight of 110,000 has been tested for lymphosclntigra phy. Computer-assisteddynamicimagingand serial bloodsamplingin 13 dogcx perimentsdemonstratedthat the tracer clearedonlyby lymphdrainagefroman In terstitlal injection site. Following interdlgftal Injection of 1.0 ml (0.5-5.0 mCi), TcDx reachedthe knee or elbowlymphnodesIn 12.4 ±6.5 (1 s.d.) sec, andthe In guinal or axlliary lymph nodes in 98.0 ±42.3 sec. It cleared from the Injection site with a half-time of 31.5 mm. In a dog with surgically Induced lymphedema, tracer migrationwas markedly delayed in the edematousleg and the radlonucildelym phosclntigramresembledthe contrast lymphangiogram.Initial studies In man yieldedhigh-qualityradlonuclldelymphogramsofthe leg, andthe pelvicandpara aortic lymph nodes. We conclude that TcDx Is very promising for Iymphosclntlg raphy. J NucIMed23: 923—929, 1982 The human lymphatjc system is conventionally im aged for diagnostic purposes by contrast lymphangiog raphy. However, standard ethiodol lymphangiography suffers from several acknowledged shortcomings, such as tedious cannulation of a lymph vessel, pulmonary oil emboli, hypersensitivity reactions to the iodine compo nent of the contrast medium, failure to study lymph flow from a primary tumor site, and failure to perform kinetic physiologic and quantitative studies since the contrast medium is administered by a perfusion pump into the lymph vessel (1). Alternatively, a variety of radionuclide approaches and labeled agents have been examined to overcome these limitations (1—9).Perfusion lymphos cintigraphy with Tc-99m-labeled albumin was proposed to assess the need for a standard contrast lymphangio gram, which requires lymph-vessel cannulation (1). Au-l98 colloids provided high-quality lymphoscintig rams after interstitial administration because of their Received Feb. 19, 1982; revision accepted April 26, 1982. For reprints contact: Eberhard Henze, MD, UCLA School of Medicine, Laboratory of Nuclear Medicine, Los Angeles, CA 90024. optimum particle size, but their use was abandoned be cause of unacceptably high absorbed radiation at the injection site (16). Among the Tc-99m-labeled com pounds proposed for lymphoscintigraphy—suchas sulfur colloid, tin colloid, phytate, red blood cells, and albu mm—only antimony sulfide colloid exhibited satisfac tory properties for this purpose (2,3,6—9). This agent has been used in numerous studies for the evaluation of the lymphatic system in patients with breast carcinoma, truncus melanoma, and pelvic lymph-node metastases (2,3,8). Despite encouraging results, there are two major limitations to the use of Tc-99m colloids, due mainly to the particulate character of the tracers used: (a) tracer migration from an interstitial injection site is only 1—35% in 24 hr (10); and (b) clearance from the interstitial space and trapping of the colloidal particles is dependent on the particle size and on the functional state of the reticuloendothelial system (6,9,1 1 ), and thus does not reflect lymphatic flow. The latter may account for the reported finding that approximately 50% of normal parasternal lymph nodes failed to trap colloid activity and thus were not distinguishable from lymph nodes with metastases (2). A noncolloidal nonparticulate tracer Volume 23, Number 10 923 by on January 29, 2018. For personal use only. jnm.snmjournals.org Downloaded from

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Page 1: Lymphoscintigraphywith Tc-99m-LabeledDextran

Lymphoscintigraphywith Tc-99m-LabeledDextran

E.Henze,H.R.Schelbert,J. D.Collins,A. Najafi,J. R.Barrio,andL. A. Bennett

UCLA School of Medicine, University of California at Los Angeles, Los Angeles, California

Currentagentsfor lymphosclntlgraphyhave limitationsbecauseof slow migratlonof the colloidaltracersfromthe Injectionsiteandthe unknowneffectof phagocytosis on the removal of the labeled particles. The usefulness of Tc-99m dextran(TcDx) with a molecular weight of 110,000 has been tested for lymphosclntigraphy. Computer-assisteddynamicimagingand serial bloodsamplingin 13 dogcxperimentsdemonstratedthat the tracer clearedonlyby lymphdrainagefroman Interstitlal injection site. Following interdlgftal Injection of 1.0 ml (0.5-5.0 mCi),TcDx reachedthe knee orelbowlymphnodesIn 12.4 ±6.5 (1 s.d.) sec, andthe Inguinal or axlliary lymph nodes in 98.0 ±42.3 sec. It cleared from the Injection sitewith a half-time of 31.5 mm. In a dog with surgically Induced lymphedema, tracermigrationwas markedly delayed in the edematousleg and the radlonucildelymphosclntigramresembledthe contrast lymphangiogram.Initial studies In manyieldedhigh-qualityradlonuclldelymphogramsof the leg, andthe pelvicandparaaortic lymph nodes. We conclude that TcDx Is very promising for Iymphosclntlgraphy.

J NucIMed23: 923—929,1982

The human lymphatjc system is conventionally imaged for diagnostic purposes by contrast lymphangiography. However, standard ethiodol lymphangiographysuffers from several acknowledged shortcomings, such

as tedious cannulation of a lymph vessel, pulmonary oilemboli, hypersensitivity reactions to the iodine component of the contrast medium, failure to study lymph flowfrom a primary tumor site, and failure to perform kineticphysiologic and quantitative studies since the contrastmedium is administered by a perfusion pump into thelymph vessel (1). Alternatively, a variety of radionuclide

approaches and labeled agents have been examined toovercome these limitations (1—9).Perfusion lymphoscintigraphy with Tc-99m-labeled albumin was proposedto assess the need for a standard contrast lymphangiogram, which requires lymph-vessel cannulation (1).Au-l98 colloids provided high-quality lymphoscintigrams after interstitial administration because of their

Received Feb. 19, 1982; revision accepted April 26, 1982.

For reprints contact: Eberhard Henze, MD, UCLA School ofMedicine, Laboratory of Nuclear Medicine, Los Angeles, CA90024.

optimum particle size, but their use was abandoned be

cause of unacceptably high absorbed radiation at theinjection site (16). Among the Tc-99m-labeled com

pounds proposed for lymphoscintigraphy—suchas sulfurcolloid, tin colloid, phytate, red blood cells, and albumm—only antimony sulfide colloid exhibited satisfac

tory properties for this purpose (2,3,6—9).This agent hasbeen used in numerous studies for the evaluation of thelymphatic system in patients with breast carcinoma,truncus melanoma, and pelvic lymph-node metastases(2,3,8). Despite encouraging results, there are two majorlimitations to the use of Tc-99m colloids, due mainly tothe particulate character of the tracers used: (a) tracermigration from an interstitial injection site is only 1—35%in 24 hr (10); and (b) clearance from the interstitial

space and trapping of the colloidal particles is dependent

on the particle size and on the functional state of thereticuloendothelial system (6,9,1 1 ), and thus does not

reflect lymphatic flow. The latter may account for thereported finding that approximately 50% of normalparasternal lymph nodes failed to trap colloid activityand thus were not distinguishable from lymph nodes withmetastases (2). A noncolloidal nonparticulate tracer

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HENZE, SCHELBERT, COLLINS, NAJAFI, BARRIO, AND BENNETF

compound, soluble in lymph fluid and with moleculeslarge enough not to penetrate the capillary membraneafter interstitial administration, would be a desirablesubstance for the purpose of lymphoscintigraphy.

Dextran, a polysaccharide used clinically as a plasmasubstitute, is known to remain in the vascular space afterintravenous administration. Accordingly, this substanceshould clear from the injection site only by lymphdrainage after interstitial administration (12,13). Werecently succeeded in labeling dextran with Tc-99m withexcellent in vivo and in vitro stability, and documentedits potential use for radionuclide angiocardiography in

animal experiments (14). It was the purpose of thepresent study to examine the potential value of Tc-99m

dextran for lymphoscintigraphy.

METHODS

Radiopharmaceutical preparation. We have describedour labeling procedure, as well as the purity and in vivoand in vitro stability of Tc-99m dextran (14). Briefly,Tc-99m is attached to dextran using stannous ion reduction of pertechnetate. One gram dextran is dissolvedin 10 ml of 0.9% saline solution and deoxygenated bypurging with nitrogen gas at 50 ml per mm for 1 hr; it isthen mixed with 1.5 mg of SnC12 dissolved in 50 jsl ofconcentrated HC1. Under aseptic conditions, 1.0-mlaliquots of this stannous-dextran solution is then dis

pensed through a sterile 0.22-zm membrane filter into5-ml sterile vials, which are stoppered and sealed in anitrogen atmosphere. Stannous-dextran kits can bestored at 2—4°Cfor several weeks, thus facilitatingroutine use. Before a study, freshly eluted pertechnetate

is added to the vial, mixed,―andleft at room temperaturefor 5 mm. Dextran with a mean molecular weight ofI I0,000* was used in order to avoid regional bloodcapillary uptake and washout from the injection site,

since it is known that dextran with a molecular weightless than 40,000 does penetrate capillary membranes(12). Sterility and nonpyrogeneitywereassuredbyrandomly testing one of the ten kits in each batch.

Imaging.Thesuitabilityof Tc-99mdextranforlymphoscintigraphy was tested in 15 mongrel dogs weighingfrom 25—3i kg an4 anesthetized with pentobarbital (25mg/kg). In eight dogs, 1.0 ml of Tc-99m dextran (0.5mCi) was injected through an infusion set interdigitallyand subcutaneously in either the front limb (4 dogs) orthe hind limb (4 dogs). Sequential gamma imagingt wasperformed over the injection site at 10-mm intervals for2 hr. A region of interest was drawn over the dog's pawfor calculation of the clearance rate from the injectionsite. In five dogs the times of tracer migration to the knee(or elbow) and groin (or axillary) areas were also measured using a large-field-of-view camera. Serial analogimages were obtained at 5-sec intervals after interdigitalinjectiQn of 1.0 ml dextran labeled with 5.0 mCi of Tc

99m. In addition, venous blood was sampled in one-mmintervals to estimate the appearance rate of the tracerin the blood. For comparison, the appearance characteristics of activity in venous blood was also measuredafter subcutaneous interdigital injection of I .0 ml (0.5mCi) of pertechnetate in one dog. In order to comparecontrast with lymphoscintigraphy, lymphedema wasinduced surgically in one dog by obstructing lymph nodes

and lymph vessels in the right groin. One month aftersurgery a lymphedema developed in the right leg, at

which time a contrast ethiodiol lymphangiogram wasobtained by cannulation of a lymph vessel, and a lym

phoscintigram by subcutaneous injection of 1.0 ml (0.5mCi) Tc-99m dextran. To provide controls, both hindlimbs were similarly treated.

At the end of each study, camera views of the thyroidgland and the stomach were obtained in search of released Tc-99m.

Finally, initial studies in man were performed. Multiple camera views of the left leg, the groin, the pelvis,and the abdomen were obtained 45 mm after interdigitalinjection in the foot of 0.5 mCi (0.5 ml) of Tc-99mdextran.

All mean values are given with one standard deviation.

RESULTS

Interstitial administration of Tc-99m dextran resultedin high-quality lymphoscintigrams, as shown by examples for the hind leg (Fig. i ), for the front leg (Fig. 2),

and for the knee areas (Fig. 3). The main lymph vesselof the legs, the pelvis, and the knee are well visualized,together with their respective lymph nodes and thesmaller lymph vessels of the dog's paw@In all five cxperiments Tc-99m dextran migrated in the lymph vesselsrelatively fast: it reached the lymph nodes of the knee orelbow within an average time period of 12.4 ±6.5 5cc,and the inguinal or axillary lymph nodes in 98.0 ±42.3sec. The tracer cleared from the injection site monoexponentially within the first hour with a half-time of 31.5mm (Fig. 4). Serial blood sampling revealed entrance ofthe tracer activity into the venous blood stream in anS-shaped time-activity curve with maximum slope between 4 and 10 mm. This is considerably later than freepertechnetate, as shown in Fig. 5. In the dog with surgically induced lymphedema in the right leg, tracer migration was markedly slower on the right side than on the

left, where a normal migration pattern was noted,placing activity in the inguinal areas after 10—30sec. Theleft pelvic lymph nodes were visualized faintly at 60 secand became more prominent during the following hour.In contrast, even one hr after tracer administration theright pelvic lymph system did not demonstrate any appreciable uptake (Fig. 6, left). On the contrast lymphograms in the same dog (Fig. 6, right), the flow pat

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,@4@ ,@.

II0 sec

FIG. 1. SerIal lymphosclntigram of dog'sright hind limb Obtainedafter Interdigitalsubcutaneousinjectionof 1.0ml (5 mCI)ofTc-99m-Iabeled dextran with molecularweight 110,000. In this experiment, Wacerreacheskneearea(arrow)in “-‘20see,andinguinal lymph nodes in “—110 sec. 50

tern was normal on the left side, whereas marked collateralization was present on the right. However, becauseof the pressure infusion, the contrast medium did accumulate in the right-sided pelvic lymph nodes.

In man, high-contrast lymphoscintigrams were obtamed with Tc-99m dextran, as shown in Fig. 7. Fortyfive mm after interdigital injection, a continuous tracerstream through the lymph vessels and lymph nodes allowed multiple camera views to visualize the calf, thigh,groin, pelvis, and abdominal lymph system. Consistentwith the fate of Tc-99m dextran after entering the bloodsteam, liver and kidneys are faintly visualized and thelow-molecular-weight ddtran had accumulated in theurinary bladder.

None of the studies with labeled dextran revealeduptake of activity in the thyroid or the stomach. Therewas also no evidence of bone-marrow uptake.

DISCUSSION

These results demonstrate the utility of Tc-99m-labeled dextran as an agent for lymphoscintigraphy. Anyagent for this purpose must be examined for three criteria: (a) molecular size, (b) physical and biologicaldistribution in the interstitial space, and (c) possible

problems related to the labeling with a radionuclide.

Molecular size. The chemical properties and thepharmacokinetics of dextran's polysaccharide moleculeare almost ideal for the purpose of lymphoscintigraphy.Its molecular size can be selected in advance to be largeenough not to penetrate the capillary membranes and toremain within the interstitial space. Garlick et al. (15)reported a sharp reduction in membrane penetration formolecules larger than 4-5 nm in radius. With respect todextran, this implies that molecules with a molecularweight larger than 40,000 should not penetrate bloodcapillary membranes because this molecular size represents an Einstein-Stokes sphere of@ nm radius.Consistent with this are observations that dextran molecules smaller than 40,000 Dalton are subject to gbiierular filtration and urinary excretion (17). Usinginterstitial microinjections of fluorescein-labeled dextranin rabbits, Rutili et al. (12) demonstrated that thetransport of dextran molecules larger than 37,000 fromthe interstitial space is due to lymphatic drainage alone.This supports the conclusion that the permeability of theblood capillary membrane for dextran is the same in bothdirections. Parallel to our work, fluorescein-labeleddextran was recently successfully used for fluoroescencemicrolymphography in man by Bollinger et al. (13).Thus, as opposed to the colloidal tracers commonly used,Tc-99m dextran offers a major advantage in that a

FIG.2. Lymphoscintigramsofdog'sfrontlegsobtained20 mmafter bilateralInterdlgitalsubcutaneouslnjectlonof 1.0ml (0.5mCI) of Tc-99m-labeled dextran. Mainlymph vessels of both front legs are visualized up to axlllary lymph nodes (doublearrow). Single arrow Indicates elbow.LymphOsclntigramof left pawwasobtainedafter multiplekiterdigM Injectionsandwasdigitized and background-subtracted.Thesmaller lymph vessels of dog's paw arewellvisualized.NoactivityIsnotedInthyroldgland. rIght paw right leg thorax

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@ 400

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Time (rein)

FiG.5. Time-activitycurvesfrom bloodafter subcutaneousinject@nof Tc-99m-labeleddextran with molecular weight 110,000(TcDx-110,closed circles)and free pertechnetate(opensquares).Tc-99m-labeled dextran enters venous blood stream with a 4- to10-mmdelaycausedby lymphatic&@ainage.Activitywasnormalized,placingmaximumbloodactivityat 100%.

particles are still too large to enter the lymphatic capillanes. These size-related limitations of colloids result ina relatively slow and variable clearance from the injection site ofonly 1—35%in 24 hr (10), whereas Tc-99mdextran cleared uniformly in a monoexponential modewith a half-time of about ½hr. We used dextran with amean molecular weight of 110,000. Consistent with thepharmacokinetics discussed above, interstitial administration resulted in high-contrast lymphoscintigramsin both human and animal studies. Background activityrose only gradually with time and the appearance ofactivity in venous blood was characterized by an 5-shaped time-activity curve, with a delayed onset relativeto free pertechnetate, when both were injected interstitially. This delay of 2—4mm is explained by the drainage

FIG. 3. Lymphoscintigramof the knee area of dog, obtained withpin-holecollimator 1 hr after bilateral Interdigitalinjectionof 1.0ml(0.5mCi)of Tc-99m-Iabeieddextran.Thisdoghadsrglcally Inducedlymphedemaon rightside. In area of left knee, there is a wellvisualized main lymph vessel with multiple lymph nodes, whereasonrightedo onlytwolymphnodesarevisualizedfaintly.(Comparealso Fig. 6.)

well-defined molecular size can be selected for lymphoscintigraphy. For Au-189 colloid, with a relativelyfavorable and well-defined particle size of about 5 nm,good removal of the tracer from an interstitial injectionsite was measured by Strand Ct al. (6). However, thelocal radiation dose of 50-100 rads/@sCiis too high forroutine clinical use of this nuclide (16). Tc-99m sulfurcolboidtracer consists ofvery large particles (50—600nm)and shows only minimum clearance from the injectionsite and minimum uptake in regional lymph nodes.Strand et al. (6) demonstrated a better size distributionfor antimony sulfide colboid (5—15 nm), consistent witha higher regional lymph-node uptake in their rabbitmodel. However, these authors believe that many TCSbS

100

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40

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7-

0 20 40 60

Time (mm)

Co

C0

C)

C

C)

FIG.4. Time-activitycurveaftersubcutaneous injection of 0.5 ml of Tc-99m-

. labeled dextran, obtained from region of. Interest over injection site. Tracer clears

t I@ in a monoexponential mode within 1 hr

80 100 120 after injection, with clearance half-time of

#@_#1/2hr.

T112 31.5 mm

n= 8

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of Tc-99m dextran from the interstitium and its subsequent collection in large lymph vesselswith a slower flowthan in the venous blood stream and, thus, a delayedentrance into the venous blood. From these studies, it

groin

knee

FiG. 7. LymphosclntigramIn man obtained45—60mm after Interdigital Injection of 1.0 ml (0.5 mCi) of Tc-99m-labeled dextran.Lymphvessel of leg is welivlsualized, along with Ingulnal,peMc,and para-aortlc lymph nodes. As dextran slowly enters the bloodstream, liver, kidney, and urinal bladdershow uptake of activfty.

cannot be excluded that a small amount of low-molecular-weight dextran (less than 40,000) did penetrate theblood capillary membranes and enter the blood streamdirectly,becausedextran witha meanmolecularweightof 110,000 contains some low-weight molecules (lessthan 40,000). This is consistent with results in preliminary patient studies using Tc-99m dextran with a meaumolecular weight of 40,000. Only a very faint lymphoscintigram could be obtained, whereas backgroundand urinary bladder activity rose rapidly. There was,however, no thyroid or stomach uptake (E. Henze, et al.,unpublisheddata). In order to developa reliableagentfor clinical routine use, either dextran with the relativelyhigh mean molecular weight (1 10,000) used in this studyis required, or purified dextran of molecular weight between 40,000 and 70,000. From a practical point of view,the narrow range of molecular weights 40,000-70,000is preferable because these dextrans are already inclinical use, whereas dextran 110,000 is not used in theUnited States. Thus, further kinetic studies are neededto evaluate the optimum fraction of dextran to be usedfor lymphoscintigraphy.

Interstitial distribution. The biological and/or physicaldistribution in the interstitial space of a tracer to be usedfor lymphoscintigraphy is of great importance. Particlessuch as labeled colloids have certain appreciated disadvantages for this purpose. They are not soluble in theliquid compartment of the interstitium and they are thussubject to phagocytosis, mainly by macrophages. Theirremoval from an interstitial injection site, therefore doesnot necessarily reflect lymph flow but is largely dependent on the specific functional state of the macrophages(6,9,1 1 ), which seems to vary considerably with mdividual anatomic, physiologic, and pathologic factors thatcontribute to the rate of removal and dispersion of thecolloidal tracer in an unpredictable manner (10). Thismay account for the failure to localize in normal mammary lymph nodes after epigastric administration,

liver

bladder

foot

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FIG. 6. SerIal lymphoscintigramsof dog's lower extremities after bilateral Interdigital Injection of 1.0 ml (0.5 mCI)of Tc-99m-Iabeleddextran (left). This dog hadsurgically InducedlymphedemaInrI@t leg. Note normal Iymphosclntlgramof left leg, with filling of left-sidedpelvic lymph system, whereasfracer migration in ri@t leg Is markedlydelayedandthere Is no uptake In rl@t-sided peMc lymph nodes.Contrast lymphogramof samedog (right).There is normal lymphflow on left side, with filling of left-sidedpeMc lymphnodes.Rl@t leg'slymphangiogram shows multiple collateralization and also visualization of rI@t-sided pelvic lymph system by contrast medium. ThisdIfference from radlonuclide lymphosclntigrammight be explainedby unphysiologlcpressure InadmInistratIonof contrast medium(seetext).

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leading to the low predictive accuracy as to whether theretrosternal lymph nodes were normal or affected bybreast cancer metastases (2).

Dextran is water-soluble and is not bound to plasmaor interstitial fluid proteins. Although dextran eventuallybecomes trapped by the reticuloendoendothelial systemof the liver for oxidation as a foreign molecule (17), thereis no evidence for phagocytosis of dextran in the interstitium (12). Therefore, labeled dextran will be distributed only in the liquid phase and will reflect onlylymph flow in a physiologic mode. This may enable usto study regional and global lymphatic flow qualitativelyand quantitatively. Initial evidencçis shown in the dogstudy with surgically induced lymphedema. The edematous right leg dethonstrated a marked (and measurable)delay, and no regional uptake in the right-sided pelviclymph system was present. This pattern most likely refleets the true physiologic situation better than thecontrast lymphangiogram, where the lymph vessel wascannulated and the contrast medium was administeredwith an unphysiologically high pressure. This may leadto the opening of collaterals and to the uptake of theright-sided pelvic lymph nodes.

The underlying mechanism of accumulation of labeleddextran in the lymph nodes (Figs. 6 and 7) is unknownat this time. Most likely the tracer remains in the fluidphase but more detailed autoradiographic examinationis needed to define the internal distribution of Tc-99mdextran within the lymph nodes. Whether changes in thespecific activity will affect the relative lymph-node uptake, and thus could be used to optimize deposition of thetracer in the nodes, awaits also further evaluation.

Labeling of dextran. The in vitro stability of Tc-99mdextran is excellent; so is the in vivo stability after i.v.administration (14). This study confirmed that there isno evidence for an appreciable amount of uncomplexedTc-99m after interstitial injection. No thyroid or stomach uptake could be seen in patient or animal studies ifthe labeling procedure was performed properly. Preparation of the stannous-dextran kits is convenient, the kitscan be kept stable and sterile for weeks, and the labelingprocedure is very simple, reliable, and reproducible (14).The possible formation of Tc-99m stannous colloid needsto be addressed because of the solution of SnCl2 in HC1and the pH of 3.6-4.0 in the final preparation. As dernonstrated elsewhere, the formation of Tc-99m stannouscolloids could be excluded by thin-layer chromatographyand paper chromatography of freshly prepared Tc- 99mdextran (14). In vivo, colloids would be trapped mainlyin the liver and bone marrow. If they are lar@geenoughnot to penetrate the capillary membrane and result ingood lymph scans, they should not be subject to urinaryexcretion. In our previously reported results (14) and inthis study, no bone-marrow or prominent liver uptakewas noted.

Clinical implications. Tc-99m dextran could become

a useful agent for lymphoscintigraphy. It compares favorably with Tc-99m colboidsand contrast lymphography. This agent reflects lymph flow from an injection sitein a more physiologic manner and might be useful totrace lymph vessels and lymph nodes after local injectioninto an area of interest—for instance close to a breastcancer, or into the ischiorectal fossa for prostatic, rectal,or uterine cancer, or subcutaneously in patients withtruncus melanoma. Further, it could be of value forstaging Hodgkin's disease or other lymphomas. Serialquantitative and qualitative scans before and after surgery and/or radiation therapy are possible because theradiation dose is very low and injection can be performedrepeatedly. This new agent may also be very helpful fordifferentiating primary or secondary lymphedema fromedema caused by chronic venous disease, by measurement of regional lymphatic flow or clearance from theinjection site.

Our initial experience with Tc-99m dextran in a limited number of patients is encouraging (see Fig. 7). Although the liver uptake could limit the quality of abdominal lymph scans, the ratio of cts/pixel in pelviclymph nodes relative to liver was 11.5 to 1.52, and thussatisfactory for visualization of abdominal nodes. Further, there was no pain caused by the injection. Althoughadverse reactions after intravenous administration ofdextran have been described, we have seen none to datein our patient studies. More experience is needed to determine whether subcutaneous injections of such smallamounts as 50—100mg per dose will cause any allergicreactions.

WeconcludethatTc-99mdextranisa verypromisingagent for lymphoscintigraphy. Animal as well as pilotstudies in man produced high-contrast images of thelymph system. For clinical use, the optimum molecularweight of dextran to be labeled, and its potential superiority over Tc-99m labeled colloids, needs to be established further. The potential value of this new radiopharmaceutical for diagnosis and followup of patientswith cancer, lymphoma, and primary lymphatic diseaseawaits clinical trials.

FOOTNOTES

S Pharmacia Laboratories, Piscataway, New Jersey.

ACKNOWLEDGMENTS

The authors thank Herbert Hansenand Tom Patin for their technical assistance. We are further indebted to M. Lee Griswoldforpreparing the illustrations and greatly appreciate Kerry Engbar'ssecretarial assistance.

This work was supported in part by Contract DE-AMO6-76-SF00012betweenthe U.S. Departmentof Energy,Washington,D.C.and the University of California at Los Angeles and the AcademicSenate of the Universityof Californiaat LosAngeles.

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Results of this study were presented in part at The Society of Nuclear Medicine, 6th Annual Western Regional Meeting,San Francisco,CA,October8-II,1981.

REFERENCES

I. STECKEL Ri, FURMANSKI S, DUNAM R, Ct al: Radionuclide perfusion lymphangiography. An experimental techniqueto compliment the standard ethiodol lymphangiogram. AmJ Roenigenol Rad Ther Nuci Med I 24:600-609, 1975

2. EGEGN: Internal mammarylymphoscintigraphyin breastcarcinoma: A study of 1072 patients. mt J Radial Oncol BiolPhys 2:755-761, 1977

3. ASPERGENK, STRANDSE, PERSONBRR:Quantitativelymphoscintigraphy for detection of metastases to the internalmammary lymph nodes. Biokinetics of 99Tcm@sulfurcolloiduptake and correlation with microscopy. Ada Radio! Onco!17:17—26,1978

4. MEYERCM, LECKLITNERML, LOoICJR etal:Technetium-99m sulfur colloid cutaneous lymphoscintigraphy in themanagement of trucal melanoma. Radiology 131:205—209,I979

5. HULTBORN KA, LARSON LG, RAGNHU HI: The lymphdrainage from the breast to the axillary and parasternal lymphnodes studied with the aid of colloidal Au'98. Acta Radio!43:52-64,1955

6. STRAND SE, PERSONBRR: Quantitative lymphoscintigraphy I: Basic concepts for optimal uptake of radiocolloids inthe parasternal lymph nodes of rabbits. J Nucl Med 20:1038-1046,1979

7. KAPLANWD,BLOOMERMD,JONESAG,etal:Mediastinal

lymphoscintigraphy in ovarian cancer using intraperitonealautologous technetium-99m erythrocytes. Br J Radio! 54:126—131,1981

8. EGEGN, CUMMINGS BJ: Interstitial radiocolloid iliopelviclymphoscintigraphy: Technique, anatomy and clinical application. mt i Radiation Oncology Biol Phys 6:1483-1490,1980

9. KAPLAN WD, DAVIS MA, RosE CM: A comparisonof twotechnetium-99m labeled radiopharmaceuticals for lymphoscintigraphy: Concise communication. J Nuc! Med 20:933-937, 1979

10. EGE GN: Internal mammary lymphoscintigraphy. Radiology118:101—107,1976

II. EGE GN: Radiocolloid lymphoscintigraphy in neoplasticdisease.CancerRes40:3065-3071,1980

12. RUTILI G, HAGANDER P: Transport of macromolecules insubcutaneous tissue. Ada Universilatis Upsaliensis 306: 1-5 1,Uppsala, Sweden, 1978

13. BOLLINGER A, JAGER K, SGIER F, Ct al: Fluoresence microlymphography. Circulation 64: 1195- 1200, 1981

14. HENZE E, ROBINSON GD, SCHELBERT HR. KUHL DE:Tc-99mdextran:A newbloodpool-labelingagentforradionuclide angiocardiography. J Nuc! Med 23:348-353, 1982

15. GARLICK DG, RENKIN EM: Transport of large moleculesfrom plasma to interstitial fluid and lymph in dogs. Am JPhysiol219:1595-1605,1970

16. ZUM WINKEL K: Lymphologie mit Radinucliden. Berlin,Verlag Hildegard Hoffman, I972

I 7. WADE A, Ed: Martindale, The extra pharmacopoeia: Dcxtrans The Pharmaceutical Press, London, 1977, pp 461-466

The Computerand InstrumentationCouncilsof the Societyof NuclearMedicinewill meet February6 and 7, 1983,atthe Cathedral Hill Hotel in San Francisco, California.

This topical Symposium on “ECT—Presentand Future―will consist of invfted presentations, contributed papers, andactive attendee discussion. There will be only one session presented at a time. The abstractsof the meeting will be availableprior to the meeting. The proceedings of the meeting will be published.

Additional information and registration forms can be obtained by writing to:

RegistrarThe Societyof NuclearMedicine

475 Park Avenue SouthNew York, NY 10016Tel: (212)889-0717

Volume 23, Number 10 929

AnnouncementofBerson-YalowAwardThe Society of Nuclear Medicine invites manuscriptsfor consideration for the Fifth Annual Berson-YalowAward.Work will be judged on originality and contribution to the fields of basicor clinical radioassay.The manuscriptwillbe presented at the 30th Annual Meeting of the Society of Nuclear Medicine in St. Louis, MO, June 7-10, 1983,and asuitably engraved plaque will be awarded to the authors by the Education and Research Foundation of the Societyof NuclearMedicine.

The manuscriptshould be approximatelyten pagesin length (typed,double-spaced).A letter requestingconsideration for the award, including the author's full mailing address and telephone number, should accompany the manuscript. Original manuscriptandeight copiesmustbe receivedby January17,1983atthe Societyof NuclearMedicineoffice, 475 Park Avenue South, New York, NY 10016,Attn: Mr. Dennis L. Park.

Deadlineforrec&ptofmanuscripts:January17,1983.

SNM Computer Council and Instrumentation Council Meeting“ECT—Presentand Future―

February6—7,1983 Cathedral Hill Hotel Van Ness at GearySan Francisco, California

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1982;23:923-929.J Nucl Med.   E. Henze, H. R. Schelbert, J. D. Collins, A. Najafi, J. R. Barrio and L. R. Bennett  Lymphoscintigraphy with Tc-99m-Labeled Dextran

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