Gallium Imaging In Current Clinical Practice

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE George C. Panoutsopoulos M...

Author: George C. Panoutsopoulos & Julia P. Christacopoulou

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GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

George C. Panoutsopoulos M.D.

l

Department of Nuclear Medicine "SOTIRIA" Chest Hospital, ATHENS

Julia P. Christacopoulou M.D. Director of the Department of Nuclear Medicine "SOTIRIA" Chest Hospital, ATHENS

with 59 figures in 71 cases

III

CONTENTS Preface and acknowledgements .

VII

1. INTRODUCTION

2. PHYSICAL AND CHEMICAL PROPERTIES ..

2

3. UPTAKE MECHANISMS

2

4. GALLIUM-67 BIODISTRIBUTION

3

5. DOSIMETRY

5

6. GALLIUM-67 CITRATE IMAGING

5

7. SCAN INTERPRETATION AND NORMAL VARIANTS

6

8. CLINICAL APPLICATIONS

10 10

8.1. INFECTIONS 8.1.1. Osteomyelitis. 8.1.2. Cardiac infections 8.1.3. Graft infections 8.1.4. Abscesses 8.1.5. Tuberculosis 8.1.6. Other infectious diseases 8.2. ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) 8.2.1. Thorax 8.2.1.1. Pneumocystis Carinii Pneumonia (PCP) 8. 2.1.2. Lymphocytic Interstitial Pneumonitis (LIP) 8. 2.1.3. Cytomegalovirus (CMV) 8.2.1.4. Bacterial infections 8.2.1.5. Tuberculosis and other mycobacterial infections 8.2.1.6. Kaposi 's sarcoma and Lymphomas 8.2.2. Abdomen 8.3. NEOPLASMS 8.3.1. Lung cancer 8.3.2. Hepatoma .................. . . 8.3.3. Malignant melanoma . 8.3.4. Other malignant diseases 8.4. LYMPHOMAS

10

16 17 17 18 19

.. ... . .. ... .

20 20 20 . 21 22 22 23 24 24 24

. .. .... ...... 24

...... 26 26 26 . 26

8.5. SARCOIDOSIS AND UNKNOWN OTHER INTERSTITIAL LUNG DISORDERS

30

8.6. FEVER OF UNKNOWN ORIGIN (FUO)

38

9. BIBLIOGRAPHY

43

10. LIST OF ILLUSTRATIONS AND CASES .

49

PREFACE This excellent, well organized, and detailed monograph, brings together close to three decades of Nuclear Medicine experience with gallium-67 and highlights how this universally widely accepted diagnostic imaging agent continues to playa significant role worldwide in the evaluation of a large number of patients suspected of having a variety of infectionslinflammatory and neoplastic processes. Even though it was first introduced in 1969 and its mechanism of action is still not fully understood, the authors have clearly delineated the versatility and practicability of this agent. Despite its limitations attributed mainly to its lack of specificity, its diagnostic value when carefully complemented by the clinical and conventional diagnostic imaging modalities has withstood the test of time and in the last decade has found renewed utility. This is attributable to a variety of causes including its low cost, availability, higher doses currently being used, improvements in imaging technology, and wide clinical acceptance by our colleagues. The authors have succinctly brought together this monograph, reviewing for us the clinical applications of gallium-67 scintigraph in a variety of infectiouslinflammatory disorders including pyogenic infections, osteomyelitis, various granulomatomous and opportunistic infection and discussed its role in the evaluation of patients with fever of unknown origin. In addition they have emphasized its role in the detection, staging and post therapy evaluation of a variety of tumors. It remains especially useful in patients suspected to have lymphoma, hepatoma, melanoma, gynecological tumors and various tumors of the gastrointestinal and genitourinary tract. The availability of an agent able to provide clinically useful information under a number of diverse situations is efficacious. This is especially true because of the ramifications of the changing spectrum of disease in the AIDS patient and the cost control factors being imposed in the health care system worldwide. These changes together with the expanding availability of Nuclear Medicine worldwide offers us even greater opportunities to implement its use to benefit those patients. There is no question, that although a number of similar new agents have been developed and continue to appear in the pipeline, gallium-67 remains a viable and vital tool in Nuclear Medicine. This monograph therefore appears timely and appropriate to meet these new challenges and opportunities.

Aldo N. SERAFINI, M.D., FACC, FANP Professor of Medicine and Radiology University of Miami School of Medicine

VII

ACKNOWLEDGEMENTS

The authors would like to thank Dr Christos Batsakis for his assistance, the technologists Mrs Voula Liotsou, Chief technologist, and Miss Stratigoula Boutsali for their technical assistance and expertise in performing the scintigraphic studies, Mrs Georgia Chantzi and Mrs Maria Fragiadaki for their invaluable secretarial support and the photographer Mr Panagiotis Negas for his excellent work in taking the photographs from the original films.

All the published scintigraphic material came from the Department of Nuclear Medicine of "SOTIRIA" Chest Hospital of Athens.

The front cover illustration shows a case of active sarcoidosis

Address of the authors: Department of Nuclear Medicine, "SOTIRIA" Chest Hospital, 152 Messogion Avenue, Athens, HELLAS.

IX

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

1.

INTRODUCTION

After the first observation of Edward and Hayes in 1969 that gallium-67-citrate concentrates in malignant tumors (1), and later, when it was demonstrated that gallium-67 is also taken up by inflammatory lesions (2), the initial enthusiasm was replaced by a certain skepticism about the value of gallium scintigraphy (3-13). This was attributed to the lack of desirable sensitivity and specificity of the tracer, as well as to the parallel development of newer imaging technologies such as ultrasound (US), transmission computed tomography (CT) and nuclear magnetic resonance (NMR) . Towards the end of the 80's, however, there was a reemergence of interest in gallium, since AIDS exploded and gallium scintigraphy was proved an impressive diagnostic tool in the evaluation of the disease. Contributory to this were the technological advances in Nuclear Medicine equipment (improved spatial resolution, three photon peak acquisition, introduction of SPECT imaging technique), the establishment of higher injected doses of gallium, the experience acqui red in the interim in the interpretation of the studies, and the fact that the newer imaging techniques (US, CT, NMR) did not manage to solve all the clinical problems where gallium scintigraphy had been applied. As a result, after 2S years of clinical use gallium still survives, despite the above mentioned techniques and the development of the novel competitive scintigraphic procedures, such as labelled leukocytes and radioimmunoscintigraphy.

It seems that, for now and for the next years, gallium will continue to be a front-line agent in the following clinical fields: a. Diagnosis and follow -up of infectious diseases and abscesses. b. Investigation of the AIDS patient with opportunistic infections and malignancies. c. Management of patients with lymphoma in conjunction with the anatomic imaging modalities, especially in the estimation of a residual mass and the early diagnosis of recurrences, since gallium represents a viability agent. d. Evaluation of granulomatous diseases such as sarcoidosis. e. Definition of the cause of a fever of unknown origin (FUO). In this particular situation its drawback of limited specificity is, in fact, an advantage, since it can detect the foci of both infections-inflammations and malignancies, which represent two thirds of the causes of FUO. Finally, given that gallium is far less expensive than Tc-99m-HMPAO or In-lll -oxine-Ieukocytes (14), regardless their other disadvantages and the fact that many institutions lack the ability to label leukocytes, it may be predicted that galJium-67 -citrate will continue to be a primary imaging agent in the foreseeable future.

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

2.

PHYSICAL AND CHEMICAL PROPERTIES

Gallium-67 is a cyclotron produced radionuclide that can be produced from targets of pure natural zinc or enriched stable zinc isotopes, in the form of oxide by a variety of nuclear reactions using either deuterons, protons or particles (15). The main used reaction is Zn-68 (p,2n) Ga-67 . Neutral zinc targets can lead to impurities such as Ga-66 which has a half life of 9 hrs, as compared to the 78 hrs half life of Ga-67. The presence of Ga-66 can be eliminated by allowing its complete decay before chemical processing of Ga-67 . Enriched zinc isotope targets produce less radioactive impurities but are more expensive to prepare (15). GaIlium-67 decays by electron capture and emits gamma rays over a broad range of energy, from 93 ke V to 880 ke V. The following four principal peaks are suitable for imaging: 93 keY, 184 keY, 296 keY and 396 ke V. It has no beta emissions. Gallium belongs to the group IlIa of the periodic table. It therefore has 3 valence electrons (3+ maximum oxidation state) (16). At pH below 2, gallium-67 exists in the ionic form. When the pH raised towards neutrality, it is able to complex numerous ligands to form chelates. Usually it is reacted with citric acid, to form gallium-67 citrate which is the most commonly used form in nuclear medicine (J 5).

3.

UPTAKE MECHANISMS

The exact mechanism of gallium-67 localization in inflammatory lesions or tumors is not clearly understood (17,18). Gallium-67, in trace amounts, is handled by the body as a fenic-ion analogue. The principal differences between gallium-67 and fenic ion are that gallium-67 has a lower affinity for most iron-binding molecules, such as transfenin, and that gallium-67 cannot be reduced in vivo, which prevents its incorporation into heme or other biologically important proteins (19). After intravenous administration, gallium-67 bound to plasma proteins, for example to transfenin (20-22), migrates from them and binds to lactofenin present in body tissues and polymorphonuclear leucocytes (23). It has been suggested that gallium-67 bound to lactofenin is responsible for the gallium-67 localization in inflammatory diseases and abscesses (19,24-28). As gallium-67 uptake has been described in neutropenic patients (25, 29), it seems that intracellular leucocyte

2

transport is not the sole explanation (23) . Another uptake mechanism may involve direct uptake of gallium-67 by infective organisms themselves (24, 25), an occurence that has been demonstrated in vitro. Microorganisms grown in a low iron environment produce siderophores that have an extraordinary binding affinity for gallium-67 as well as iron (23) . Because of the minute quantity of free iron in most tissues, it is assumed that pathogenic microorganisms produce siderophores, and the siderophore-gallium-67 complex is then presumably transported directly into the cell (30).

The mechanism of gallium-67 uptake in tumors is even less well understood. The uptake of gallium-67 varies with the tumor type, among patients with tumors of the same histologic type, and even with tumor site in a given patient (24). Transferrin appears to play an important role in the localization of gallium-67 citrate in tumors. Transferrin acts primarily as a carrier protein for gallium-67, transporting it from the site of injection to the site of cellular localization. The intracellular localization occurs in lysosomes or lysosomelike granules of the cell (31). The gallium-67 uptake is also influenced by vascularity, increased permeability of tumor cells, rapid proliferation, and pH decrease in the tumor fluid due to increased glycolytic activity in the cell (26). The low cellular pH dissociates gallium67 citrate and then gallium-67 ions bind to the intracellular proteins in tumors (26). Finally, another theory is that gallium-67 uptake is mediated through specific transfenin receptors present on the cell membrane (32).

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

4.

GALLIUM-67 BIODISTRIBUTION

The normal gallium-67 image (33) displays characteristic features based upon the biodistribution of gallium-67 citrate (Fig. 1). However, there are many important variations of the normal pattern. These variations may appear in the absence of disease, under the influence of several clinical situations . Also, neoplastic and inflammatory lesions may cause gallium-67 uptake that may closely resemble normal patterns. The appearance of the normal gallium-67 image is strongly dependent on the time between injection of the radiopharmaceutical, and the performance of the study. For this reason, it is suitable to standardize as much as possible the procedure in each laboratory with respect to this time interval, the views obtained, and

the format in which the data are presented (24). We found that whole body gallium-67 scan is more helpful than spot views. Knowledge of the normal gallium-67 biodistribution and its variations related to sex and age is necessary for a correct interpretation. Approximately 10%-25% of the tracer dose is excreted via the urine during the first 24 hours after intravenous injection (19, 34). Therefore kidneys and bladder are normally visible up to 24 hrs. After 48 hI's, persistence of renal activity or progressively increasing activity or unilateral discrepancy in gallium-67 activity in the kidneys should be considered as abnormal suggesting pyelonephritis, inflammatory nephritis, obstructive uropathy, etc. (16, 30) (Fig. 2).

Fig. 1. Normal gallium images, A8 hours postin jection, in a A5-yr-old male in anterior and posterior views.

Fig. 2. Intense renal activity (arrowheads) more

ANTERIOR Fig. 1

prominent at the left side 6 days post-injection of 185 MBq of Ga-67-citrate in a 71-yr-old woman with bi latera l pyeloneph ritis (posterior view).

POSTERIOR Fig. 2

3

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

However persistence of renal activity may be observed in patients with severe hepatic failure or with compromised renal function and delayed urinary excretion of the radiopharmaceutical, or after transfusion or administration of parenteral iron supplements (16). About 9% of the administered activity is excreted in the feces during the first week (19,35). Due to the rather slow plasma clearance of gallium-67,

about 75% of the injected radioactivity is kept in the body, with a biological half life of 27 days (35) and is distributed throughout plasma and body tissues rich in lactoferrin. This accounts for the intense uptake seen in the liver which metabolizes both lactoferrin and transferrin, and also in the bone marrow, spleen, lacrimal and salivary glands (34) (Fig. 3, 4).

ANT

ANT

Fig, 4

Fig, 3

Fig. 3 . Normal scan in anterior view 48 hours postinjection of 148 MBq Ga-67-citrate in a 25-yr-old female, The visualisation of the nipples (arrows) as well as the nasapharynx, the lacrimal glands, the liver, the spleen (arrowheads) and the osseous structures are normal findings,

Fig. 4 , Forty eight hours post-injection of 185 MBq Ga-67-citrate in a 57-yr-old male with advanced cirrhosis of the liver, Very low liver uptake (arrows), equal to lung uptake (arrowheads), due to hepatic failure,

4

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

5.

DOSIMETRY

After an intravenous inj ection of gallium 67-citrate the absorbed doses to various tissues depend on the administered dose of the radiopharmaceutical and the age of the patient. In adults the highest dose is delivered to the distal large bowel, which receives about 0,90 rads/mCi, while the total body radiation dose is estimated at 0,26 rads/mCi.

In children the following general rule is valid: the younger the child, the greater the amount of the absorbed dose, because of the relatively greater body surface area to weight ratio in children (37) . In children gallium-67 is localized in the epiphyses or growth plates (38), that results in delivering the highest dose in bone surface and red marrow, the large intestine being the second critical organ.

Estimation of Absorbed Dose* in rads to Various Tissues from a Single Intravenous injection of Gallium 67-citrate in Adults and Children (36) Adults Age (yrs) >18 1 Body weight (kg) 70 9.1 Administered Dose (mCi) 3.0 0.58 Total body (rads) 0.78 0.81 3.38 Marrow l.74 Bone surface 27AO Kidneys 1.23 l.39 Liver 1.68 1.38 Spleen 2.14 1.59 0.84 0.93 Ovaries 0.64 Testes 0.72 Stomach 0.22 Small intestine 1.08 1.1 Upper large colon 1.83 1.68 3.2 2.70 Lower large colon

* Based on

6.

(a) (b)

Children 5 19.1 l.0 0.78 2.92 19.74 lAS 1.58 2.1 0.86 0.57 1.0 l.32 2.89

10 32.1 lA 0.69 2.37 17.20 l.29 1.51 1.83 0.81 0.51 0.94 lAO 2.35

MfRD Dose estimate Number 2; J Nucl Med 14: 755, 1973. Recommendation of Paediatric Task Group of EANM in Administered · Dose in children.

GALLIUM-67 CITRATE IMAGING

Radiopharmaceutical: Administered adult dose: Patient preparation: Time to imaging:

Gallium-67 citrate. IV. 74-370 MBq (2- 10 mCi)*. Laxatives or enemas?** 6 - 48 hr for infections, inflammations. 2 - 10 days for malignancies"'.

Instrumentation: Collimator: Photopeak selection: Images acquired:

Wide field of view - SPECT camera (dual-head desirable).

SPECT:

Matrix 64 x 64, frames 64 , 25-35 sec/frame, arc of rotation 360 0

Medium energy, parallel hole. 93, 184 keY, 20% windows, 296 keY, 15% window. Anterior and posterior whole body images (about 2.000.000 counts/view in 48 hours imaging) SPECT/spot views/serial images depend on circumstances***.

* The administration of larger doses and the acquisition of delayed images are especially recommended in cases of lymphoma (39-41) ** The use of enemas and/or laxatives in discussed in the chapter "scan interpretation and normal variants" *':'* We recommend to scan the whole body in anterior and posterior position in every case. Spot views might be used only in cases where the problem is specific anda quite localized (e.g. investigation of the course of known osteomyelitis).

5

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

7.

SCAN INTERPRETATION AND NORMAL VARIANTS

In the THORAX, the concentration of gallium-67 in the lungs at 48 hours and beyond is normally low, making abnormal uptake easily recognizable (42) (Fig. 5). Prominent pulmonary uptake may be seen on scans performed after lymphangiography, or under the influence of various drugs including bleomycin, nitrofurantoin, cyclophosphamide, methotrexate, busulfan, vincristine, procarbamide and amiodarone or after radiation therapy (43, 44) (Fig. 6). Normally, gallium-67 is distributed within the rib cage, spine and scapulae. Uptake by the sternum is sometimes so prominent as to mimic abnormal uptake in the mediastinum (24). Tomographic imaging or additional lateral or oblique planar views may be helpful in distinguishing normal uptake in the sternum from hilar or peritracheal lymph nodes (16). On the posterior view, the lower end of each scapula may show a prominent concentration of activity that can mimic either a rib lesion or axillary or lateral thoracic nodes (24). In such situations lateral views of the chest are of help to differentiate scapular from nodal

activity (45, 46). In early images (4 to 6 hours) blood pool activity in the heart and great vessels may be noted (16). Symmetrical accumulation of gallium-67 in the breast and nipples interferes with chest imaging, especially under the stimuli of menarch, pregnancy, lactation or hormonal agents such as birth control pills (16, 24, 34) (Fig. 7). In children, gallium-67 activity may be seen in normal thymous tissue (34). The pattern of gallium-67 uptake in the thymus is highly variable. Thymic uptake of gallium-67 often constitutes a clinical dilemma when a gallium-67 scan is ordered to exclude the possibility of a lesion in a child in whom a "mediastinal mass" is seen on chest-X-ray (16,47-50). Gallium-67 uptake in thymic tissue is especially prominent in thymic hyperplasia, a condition that occurs at about 4 weeks following chemotherapy for lymphomas or other malignant disorders (51,52) . In general it is best to assume all uptake in the thymic region of young children as normal thymus, until proved otherwise (19).

POST

)'.

Fig. 5

Fig. 5. Normal uptake in the lungs (the same patient as in figure 3). The visualization of the nipples (arrows) is a normal finding. Fig. 6. Forty eight hours post-injection of 296 MBq Ga-67-citrate in a 68-yr-old male during chemotherapy with cyclophosphamide. Diffuse increased activity in both lungs is seen in anterior (A) and posterior (8) views as well as normal pattern of the intestine (anterior view) and minimal renal uptake (posterior view).

6

Fig. 6 - A

Fig. 6 - B

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

ANT

Fig. 7 - A

POST

Fig. 7 - B

P O ~3TE R IOR

/'

Fig. 7. (A) Normal gallium uptake is seen in the breasts (arrows) in a 28-yr-old female. In posterior view (8) the lower end of each scapula is seen (arrowheads). (C) Normal visualisation of the nipples (arrows) in another female 58-yr-old. (0) Normal gallium scan in a 38-yr-old female in posterior view; foci of increased activity at the lower end of each scapula (arrowheads). Fig. 7 - C

Fig. 7 - D

7

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

including enemas, laxatives, or no preparation, with various results reported (16, 19, 34, 54). A rational approach might be no preparation, si nce the evidence is not convincing that enemas are generally effective. The use of enemas should be reserved for determining if a questionable focus of abdominal activity on an image is a normal bowel content or an abnormal finding. If the abdominal activity moves on a post enema image it is most likely normal GI tract activity. Male patients show some degree of activity in the scrotum and testes (19) (Fig. 1, 6, 8b).

Within the ABDOMEN, in addition to liver and occasionally spleen uptake, activity is often seen in the bowel, particularly in the ascending and transverse colon (24). Extensive and even intense large bowel activity often represents a normal finding and must be interpreted cautiously (23, 53). Retention of gallium-67 in the caecal region is a common finding (19) (Fig. 8). Bowel activity occurs less frequently in children, and therefore the abdominal distribution of activity is more easily interpreted than in adults (19). Various approaches to bowel preparation have been proposed,

ANTERIOR

ANT

R Fig. 8 - A

Fig. 8 - B

Fig. 8 - C

Fig. 8. Normal gallium images. A. Normal colonic activity in 65-yr-old female B. Normal activity in the caecum (arrowheads) and transverse colon in 65-yr-old male. Markedly increased activity in the transverse colon in a 38-yr-old male.

e.

Fig. 9. Normal whole-body Ga-67 scan in a 26-yrold female. Low activity in the extremities and slightly increased concentration in the large ioints are seen. Some activity is demonstrated in the nasopharynx and the lacrimal glands. Fig. 10. High, however normal uptake in the nasopharynx.

ANTERIOR Fig. 10

8

Fig. 9

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

In the EXTREMITIES, the concentration of gallium67 is normally low, apart from slightly increased concentration seen around large joints such as hips, shoulders, elbows and knees (Fig. 9). In children, acti vity is seen in the epiphyseal regions. It is not known, whether epiphyseal uptake occurs in the bone matrix, the cartilaginous structures or the adjacent marrow. The uptake is mainly marked in the region of most active bone growth (19). In the HEAD and NECK gallium-67 activity is noted in the osseOllS structures of the skull and variably in the

nasopharynx, in the lacrimal and salivary glands (Fig. 9, 10). Activity in the salivary glands may be especially prominent in patients who have undergone radiation therapy on that area (16). Recent surgical incisions in any part of the body will cause temporary gallium-67 localization in the incision or wound, during the healing process, usually for a few weeks (34). The relative distribution of activity in all of these normal sites of localisation may vary considerably. Some additional normal gallium-67 images are seen in figure 11.

ANT

Fig. 11 - B

Fig. 11 - A

ANT

48 hours

Fig. 11 - E

AN

ANT

Fig. 11 - C

Fig. 11 - D

ANT

6

da!::js

Fig. 11. Normal patterns of Ga-67-citrate uptake. A 35-yr-old male B. 50-yr-old female D. 56-yr-old male C 46-yr-old male E. 38-yr-old female 48 hours and 6 days postinjection without any preparation of th e bowel.

9

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.

CLINICAL APPLICATIONS

8.1. INFECTIONS

8. 1. 1. Osteomyelitis

Scintigraphic diagnosis of infections and inflammations with gallium-67 has been described in innumerable inflammatory conditions. We will survey those areas for which gallium-67 scintigraphy has a continuing clinical utility.

Three-phase bone imaging is the most widely used method to early detect uncomplicated osteomyelitis, with an accuracy exceeding 90% (55) . However the 99mTc-phosphate skeletal study has a high incidence of false negative results in neonates with bone and

1; seel frame .~

Fig. 12 - B

Fig. 12 - C

Fig. 12 - D

Fig . 12 - E

Fig. 12· A

Fig. 12 . A case of a 37·yr-old male six months after a fracture of the right tibia treated by internal fixation and subsequent metal removal complicated by osteomyelitis. (A) Radiography shows the fracture and the healing process of the right tibia. A three phase bone scan with Tc-99m·MDP shows increased perfusion (B, arrows), blood pool (C, arrow) and increased bone activity (0) in the area of the fracture. Ga llium scan (E) shows markedly increased activity in the same area (arrow). Biopsy of the tibia revealed staphylococcus aureus.

10

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

joint space infections (36, 56 - 58). Gallium-67 scintigraphy has successfully been used in patients in this age group as well as in adults to confirm the diagnosis of infection in clinically suspicious cases, where the bone study has been equivocal or negative. On the other hand the bone scan has been less successful in diagnosing osteomyelitis superimposed on noninfectious conditions that may cause increased bone mineral turnover (fractures, etc) (Fig. 12). Under these conditions, the specificity of the study would range from 0% to 78 % (55) . Therefore gallium-67 scintigraphy has been used in conjunction with bone scintigraphy in an

L

effort to enhance the specificity of the technique (23). In figures 13, 14 are illustrated two cases of combined bone and gallium-67 scans in sacroilitis melitensis and septic athritis . Lisbona and Rosenthal found that sequential bone/gallium-67 imaging was superior to bone scintigraphy alone for distinguishing cellulitis from osteomyelitis in the precise localization of an infection focus, and for discriminating active from inactive osteomyelitis (7). Since gallium-67 scan does not show bone details well, it is often difficult to distinguish bone from soft tissue inflammation.

R

R

Fig. 13· A

Fig. 13. A case of sacroilitis melitensis (AI Metaboli c phase of bone scan with 99m·Tc MDP shows increased activity in the right sacroiliac joint (arrowheads) . (B) Ga lli um sca n of the same patient confi rms the infection of the right sacroiliac joint (arrows).

Fig. 13 - B

Fig. 14. A cose of septic arth ri tis in a 50-yr-old fema le. Ea rly blood pool phase of Tc-99m-MDP (A) ond delayed image (B) revealed increased perfusion and bone activity in the a rea of rig ht knee. Ga lliu m image (C) confirmed the septic arthritis of the right knee.

L

Fig. 14 · A

Fig. 14 - B

L

Fig. 14 - C

11

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

A comparison with a Tc-99m MDP scan helps to resolve this problem (Fig. 15) . Gallium-67 imaging was also successfully used in the evaluation of bone involvement in the malignant external otitis (59, 60). Combined bone/gallium-67 scintigraphy has been carried out to evaluate suspected osteomyelitis in patients with orthopedic prostheses (61) (Fig. 16). The overall accuracy for combined bone/gallium-67 imaging in this particular pathology ranged between 60%-80% (62 -64). The investigation of infected prostheses with indium-

lll-leucocytes is more appealing than with gallium67. Several studies showed sensitivities greater than 88% with indium-lll-WBC and similar specificities (65-68). The gaUium-67 scan however seems to be more successful in the evaluation of vertebral osteomyelitis (69), in which the reported accuracy of 86% is similar to the NMR accuracy (70) (Fig. 17). Finally sequential galli um-67 scanning also offers the opportunity to monitor response to antibiotic therapy (71) (Fig. 18, 19,20 ).

1 sec/frame

iI I

,i.

\I

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'! '

k "

'

'\

~.

Blood pool Fig. 15 · A

Fig. 15 - B

3h Fig. 15. A 69·yr-old potient with diabetes melitus amputation of the first distal phalanx of the right great toe 3 years ago and swelling of the left 3rd toe, underwent 3 phase bone scan with Tc·99m-MDP and Ga-67-citrate scan. A radiograph wa s non diagnostic. The bone scan showed increased perfusion in both feet (A) increased blood pool (B) and highly increased bone activity in th e right great toe (arrow) with severa l foci of increased activity in the left foot (arrowheads) (e). The gallium scan (0) showed only 2 foci of increased octivity: right great toe (arrow) ond left third toe (arrowhead). The findings we re co nsidered as osteomyelitis and cellulitis respectively, which were proved by bone biopsy a nd cultures .

A

t t Ga-67 (24 h) Fig. 15 · C

12

Fig, 15 · D

A

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

Fig. 16 - C

L

Fig. 16 - A

Fig. 16 - D

MOP Fig. 17 - B

Fig. 17 - A

R

Fig. 16 - E

Fig. 16. A case of right hip arthroplasty in a 43-yrold woman who had pain and difficulty in wa lki ng 8 months after prosthetic hip replacement. (A) Radiograph of the right hip. The Tc-99m-MDP study demonstrates abnormal increased perfusion (B) and blood pool around the joint and trochanteric region Ie) and increased bone activity in the areas of the trochanters and the right acetabulum (D). This may be seen with either heterotopic bone formation ond loosening or infection. The Ga -67-citrate scan 24 hours post injection (E) shows an abnormal increased activity around the right trochanter cons istent with an infectious process. Infection was found at surgery.

Fig. 17. A case of vertebral (L3) osteomyelitis from Brucella Mel itensis in a 62-yr-old male before IA,B) and after a six months period of treatment with tetracycline (e,D). (A) Bone scan showed increased activity in the L3 vertebra (arrow). (B) Gallium scan showed increased concentration of the tracer in the same vertebra (arrow). (e) After six months of antibiotic therapy the increased activity of the L3 vertebra remains (arrow) but gallium scan shows no evidence of active osteomyelitis {OJ.

MOP Fig. 17 - C

Fig. 17 - D

[3

GALLIUM IMAGING IN CURRENT CLINICAL PRA CTICE

Fig. 18 - A

Fig. 18

Fig . 18 - B

Fig. 18. A 57-yr-old mole with known osteomyelitis of the right acetabulum 6 months after antibiotic treatment, underwent 3 phase bone scan with Tc' 99m-MDP and Ga-67 scan to evaluate the effect of therapy. Increased perfusion (arrow) was noted in the blood pool image {A} and increased osseous activity in the delayed image {B} in the area of the right acetabulum (arrow) . Abnormal gallium concentration was revealed in the same area (arrow) in the gallium scan 24 hours post injection {e} showing that the process is still active despite the long-lasting treatment. (The same patient as in figure 4 who was suffering from severe cirrhosis and ulceral colitis in remission).

','.

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Fig. 19. A 57-yr-old male had undergone a below the knee amputation {A} two years ago, because of a very severe third-degree burn of the lower right leg. He presented with clinical findings of infection at the amputation site. A 3-phase bone scan with Tc-99m-MDP showed increased perfusion {B} and blood pool (C) in the end of the amputated leg. In the delayed image {OJ increased bone activity at the end of the right tibia was demonstrated. Two days later gallium scan showed increased concentration of the tracer in the same area {E}. Bone biopsy and culture proved osteomyelitis and the patient was given antibiotic therapy. Six months later a combined Tc-99m -MDP and Ga-67-citrate study was performed that showed some increased perfusion (F and G) and bone activity (H). Gallium scan was completely normal at that time suggesting no evidence of active osteomyelitis {I}.

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GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

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Fig. 19 - E

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Fig. 20. A 62-yr-old diabetic female with malignant externol otitis (MEO). In diabetics MEO is a very severe otitis associated with high mortality, wich very often involves the petrous temporal bone. The duration of antibiotic treatment dependes on bone involvement. {A} Bone scan shows bone involvement (arrows). (B) Gallium scan confirms the infection of the bone (arrows). (e) A new bone scan after 6 months of intensive therapy, although less intense, remains positive (arrows). {O} A second gallium scan shows no evidence of active osteomyelitis.

METAB OLIC Fig. 19 - I

Fig. 19 - H

MOP

POSTERIOR

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Fig. 20 - A

fig. 20 - C

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ANTERIOR Fig. 20 - B

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15

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.1.2. Cardiac infections Cardiac infections that may be visualised on gallium67 scanning include endocarditis, myocarditis and pericarditis (72-75). In case of suspected myocarditis the clinical value of gallium-67 scintigraphy has not been clearly established (76) since there is a controversy in the litterature (77, 78). In these cases indium-111-antimyosin scintigraphy should be considered as the method of choice (76) (Fig. 21). For the diagnosis of infective endocarditis gallium-67 scan was the first used imaging procedure. However, the results have not been convincing in clinical practi-

ANT

LAO 70°

Fig. 2 1 - A

Fig. 21. Acute myocarditis in a 39-yr-old woman . The patient gradually developed over the previous month shortness of breath. A radionuclide equi librium ventricu lography revealed global hypokinesia and a LVEF of 25%. The gallium scan showed concentration of the tracer throughout the myocardium (A, arrows) but a few days later an Inlll-antimyosin scan showed the myocarditis more clearly (B, arrows). The arrowheads point to the concentration of the gallium in the breasts.

16

LAO

ce (76). In patients with predominantly right-sided endocarditis its sensitivity is rather low (79). When the endocarditis is complicated by the development of ring or aortic root abscesses gallium-67 scintigraphy proved to contribute to diagnosis (80). Finally for the diagnosis of pericarditis, the reported sensitivity and specificity of gallium-67 scintigraphy is low (81,82). Although gal]ium-67 scanning is seldom clinically indicated in cardiac infections, when being used for the investigation of prolonged fever of unknown origin, the scan can show occasionally cardiac abnormalities.

ANT

LAO 70°

Fig. 2 1 - B

LAO 40°

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.1.3. Graft infection Gallium-67 scintigraphy has been successfully used to detect access graft infection in patients with end stage renal failure receiving hemodialysis (83), and also in infected peripheral by-pass grafts (84) (Fig. 22).

8.1.4. Abscesses In current practice gallium-67 scintigraphy has significantly reduced the number of liver/lung scans done for detecting right subdiaphragmatic infections (85). Gallium-67 scintigraphy can also be efficacious when combined with a Tc-99m-sulfur colloid liver/spleen study in the diagnosis of intrahepatic (Fig. 23) and

Fig. 22 - A

Fig . 22 - B

Amoebic abscess gives a characteristic pattern : a peripheral shell of activity with a cold center (ring sign). The sign however is not pathognomonic as it can also be seen in large bacterial abscesses and necrotic tumors (34). Gallium-67 scan is useful for determining the presence and extent of a pyogenic psoas muscle infection, an uncommon and frequently misdiagnosed condition, before and during the abscess phase (87-89).

Fig. 22. A 56-yr-old male had undergone surgery for abdominal aorta aneurysm and by pass grafting of the right femoral artery. Three weeks later the patient developed fever and was referred for a gallium scan (A) that revealed in creased concentration of the tracer along the femoral graft (arrows), focal intense activity in the right shoulder (open arrow), demonstration of the caecum and the ascending colon (curved arrows) and finally foci of intense activity in the abdominal incision (arrowheads). The finding s of the gallium scan correlated with infection of the femoral graft, osteomyelitis of the right acromion and focal infection of the abdominal incision . The colonic activity was a normal variant. A second gallium scan (B) 6 months later, after proper surgical and antibiotic therapy, shows no evi dence of i nfeclion in the above mentioned areas. The caecum and the ascending colon are demonstrated again. N.B. the poor resolution of the image (B) was due to the distance of the camera -head from the patient because of technical reasons. Fig. 23. A case of an intrahepatic abscess after abdominal surgery. A 57-yr-old male after an abdominal surgery developed fever with intermittent abdominal pain. A sulfur colloid scan in anterior view reveals a large defed in the middle portion of the liver (A, arrows). The next day 148 MBq of Ga-67-citrate was iniected and 48 hours later the tracer fills in the defect (B, arrowheads), which in a second surgery was proved to be an abscess.

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\ Fig. 23 - A

intrasplenic abscesses (19). The diagnosis of intestinal and peritoneal abscesses caused by inflammatory bowel disease can also be accomplished by gallium-67 scintigraphy (86).

Fig. 23 - B

17

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.1.5. Tuberculosis Gallium-67 scintigraphy is a sensitive indicator of the presence of active tuberculosis (11,90) (Fig. 24). It has therefore been used in patients with acute disseminated (miliary) tuberculosis where the chest X-ray does not always diagnose the disease (91) , in patients with extrapulmonary localization of the disease (91,92) and also in order to increase the prior probability of active pulmonary tuberculosis in patients suspected of having it, with negative sputum smears (93, 94). Additionally gallium-67 scintigraphy has been successfully used for the estimation of the therapeutic response (11). Because gallium-67 uptake is rarely observed in inactive tuberculosis, imaging with this agent has been reported to be superior to conventional radiography in establishing reactivation of the disease (11). In cases of miliary tuberculosis gallium-67 scan demonstrates a variability of patterns, from negativity to positivity greater than liver uptake, which can be localized or diffuse (91) . These patterns (Fig. 25) are usually associated with an abnormal. chest X-ray indicating a miliary pattern. However, it has been reported that the chest X-ray can be negative or with localized findings (91,95). Therefore the combination ofthe two examinations is highly recommended in order to achieve early diagnosis especially in high-risk patients (91). As the extrapulmonary localization of tuberculosis is usually presented as a prolonged fever of undetermined origin, gallium-67 scan should be considered in the diagnostic workup (92). Comparative gallium-67 and indium-lll-WBC studies in tuberculous enteritis revealed a slight advantage of gallium-67 over indium-l 11-WBC scan (96) since its sensitivity is higher in the detection of chronic and granulomatous lesions (97). Finally it would be also recommended to perform gallium-67 scan in patients with documented extrapulmonary tuberculosis, as a follow up procedure, as there are few other methods for determining disease activity (92).

Fig. 24 - A

R ill

MARK ARMS

Fig. 24. A 53-yr-old man was admitted to the hospital because of weig ht loss (6 kg in 4 weeks), weakness and fever during the previous month . On physical examination a skin ulcer of the left forearm was observed. Few days later a whole body gallium scan was done (A) and a focal accumu lation of the radiopharmaceutical was noted in the middle field of the right lung (arrow). A spot view of the arms (B) showed accumulation of the tracer in the skin ulcer (thick arrow) and in the site of a Mantoux test, which had been performed 6 days previously. In the left arm the site of injection of the tracer is noted (arrowhead). Biopsy of the skin lesion revealed tuberculosis. Fig. 24 - B

18

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.1.6. Other infectious diseases Fungal diseases: Gallium-67 imaging has been successful in detecting various mycosic infections in human, such as paracoccidioidomycosis, blastomycosis, actinomycosis, histoplasmosis, aspergillosis etc. (98-103) . Fungal pneumonia represents a common complication in patients with AIDS, as well as in those with transplantation of solid organs (103). Gallium-67 scintigraphy in this group of patients can define the degree of activity of the disease process, the response to treatment and in conjunction with bone scintigraphy the evaluation of spatial extent of the disease when bones are affected (103 -105). Leprosy : There are few papers in the litterature concerning the use of gallium-67 scintigraphy in leprosy (106, 107). Gallium-67 imaging showed a good correlation between clinical and scintigraphic findings in multibacillary leprosy, and its distribution gave a characteristic pattern for this disease, that is a "beard distribution" for the face, and "skin outlining" for the skin of the entire body besides the face (106).

Fig. 25 - A

Fig. 25 - B

Fig. 25. A 57-yr-old man had a persistent non productive cough, weakness, low grade fever and dyspnea. The chest X- ray (A) showed a mi cronod ular pattern throughout the lungs. The thorax CT scan showed the same pattern (B), Ga llium scan (C) demonstrated homogeneous, diffuse, very intense (greater than in the liver) accumulation of the tracer in both lungs. A needle biopsy confirm ed the suspicion of miliary tuberculosis (TBC). The patient was immediately given anti-TBC therapy and 10 months later is in a very good condition. Fig. 25 - C

19

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.2. ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS) Since 1981, when the first cases of acquired immunodeficiency syndrome (AIDS) were reported, until now, a large amount of information regarding the biology of the virus, the natural history of the disease, the common manifestations of HIV related disorders, the diagnostic approaches and therapeutic modalities, came up. The vast majority of infected individuals, if not all, can be expected eventually to develop symptomatic disease, characterized by progressive and ultimately profound immunosuppresion as the virus invades the host immune system (108). The primary target of the virus is the CD4 lymphocytes. As CD4 cells progressively decrease and immunosuppresion establishes a number of clinical manifestations (opportunistic infections and malignancies) are expected. Every organ system of the human body infected by the virus can be involved. Howe ver pulmonary, gastrointestinal, neurologic oncologic and ophtalmologic manifestations are the most common (109-117). Gallium-67 scintigraphy is prescribed for the early detection of opportunistic infections and malignancies, to assess disease activity pre and post therapy, and to evaluate the total extent of disease involvement.

8.2.1. Thorax Opportunistic pulmonary diseases remain an important cause of acute illness and death in patients with advanced HIV disease.

8.2.1.1. Pneumocystis Carinii Pneumonia (PCP) Pneumocystis Carinii Pneumonia was the first pulmonary manifestation in over two thirds of AIDS patients (118).

The widespread use of primary prophylaxis for the prevention of PCP in the USA, resulted in a marked decline in the prevalence of this illness in newly diagnosed AIDS patients (119). In the Multicenter AIDS Cohort Study, the incidence of PCP as an initial manifestation of the disease peaked in 1987 and has declined since then, while other infections rose (120). PCP however continues to be the most common AIDS indicator illness in the USA and other developed countries. In constrast, the disease has a much lower prevalence in developing countries (121). Gallium-67 scan is abnormal in over 85 % of PCP cases (53, J22, 123) and will even detect PCP in asymptomatic patients , with normal chest x-rays (124-126). The characteristic pattern of diffuse, increased bilateral lung uptake of gallium-67 with an intensity greater than the liver one (without nodal or parotid uptake) has a specificity of 90% for PCP (53, 118, 122) (Fig. 26,27).

NECK-HEAD

Fig. 26

Fig. 26. Gallium scan in a 38-yr-ald male AIDS patient with Pneumocystis Carini i Pneumonia (PCP) shows the typical pattern of diffuse intense bilateral lung uptake without nodal or parotid uptake. The chest X-ray was normal. THORAX

Fig. 27. Another AIDS patient with PCP and characteristic gallium scan.

20

Fig. 27

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

The presence of heterogeneous diffuse, lung uptake may have a higher predictive value than homogeneous uptake (127), and when the concurrent chest radiograph is also normal, the specificity approaches 100% (118). Ganz and others reported that, if lung intensity uptake is lower than Ii ver uptake, the specificity falls to 50% since this may reflect other types of diffuse, underlying lung diseases including viral infections such as Cytomegalovirus (CMV), Lymphocytic Interstitial Pneumonitis (LIP) and other gallium-67 avid disorders (118). Because of the aerosol pentamidine therapy, gallium67 uptake may be limited to the upper lobes due to less effective access to this region by the aerosol treatment (128, 129). Usually the initial PCP presentation has a higher gallium-67 avidity, than the one seen following treatment or with recurrences (130) (Fig. 28). An almost normal, low grade gallium-67 uptake has also been described in cases of fatal PCP (130) but in this situation, chest radiography is usually markedly abnormal (118). A low grade, almost normal, gallium-67 uptake in extremely ill patient may reflect the abnormal inflammatory response which is devoid of granulocytes and presumably gallium-67 receptors (J 30).

In contrast, a normal chest X-ray together with a negative gallium-67 scan in an AIDS symptomatic patient should lead to search for infection outside the chest region (23 ).Finally, it is noted that PCP is often persistent or recurrent with at least one third of cases being positive after one month of therapy. Therefore baseline and follow-up gallium-67 scans are recommended to determine cure or etiology of new pulmonary symptoms without biopsy follow up (131, 132).

8.2.1.2. Lymphocytic Interstitial Pneumonitis (LIP) The etiology of this inflammatory disease is unclear. It is common in the pediatric AIDS group while rare in adult AIDS patients (J 33 -137). However it is not unusual in immunocompetent adults (Fig. 29). The chest X-ray may appear either normal , resemble PCP, mimic viral infections such as cytomegalovirus disease, or miliary tuberculosis. Gallium-67 scintigraphy appears to have a diagnostic pattern for LIP with symmetrical parotid uptake and low grade diffuse lung uptake, without nodal uptake (118, 133, 138).

Fig. 28.

Gallium scan

48

hours post injection in a

37-yr-old male AIDS patient with PCP under therapy shows heterogeneous diffuse lung uptake more prominent in the right side. Even in anterior view, a bnormal renal uptake is also noted (arrowheads).

Fig. 29. Gallium sc inti graphy in a 65-yr-old woman with

ANTERIOR

Lymphocytic

Interstitial

Pneumonitis

(LIP).

Symmetrica l intense parotic and low grade diffUSE lung uptake without nodal involvement are noted.

Fig. 28

Fig. 29

21

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.2.1.3. Cytomegalovirus (CMV) Ganz and Serafini reported that infection with CMV is a frequent occurrence in individuals with HIV infection (118). Pulmonary CMV infection detection is uncommon and usually occurs in conjunction with more aggressive PCP (118,122). Due to the difficulty of diagnosing CMV, the pattern of uptake seen in whole-body gallium-67 scan may be important. A pattern of low grade lung uptake with perihilar prominence, associated with eye uptake (due to the frequent presentation of CMV as retinitis), adrenal uptake (due to the most freque nt pathological findings of CMV as adrenalitis), renal uptake at 48 hrs and/or persistent colon activity (118, 139), with diarrhea but, without other pathogens found in multiple stool specimens, suggests CMV (118). If high grade

pulmonary uptake is observed superimposed, aggressive PCP must be considered (Fig. 30). 8.2.1.4. Bacterial infections A wide spectrum of bacterial infections occurs in patients with HIV disease (118). Intense uptake in a lobar configuration in the absence of nodal and parotid uptake suggests the diagnosis of bacterial pneumonia (127). This is usually visible on chest-X-ray and there is positive sputum. When gallium-67 scintigraphy shows uptake in multiple pulmonary lobes as well as bone, one must consider aggressive bacterial infections such as actinomycosis or nocardia (53, 124). Needle biopsy is often negative in these aggressive bacterial infections. Soft tissue aggresive extension uptake patterns may also be seen in fungal infections (118).

ANT

Fig. 30. A 30-yr-old male AIDS patient with fever, coug h and diarrhea underwent a gallium study. Forty eight hours post-injection, intense gallium uptake is noted in upper fields of both lungs as well as prominent activity in the large bowel. The final diagnosis was cytomegalovirus (CMY) infection in conjunction with PCP. Fig. 31. A case of tuberculosis in a 29-yr-old black A IDS patient. A gallium scan, 24 hours post injection, showed bilateral hilar uptake more prominent on the right side with a focal concentration in the apex of the right lung (arrow), where the chest X-ray demonstrated a non homogenous opacity with a small cavity. Intense focal uptake was also noted in paraortic and mesenteric lymph nodes (arrowheads). The patient was treated w ith anti-TBC drugs and 2 months later was in a good condition. Fig. 30

22

Fig. 31

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.2.1.5. Tuberculosis and other Inycobacterial infections Tuberculosis and atypical mycobacterial disease are common manifestations of HIV infection, particularly in developing countries where they increase rapidly (140).

Disease caused by Mycobacterium Tuberculosis most often occurs early in the course of HIV induced immunosuppression (CD4 cells 200AOO/mm 3 ) (/41). Reactivation of laten t tuberculous infection or accelerated progression of primary tuberculosis are more likely to occur in people co-infected with HIV (142). Multidrug resistant tuberculosis among this group of patients is problematic, and epidemic phenomena with very high fatality rates within several months after the diagnosis have been described (143-145) . Mycobacterium Tuberculosis bacteremia has been frequently reported in AIDS patients, particularly with low CD4 cells counts (146). Infections with less virulent non tuberculous organi sms such as Mycobacterium Avium Comple x

(MAC) and Mycobacterium Kansasii generally manifest themselves later in the course of severe immunodeficiency. The incidence of MAC disease increases as HIV disease progresses and the CD4 cells counts decreases (147, 148), causing widespread disease in 25%-50% of AIDS patients (149). In these patients continous bacteremia is a common finding (148). Patients who are treated for tuberculosis develop MAC infections and do not respond to therapy. In mycobacterial lung infections, gallium-67 scintigraphy pattern may demonstrate increased activity associated with tuberculous pleural effusion, tuberculous lobar pneumonia or show patchy low grade lung uptake along with hilar and nonhilar nodal uptake (118) (Fig. 31). The atypical mycobacterial infections present more frequently with extrahilar nodes while tuberculosis tends to be more commonly confined to hilar uptake (Fig. 32-33). Nodal gallium-67 uptake along with normal lung appearance has been described in lymphoma (127, 130) and possibly in AIDS related complex lymphadenopathies (130).

Fig. 32. A case of Mycobacterium Avium Complex (MAC) infection in a 45-yr-old male with prolonged fever. A gallium study usua lly shows extrahilar uptake but in this particular case activity is noted in the right paratracheal and in the hilar nodes (arrowheads). The colon ic and occular uptake probably is due to CMY infection, but was not proved at thi s time. Fig. 33. Another case of MAC infection with coexisting CMY retinitis in a 40-yr-old AIDS woman. A gallium scan demonstrated med iastinal and right hilar concentrations (arrows ) and eye uptake ' -_ _ _ _ _ _ _ _ _ _ _ _ _---' (arrowheads) due to CMY infection. Fig. 32

Fig. 33

23

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.2.1 .6. Kaposi's sarcoma and Lymphomas Kaposi's sarcoma is the most common tumor seen in AIDS patients (118). Pulmonary Kaposi's sarcoma rarely has gallium-67 uptake (53, 124, 133). Thus, an ill defined lung or mediastinal mass associated with a normal gallium-67 uptake suggests Kaposi's sarcoma (Jl8) . The diagnosis of Kaposi's sarcoma can be confirmed with a positive thallium-201 uptake in the mass (150). The lack of gallium-67 uptake may distinguish Kapo si's sarcoma from lymphoma which also occurs in AIDS patients and often demonstrates lymph node chain nodal uptake (118). In summary, gallium-67 imaging plays an important role in the diagnosis of AIDS related lung diseases. A negative scan is a strong evidence against an infectious process. Lymph node uptake is most often associated with mycobacterial disease or lymphoma, whereas focal lung parenchymal uptake is usually seen in the presence of bacterial or fungal infections. Diffuse lung uptake should be considered suspicious for PCP, especially when the uptake is intense and heterogeneous (23). In general a normal whole body gallium-67 scan associated with a normal head CT and chest X-ray can be used to exclude infections or tumors in HIV patients (Jl8).

8.2.2. Abdomen In constrast to the thorax, where patterns and intensity of galliurh-67 uptake can often correctly characterize the identity of a pathogen, no such correlations exist in the abdomen (23).

8.3. NEOPLASMS In the proper clinical setting and with meticulous attention to the technique, gallium-67 imaging can be a useful adjunctive tool in the investigation of selected neoplasms. The technique is most successfull when clinical findings are correlated with those of other imaging procedures, such as computed tomography ultrasound or nuclear magnetic resonance. The use of gallium-67 in lymphoma is discussed in the next chapter because of its particular interest. 8.3.1. Lung Cancer Gallium-67 scintigraphy has proved to be successfull in diagnosing lung carcinoma. Detection of lung cancer was first reported by Edwards and Hayes in their original article where gallium-67 concentrates in tumors (151). Since 1970 many investigators have studied primary lung carcinoma and hilar and mediastinal lymph nodes local metastases using gallium-67, and have demonstrated a variety of sensitivity values ranging from 65% to 100% (5, 43,152-159), with an average value of about 85%. Although the sensitivity is high, the specificity is rather low, since gallium-67 has been shown to concentrate in a variety of non neoplastic lesions, such as several inflammatory and granulomatous tissues. Lesions greater than 2 cm are usually detectable (Fig. 34). Some workers have shown that anaplastic and epidermoid tumors are more gallium-67 avid than adenocarcinomas (90, 158, 160) but others have found no correlation between gallium-67 uptake and the histologic type of the cancer (159,161, 162). In most cases, gallium-67 scintigraphy detects with great accuracy mediastinal involvement and therefore contributes to the non invasive staging of the disease avoiding the need for mediastinoscopy (155).

However, evaluation of the abdomen after gallium-67 administration should be routinely undertaken in immunocompromised patients, even when the clinical signs indicate infection elsewhere (96). Sometimes the study may be complicated by the normal excretion of gallium-67 via the large bowel which may require the use of bowel preparation or delayed imaging.

However, it has been recently reported that gallium-67 scintigraphy is not as informative as CT scan for the initial diagnostic workup (159). Occasionally, wholebody gallium-67 scan is useful for the detection of distal metastases, although bone scan for osseous metastases and CT especially for brain metastases remain the imaging modalities of choice (163) (Fig. 35).

Generally, absence of any colonic activity probably excludes significant bowel pathology and the presence of such activity, even when very intense must be interpreted cautiously (23, 53).

Finally, gallium-67 scan has been shown to be helpful in assessing the effects of therapy, the early detection of radiation pneumonitis (2-6 months after irradiation) and the pulmonary toxicity related to bleomycin or cyclophosphamide chemotherapy (44, 164, 165).

24

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

Fig. 34 - A

Fig. 34 - C

Fig. 34 - B

NT

POST

Fig. 35 - A

Fig. 35 - D

Fig. 34. A case of a 46-yr-old male smoker, who presented with persistent cough for the last 3 months. A chest radiograph (A) demonstrated an opacity with a central cavity in the middle field of the right lung. A CT scan (8) confirmed the lung lesion and did not reveal any additional abnormal findings. A whole body gallium 5con 48 hours post injection showed the lung lesion, and no uptake of the trocer in the hilar or mediastinal lymph node5 (C); No argument was found for the highly increased large bowel activity. A biopsy revealed adenocarcinoma of the lung. Since no remote metastases were noted, the patient was scheduled for a right lung section.

Fig. 35. A gallium whole body scan in anterior and posterior view (A) shows multiple osseous metastases throughout the skeleton from a lung cancer in a 60yr-old male smoker but a Tc-99m -MDP scan in spotviews demonstrates them more clearly (B-F). B-C anterior views, O-F posterior views. Fig. 35 - E

Fig. 35 - F

25

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.3.2. Hepatoma

8.4. LYMPHOMAS

Hepatocellular carcinoma accounts for 80% to 90% of primary liver epithelial neoplasms in adults, and accounts for 1% to 2% of malignant tumors found at autopsy in North America, South America, and Europe (166). As cirrhosis is a frequent underlying disease (60% to 75% of autopsies) pseudotumors and/or regenerating nodules make hepatoma diagnosis difficult on sulfur colloid liver scan, CT and ultrasound (34, 166). Liver biopsy may also be falsely negative (166). In front of a cold lesion on a Tc-99m sulfur colloid scan, uptake of gallium-67 points towards hepatoma or inflammation (34) (Fig. 36).

Tumor uptake of gallium-67 has been most extensively studied in lymphoma, the disease in which gallium67 usefulness was first recognised (1 ). As expected, the sensitivity of gallium-67 in detecting lymphomatous disease is greatly dependent upon SIZE, LOCATION and HISTOLOGIC TYPE of the lesions (16). Lesions of less than 1 cm in size are often not detected. Sites of involvement in the abdomen and pelvis may be difficult to identify because of interfering activity within the liver and colon, and because of their often deep seated location (16). SPECT, due to its ability to separate different foci of abdominal uptake and to display images in transaxial, coronal and sagittal slices, depicts the different abnormal nodal groups better than planar imaging does (169). For Hodgkin's disease, histiocytic type of nonHodgkin's lymphomas and Burkitt's lymphoma, the sensitivity is greater when compared to the lymphocyte predominant category, probabl y because of the generally poor affinity of lymphocytes for gallium-67. On the other hand, in cases of non-Hodgkin's lymphoma the degree of gallium-67 avidity depends also upon tumor grade. Higher grade tumors demonstrate a greater degree of gallium-67 uptake than low grade lymphomas do (J 70). Nevertheless, more than 90 percent of patients with untreated lymphomas show some degree of gallium-67 concentration (Fig. 38-39). The false positive rate in both treated and untreated patients in approximately 5% (16). In the evaluation of newly diagnosed patients with Hodgkin's disease and non-Hodgkin's lymphoma, CT is currently the imaging method of choice for staging ( J7 J). However, Front and Israel stress that gallium-67 scintigraphy should always be performed before treatment to determine if the individual patient has a gallium-67 avid lymphoma and to obtain a baseline documentation of scintigraphic location and form of the lesions (40). Gallium-67 scintigraphy after treatment in a non-gallium-67 avid lymphoma is of no benefit due to the inability to compare the post-treatment study with that performed before treatment (40).

Gallium-67 uptake, however, can also be seen in regenerating nodules and metastases, but the degree of uptake is usually less than with hepatoma (34) . The gallium-67 scan sensitivity is about 90% for primary hepatoma, and 50% for metastatic liver disease (19,34). 8.3.3. Malignant melanoma Gallium-67 scintigraphy has been used for the patient evaluation with malignant melanoma. The SPECT technique has an overall sensitivity of 82% with a specificity of 99% (34) . Bone, brain and lung metastases are usually detected (19). As is expected, the sensitivity of the method falls for lesions smaller than 2 cm m size (34).

8.3.4. Other malignant diseases In general, gaUium-67 scintigraphy has a low sensitivity in the detection of gastrointestinal tract, genitourinary and gynecologic tumors as well as breast cancer, thyroid cancer, neuroblastoma and occult tumors. However, it may be useful in testicular carcinoma, and especially in seminoma (34) while it has been shown that it has a definite role in the management of pediatric solid tumours (167) and in cases of soft tissue sarcomas (168) (Fig. 37). In this situation, it appears to have an adjunctive role particularly in identifying foci of active tumors, clinically and radiographically unsuspected, within residual post-treatment masses (168).

The current interest of gallium-67 scintigraphy after treatment is to monitor response to therapy, to predict outcome and prognosis, to assess disease activity status in residual masses seen on CT and, to detect early recurrences after a continuous clinical remission (40, 169, 172-186).

26

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

Fig. 36. A 52-yr-old Female was admitted to the hospital because of weakness, low grade Fever and loss of weight. A Tc-99m-suIFur colloid scan demonstrated a large deFect in the posterolateral aspect of the liver (A) (posterior view, arrow). Injection of 148 MBq of Ga-67-citrate 48 hours later Filled in the deFect (8) (posterior view, arrow). At surgery a hepatoma was Found.

Fig. 36 - A

Fig. 36 - B

POSTERIOR

Fig. 37 - A

Fig. 37. A 20-yr-old male was admitted to the hospital For evaluation of a gradually increasing mass in the posterior aspect of the right thigh. The three phase Tc-99m-MDP scan in posterior view showed highly increased perFusion (A) and blood pool (8) of the mass. The delayed image (C) did not reveal bone involvement. (The lower activity seen in the diaphysis of the right Femour was due to the absorption of the radioactivity From the superimposed mass). A further gallium scan (0) showed high concentration aF the tracer in the mass. The patient was operated on and the biopsy findings were consistent with a fibrosarcoma.

VIEWS

POSTERIOR VIEWS

Fig. 37 - B

Fig. 37 - C

Fig. 38. A 45-yr-old man was presented at the hospital with Fever of 6 weeks duration and sweating. The chest radiograph demonstrated enlargement of the mediastinum. A gallium scan 72 hours post injection of 370 MBq of Ga-67-citrate showed a high increased concentration of the tracer in the subclavicular, mediastinal and hilar lymph nodes bilaterally. Needle biopsy demonstrated a Hodgkin's lymphoma.

~NT

ANTERIOR POSTERIO Fig. 38

Fig. 37 - D

Fig. 39. A 18-yr-old female with a seven month non productive cough , slight degree of dyspnea during exercise and palpable submaxillary, axillary and bilaterally inguinocrurallymph nodes was admitted to the hospital For evaluation. On clinical examination besides the lymph nodes a splenomegaly was Found. Laboratory workup revealed anemia (hematocrit: 34%) and leukopenia (WBC=2,900/mm' ). Pulmonary Function tests demonstrated moderate restricitive pattern. A whole-body gallium scan in anterior and posterior views 48 hours post injection of 282 MBq of Ga-67-citrate showed intense uptake in submaxillary, left axillary hilar, mediastinal, right hyperclavicular and inguinal lymph nodes. Moderate uptake was demonstrated in salivary and parotid glands. Moreover spleen enlargement with very intense uptake was noted. Most probable diagnosis was lymphoma or sarcoidosis. Surgical resection of a lymph node histologically confirmed the diagnosis of lymphoma.

Fig. 39

27

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

It has been shown that if gallium-67 scan findings convert from positive to negative at the therapeutic halfway point (Fig. 40) prognosis is extremely favo rable, and if the gallium-67 study findings are positive at the halfway point of therapy, the prognosis for the patient is extremely poor. Then the positive gallium-67 scan findings highly correlate with accelerated mortality (175). In contrast no significant difference was found between positive and negative CT studies after treatment (40). A residual mass seen after treatment of lymphoma is a tricky clinical problem (187). Although up to 64% of lymphoma patients may show a residual mass, only 18% of these ever relapse (179). Computer tomography is unable to determine whether a residual mass after treatment represents tumor or fibrotic and necrotic tissue (187). As gallium-67 is a viability agent, and is taken up proportionally to the amount of viable tumor cells in the mass after treatment, gallium-67 scintigraphy has proved to be a reliable technique for the evaluation of viability in a residual mass after treatment (40). This has

been demonstrated by histological examination of the mass after treatment (177). For this purpose, the gallium-67 scan should be performed at least three weeks after the last cycle of treatment, because if performed earlier, chemotherapy may prevent gallium-67 uptake, although viable tumor still exists (188). The early detection of recurrence after continuous clinical remission after treatment is an other problem in the therapy of lymphoma (189) . There is no diagnostic test that can reliably detect lymphoma before or even when clinical evidence for recurrence appears (189). The sensitivity of CT in this particular situation was found to be 45% for the chest and 55% for the abdomen (189) . In constrast using gallium-67 scintigraphy the results were impressive. Both sensitivity and specificity for diagnosis of recurrence were found to be high 95% and 89% respectively (172). Early diagnosis of recurrence, before clinical evidence, indicates the necessity for performing gallium-67 scintigraphy on a routine basis after treatment.

POST

HEAD

l Fig. 40 - C

Fig. 40 - D

PELVIS Fig. 40 - A

28

Fi g. 40 - B

Fig. 40 - E

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

Front and Israel propose the following protocol: gallium-67 scintigraphy should be performed at 6 and 12 months after the patient has achieved a complete remission , and once a year thereafter (40). The routine use of SPECT is essential. SPECT imaging is more accurate not only in depicting foci of gallium67-avid lymphoma in the chest and abdomen, but also in excluding disease when planar imaging is equivocal (169).

In order to increase the sensitivity, in addition to SPECT imaging, Kaplan recommends high-count density images acquisition (one million counts per view) which allow definition of subtle foci of active tumor (190). He recommends also that the first set of images should be obtained no earlier than 72 hrs after gallium67 injection with follow up studies performed even as late as 10-14 days post-injection. This format of delayed images will result in high tumor to background ratios and the subsequent increased sensitivity needed for detecting subtle foci of residual tumor (41). To achieve SPECT imaging, high density images, and

!

(40) .

Gallium-67 images should be interpreted along with the CT or NMR image because of the complementary nature of the anatomic imaging modalities (CT, NMR) and of the functional imaging gallium-67 scan. In that way it would be possible to determine more accurately the significance of post therapy residual abnormalities, residual viable tumor or benign fibrotic change. The most appropriate method to use these tests is to interpret concomitantly the set of images. A CT mass win be defined as (a) residual tumor by a corresponding positive gallium-67 planar or SPECT image, or as (b) fibrosis when the gallium-67 images are negative (190) .

Additionally, a positive gallium-67 focus in a patient with a CT scan initially interpreted as negative will, with reinterpretation, commonly be found to represent a CT mass of borderline size which corresponds 111 location to the gallium-67 finding (190).

Fig. 40. A 3S·yr·old male with gradually worsened claudication and swel ling of the right leg was admitted to the hospital. A whole body bone scan in anterior (A) and posterior (B) views showed increased bone activity in the right humeral head (large arrow) diffuse increased activity in the right hip and pubes (arrowheads); a focal increased activity in the right orbit was noted as well (small arrow). The findings are more clearly shown in the spot views (C, D, E arrows). A ga llium whole body scan 96 hours post iniection of 296 MBq Ga·67· citrate in anterior (F) and posterior (G) views demonstrated massive multifocal uptake in the right inguina l area (arrowheads). Focal increased uptake was noted in the right humera l head (large arrow) and in the right axilla (small arrow). The diagnosis of lymphoma was mostly probable. A lymph node biopsy confirmed the diagnosis and the patient started chemotherapy. Consequently a second ga llium study was performed at the therapeutic halfway point (H) which was almost normal. Although in the first ga llium study (F, G) there was no increased uptake in the area of the right orbit corresponding to the bone scan finding, in the second gallium study (H) a slightly increased activity was seen in this area (arrowhead). Nevertheless, the patient had an excellent prognosis and three years later is free of disease.

/'

Fig. 40 . F

delayed imaging in a relatively short period of time, higher doses of gallium-67 should be injected in adults, such as 8-10 mCi (39-41), and in children, 75 /-lCi/kg

Fig. 40· G

Fig. 40· H

29

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.5. SARCOIDOSIS AND OTHER INTERSTITIAL LUNG DISORDERS Sarcoidosis is a chronic granulomatous disease of uncertain etiology and pathogenesis which can involve almost any organ in the body, although pulmonary manifestations often predominate (191, 192). Pulmonary sarcoidosis is the most common interstitial lung disorder. Intrathoracic involvement with sarcoidosis is by far the most frequent localization of disease activity, occuring in 90% of patients. The intrathoracic manifestations of the disease may consist of hilar or mediastinal adenopathy, interstitial or alveolar pulmonary infiltrates, endobronchial granuloma formation or pulmonary fibrosis (193). The diagnosis of pulmonary sarcoidosis is often one of exclusion, although the confirmation of non caseating granulomas in the absence of evidence of vasculitis, or fungal or mycobacterial disease is considered to be diagnostic. Most patients have a self-limited form of the disease, but 20% to 30% present a permanent lung dysfunction, and the disease is fatal in 5%-10% (193). Current concepts of the pathogenesis of pulmonary sarcoidosis suggest that the earliest lesion is an al veolitis with an inflammatory infiltrate comprising mononuclear phagocytes and lymphocytes especially CD4 cells. These cells play a critical role by recruiting monocytes to the lung, thus providing the source of cellular building blocks of granuloma formation ( 194198). Nearly two thirds of untreated patients with sarcoidosis have abnormal gallium-67 scintigrams (199, 200). Gallium-67 scintigraphy is effective in the detection of lesions not revealed by traditional methods of investigation, particularly those affecting mediastinum, spleen, lacrimal glands and salivary glands (201,202).

Fig. 41 · A

30

Fig. 41 - B

Sulavic et al described a distinctive intrathoracic lymph node gallium-67 uptake pattern, resembling the Greek letter lambda (L) (Fig. 41), which was observed in 72% of sarcoidosis patients. Symmetrical lacrimal glands and parotid glands gallium-67 uptake (panda appearance) was noted in 77% of sarcoidosis patients in their series (Fig. 42). Sixty-two percent of their patients appeared with a simultaneous lambda and panda pattern (Fig. 43, 44) and 6% had a panda appearance with radiographic bilateral symmetrical hilar lymphadenopathy. The presence of one of these patterns was particularly prevalent in Roentgen stages I or II. They conclude that simultaneous (a) lambda and panda images, or (b) panda image with bilateral symmetrical hilar lymphadenopathy on chest X-ray represent distinctive patterns which are highly specific for sarcoidosis as a result of its unique characteristics of symmetry and predilection for the salivary glands, lacrimal glands and the hilar and mediastinal lymph nodes. Such a gallium-67 appearance may obviate the need of invasive diagnostic procedures (201). Some additional cases of sarcoidosis are demonstrated in figure 49. It is difficult to estimate the activity of sarcoidosis by

conventional clinical, radiological and physiologic parameters as none of these are specific for the inflammatory process but rather reflect the degree of parenchymal derangement. Hense, there has been particular interest of gallium-67 imaging as a means of evaluating the activity of sarcoidosis (203-205). Several studies have shown good correlation between pulmonary gallium-67 uptake and the intensity of the alveolitis of this disease as assessed by both biopsy morphology and bronchoalveolar lavage (200, 204) (Fig. 45).

Fig. 42

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

ANT

Fig. 44 - B

Fig. 43

Fig. 44 - A

Fig. 41. Lambda sign in a 34-yr-old man (A) and in a 39-yr-old female (B) patients with sarcoidosis. Bilateral hilar and mediastinal lymph node gallium intense uptake is noted. Fig. 42. Panda sign in a case of sarcoidosis. Symmetrical increased activity in the lacrimal and parotid glands is noted. Fig. 43. Lambda and panda signs in a 30-yr-old man with sarcoidosis. Fig . 45 - A

Fig. 44. Another case of active sarcoidosis in a 48yr-old woman with lacrimal and parotid gland as well as intrathoracic lymph node increased gallium uptake in a whole body anterior view (A) and a spot view (B). Fig. 45. A 46-yr-old male was admitted to the hospital because a prolonged cough and dyspnea during exercise. His chest radiography (A) showed an diffuse interstitial pattern with hilar enlargement. A whole-body gallium scan 48 hours, post injection of the tracer (B) demonstrated diffuse homogeneous intense gallium uptake in both lungs, without lacrimal salivary or lymph nodes uptake. The increased serum angiotensin converting enzyme (SACE), the bronchoalveolar lavage findings and the biopsy are supportive of lung parenchymal involvement of sarcoidosis. Fig . 45 - B

31

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

In that way, gallium-67 scintigraphy permits differentiation between fibrotic lesions which do not show uptake and granulomatous lesions, which are gallium67 avid (204). In addition gallium-67 scintigraphy gives the opportunity to estimate the therapeutic effect, and to follow the evolution of the disease (200) (Fig.

46,47,48). The ability to discriminate between these processes has a prognostic value. Serial scans and bronchoalveolar

Fig . 46 - A

lavage have been successfully used to predict which patient will show deterioration in pulmonary function over several year intervals (200). This longitudinal evaluation of gallium-67 scintigraphy better reflects the activity of the disease, if the assessment of the degree of parenchymal inflammatory infiltration is based not only on the qualitative estimation of the pattern of the abnormal gallium-67 uptake but also on semiquantitative or quantitative estimation of it (206-209 (Fig. 49)) .

Fig. 46 - B

At'lT

Fig. 46. Case of 61·yr-old woman with sarcoidos is. A pretreatment ga llium scan (A) shows increased lacrimal and sa livary glands uptake, as well as paratracheal and infrahilar lymph nodes uptake. Two months later a second gallium scan (B) during therapy with corticasteroid s is quite normal. Fig. 47. A 35-yr-old man was presented with chest pain weakness and dyspnea. A gallium scan (A) revealed massive uptake in the middle field of both lungs as well as in the mediastinal and the hilar lymph nodes. Normal uptake in the salivary glands and faint uptake in the lacrimal glands is noted. An open biopsy revealed sarcoidosis and the patient underwent corticosteroid therapy. Five months later a follow-up galli um scan was done (B), which showed a normal pattern of the thorax and faint uptake in the parotid gla nds. Two years later the patient without any medication was in excellent condition. Fig. 47 - A

32

Fig. 47 - B

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

Fig. 48 - A

Fig. 48 - B

AN

Fig. 48 - C

Fig. 48 - D

Fig. 48. A 42-yr-old latin female presented with fever and pain in the legs far the last month. A plane chest radiograph (A) showed hilar adenopathy and mediastinal widening. A gallium scan !wo days later (8) revea led a typical lambda sign, and biopsy confirmed the diagnosis of sarcoidos is. Patient initiated corticosteroid therapy and the fever resolved quickly. After 6 months the patient gradually withdrew the medication. Twelve months later he underwent a follow-up study. A lthough the new chest X-ray (e) showed some improvement, the hilar lymphadenopathy was still prominent. The gallium scan (0) showed no evidence of active disease as it was completely normal. One year later the patient, free of symptoms, underwent a second follow-up study. The new chest X-ray remained unchanged (E) but the gallium scan revealed recurrence of the disease (F). Th e lambda sign reappeared and abnormal increa sed uptake in the lacrimal and parotid glands was observed (arrows). Abnormal uptake in both inguinal lymph nodes was noted (arrowheads). Fig. 48 - E

Fig. 48 - F

33

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

ANT

Fig. 49 - A

Fig. 49 - B

Fig. 49 - C

Fig. 49- D

Fig. 49 - F Fig. 49 - E

Fig. 49 - H

34

Fig . 49 - G

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

Fig . 49 - J

Fi g. 49 - I

Fig. 49. Several cases of active sarcoidosis. rAJ 27 yr-old mon with introthoracic lymph nodes

Fig . 49 - L

Fig. 49 - K

Fig. 49 - M

Fig. 49 - N

uptake. Faint lacrimal and sa livary glands uptake, almost normal. (8) 55 yr-old woman . Abnormal lacrimal uptake plus lambda sign. The arrows show the focal uptake of the breasts. (e) 43 yr-o ld male. Bihil ar increased uptake, increased uptake in the lacrima l glands, faint uptake in the parotid glands. (0) 22-yr-old fema le. Lambda sign, Faint uptake in lacrimal and saliva ry glands. (E, F, G, H) 64 yr-old man. The chest radiograph (E) shows pronounced hilar lymphadenopathy. The CT scan (F, G) shows mediastinal lymphadenopathy and micronodular interstitial densities in the posterior aspects of the lung . Th e galli um scan (H) demon strates a character istic lambda and, panda sign plu s a symmetrica l inguinal lymph nodes uptake. (I, J, K, L) 6 1 yr-old woman . In an ordinary chest radiography (I) was revea led bilateral pulmonary interstitia l opacities in the lower fields more pronounced in the right sight. A CT scan (J, K) showed interstitial pattern. A galli um scan (Ll demonstrated increased uptake in the lacrimal and submaxillary glands plu s increased uptake in a left preotic node (arrowhead), right axi ll ary (small arrow) and a left inguinal lymph node (large arrow). The nipples are seen as well (thic k arrows). A lymph node biopsy confirmed sarcoidosis. The curved arrow points to the left great toe, where there was a skin infection. (M, N) 39 yr-old female. Uncommon pattern of gallium scan is showed (M) . Increased activity in the upper fields of both lungs plus increased lacrimal uptake. The chest X- ray (N) shows some bi latera l interstitial densities in the lower fields.

35

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

A variety of quantitative procedures have been developed which express total lung uptake in relation to control regions of the image, i.e. liver, or external standards (206, 207). Data provided from quantitative procedures have demonstrated differences in the average intensity of gallium-67 uptake in the different disease stages of sarcoidosis as well as in other interstitial lung

Fig. 50 - A

diseases such as interstitial pneumonitis due to rheumatoid arthritis (Fig. 50), adu lt respiratory distress syndrome (ADRS) (Fig. 51), drug induced interstitial pneumonitis (Fig. 52), idiopathic interstitial pneumonitis (Fig. 53), pulmonary fibrosis (Fig. 54), silicosis, absestosis etc (204-206).

Fig . 50 - B

At··~T

Fig. 50. A 62-yr-old female sufferin g from rheumatoid arthriti s since 1989 presented with shortness of breath. A chest X-ray showed bilateral pulmonary interstitial and alveolar densities more pronounced in the lower fields (A). A transverse CT scan of the thorax showed diffuse interstitial and micronudular pattern w ith locally sma ll cysts formation (B). A whole-body gallium scan 48 hours post-injection of the tracer demonstrated diffuse gollium uptake in both lungs and intense parotid uptake (C, arrows) findings cons istent wi th lung parenchymal involvement of the disease.

~

Fig. 51. Gallium scan in 73-yr-old man with Ad ult Respiratory Distress Syndrome (ARDS). Diffuse gall ium activity is seen in both lungs more prominent in the lower fields. Fig. 50 - C

36

Fig . 5 1

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

POST

Fig. 52 - A

Fig. 52 - B

AN

Fig. 52 - C

ANT

POST

Fig. 53

AN

Fig. 52.

A cme of interstitial pneumonitis due to

pulmonary toxicity, secondary to chemotherapy. Diffuse lung uptake and decrease liver uptake are noted in the gallium scan (A anterior, B posterior views) at the end of the chemotherapy. In a repeated gallium scan 1 year later (e) it turns to normal.

Fig. 53.

A case of idiopathic interstitial pneumonitis

in a 42-yr-old man. The gallium scan 48h post injection in anterior and posterior views shows diffuse lung uptake in both lungs.

Fig. 54 .

A case of idiopathic interstitial fibrosis in a

69-yr-old male, with progressive dyspnea. (A) Grossly abnormal chest X-ray shows a honeycomb pattern. A gallium scan of the thorax is absolutely normal (B). Obviously the disease is inactive but a respiratory failure must have been constituted. The arrows point Fig. 54 - A

Fig. 54 - B

towards the site of injection in the right arm.

37

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

8.6. FEVER OF UNKNOWN ORIGIN Fever of unknown origin (FUO) has been defined as an illness of more than 3 weeks duration with repeatedly documented fever greater than 38,3°C (101 OF) and in which a diagnosis has not been made despite intensive hospital or office investigation (210-212). The diagnosis of FUO falls into five general categories (213,214).

- Infections: abscesses, osteomyelitis, tuberculosis, endocarditis, urinary tract infections, fungal diseases, parasitic diseases, opportunistic infections in AIDS patients, etc. - Non-infectious inflammatory disorders: sarcoidosis, granulomatous hepatitis, Crohn's disease, autoimmune-collagen-vascular diseases. - Neoplastic diseases: Hodgkin's disease, nonHodgkin's lymphoma, leukaemia, carcinoma of kidneys, lung, liver, etc. - Drug fevers: sulfonamides, penicillins, thiuracils, barbiturates, quinidine, laxatives, etc. - Other rare causes: familiar Mediterranean fever, Fabry's disease, etc. Generally, infections, malignancies and collagen-vascular diseases are the most common causes of FUO (210,215 -223) .

Patients under 6 years of age have a high incidence of infections, while collagen vascular diseases and inflammatory bowel diseases are the most common causes in patients from 6 to 16 years old (215-217).

Several studies before 1980 (210, 218-222) have shown that infections are the most common causes of FUO in adults (21-43%). In a recent study (223) it has been pointed out that systemic diseases such as sarcoidosis, Still's disease and temporal arteritis consti tute a great proportion of FUO. In the same study 22,5 % of the cases remained undiagnosed. In general, as the duration of fever increases, the likelihood of an infectious cause decreases (214, 224). Infections, however, still remain a common cause of FUO, but malignancies are increasi ngly identified as a cause of it (225-227) . Among malignancies, lymphomas and leukaemias are most prevalent in both children and adults . In patients with FUO lasting longer than 12 months, granulomatous causes are more common than neoplasms or autoimmune diseases (224, 228). However, in all studies there is a group in whom diagnosis cannot be established after years of fever and despite all the available tests . In order to elucidate the cause of FUO the work-up may be divided into the following categories: ] . medi cal history, 2. physical examination, 3. observation of the temperature pattern, 4. laboratory tests, non invasive procedures and invasive procedures. Since infections, tumors and multisystem diseases account for about two-thirds of reported cases of FUO, gallium-67 scintigraphy is expected to be a valuable tool in the diagnostic approach of this entity (229, 230) (Fig. 55, 56). Its contribution to the final diagnosis depends upon the composition of the studied group of

Fig. 55. A 6 1-yr-old female was referred to the Nuclear Medicine Department by the phys icia ns of the Internal Medicine Depa rtment for a ga llium sca n in order to eva luate a one month Feve r of Unknown Origin (FUO). She also had a pa in of the left thigh. The X-rays of the left fem ur were equivoca l. The patient had very high sed imentation rate, but the rest of th e labo ratory tests a nd th e noninvas ive procedures (US, CT etc) were non diagnostic. The galli um scan was completely norma l except the area of the rhi nopharynx (A) where the uptake was more intense than usual. A biopsy from thi s area revea led a T-Iymphoma. The patient started chemotherapy and the fever rapidly resolved. A second gallium sca n 5 months later du ri ng therapy (B) was norma l. Two years later the patient was doing well.

.,

Fi g . 55 - A

38

Fig. 55 - B

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

patients, that is the pretest probability (231), though the percentage of diagnostically useful gallium-67 scans is hi gher in pati ents with abscesses, infections and tumors (232-235) th an in an FUQ population which encompasses a broad variety of diseases, with a significant number of undiagnosed cases (231). Many di seases causing FUO can be diagnosed by ultra-

ANT

sonography, computed tomography, or magnetic resonance imaging. However whole-body scan by these techniques is not feasib le because of the required time and the level of radiation exposure. The great strength of gallium-67 imaging is that the whole body is evaluated at once and serendipitous findings were reported in 12% of this group of patients (236,237) (Fig. 57).

PO ~5T

Fig . 56

ANT

POST

Fig. 56. A 30-yr-old female with AIDS and extrapulmonary Kaposi's sarcoma was referred for a gallium scan because a prolonged fever. The gallium scan showed liver enlargement and mediastinal and left hilar accumulation of the gallium most probably due to either tuberculosis, MAC or lymphoma . The biopsy proved a lymphoma. Fig. 57. A 82-yr-old male was referred to the Nuclear Medicine Department for a gallium scan because of a Fever of Unknown Origin (FUO) lasting longer than 40 days. None of the performed routine or specific tests were able to help for defining the cause of the fever. A whole-body gallium scan in anterior and posterior views was performed 48 hours post iniection of 300 MBq Ga-67 -citrate, which showed abnormal accumulation of the radiopharmaceutical in the abdomen along the middle line and multifocal activities which most probably represented aortic and paraortic lymph nodes. After the gallium scan a CT-guided needle biopsy revealed a non -Hodgkin's lymphoma. After the initial chemotherapy remission was achieved but 5 months after the diagnosis the patient worsened quickly and finally died.

Fig. 57

39

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

The inability, however, of gallium-67 scintigraphy to distinguish between infectious and non-infectious lesions is a drawback especially in cases of known malignancy (231) ; but for classic FUO this lack of specificity is actually an advantage, because not only infections and tumors, but also other causes must be sought (231,236) (Fig. 58).

Unfortunately, a number of abnormal gallium-67 scans do not contribute to diagnosis. This fact represents another well recognised drawback of the technique (238) (Fig. 59). The same, however, happens with the other imaging modalities (US and CT) which also revealed a high rate of abnormal findings which were not helpful to diagnosis (227, 231).

.

,'.

Fig . 58 - B

Fig. 58 - A

40

Fig. 58. A 60-yr-old male was admitted to the hospital for evaluation of a fever lasting more than 3 months. As an outpatient he underwent th e routine laboratory tests (blood, urine analysis etc), antibody titers , multiple cultures, X-rays, ultrasonography, CT and MRI of the thorax and the abdomen without discovering the underlying source of the fever. The whole-body gallium scan (A) and a static view (8) demonstrated moderate, diffuse uptake in both lungs without any foca l abnormal finding throughout the body. After bronchoscopy, bronchoalveolar lavage and biopsy of the lung a final diagnosis of sarcoidosis was established.

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

In a prospective study of patients with FUO using Receiver Operating Characteristic analysis it has been shown that CT, US, and gallium-67 scans have similar capabilities in detecting septic foci and that sensitivity can be increased by using any two of them (239). Finally, it must be highlighted that gallium-67 scan in patients with FUO should be considered in the diagnostic workup before administrating drugs that may mask the site of infection (92). In conclusion, gallium-67 scintigraphy plays an important role in the evaluation of FUO as a second step (as opposed to a last-resort) procedure, since it can show a high diagnostic sensitivity (240, 241).

Fig. 59. A case of a 17-yr-old male who underwent a gallium sca n for evaluation of a fever lasting longer than 2 months. The gallium scan showed marked increased activity (more intense than in the liver), in the caecum , ascending and transverse colon, and increased occu lar and nasopharynx activity. These findings were noted on the patient's report and further evaluation was recommended because the bowel finding was considered definitely abnormal. The clinicians performed repeated colonoscopy, biopsies and multiple stool cultures but none were diagnostic. Th e patient discharged without any therapy and was followed in an outpatient basis. Three month s later the fever resolved spontaneously and one and half year loter the patient is still free of symptoms.

Fig. 59

41

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

9 . BIBLIOGRAPHY 1.

Edwards CL, Hayes RL. Tumor scanning with 67Ga-citrate. J Nucl Med, 1969; 10: 103.

2.

Lavender IP, Lowe J, Barker JR, et al. Gallium-67 citrate scanning in neoplastic and inflammatory lesions. Br J Radial, 1971 ; 44: 36l.

3.

Littenberg RL, Taketa RM, Alazraki NP et al. Ga-67 localization of se ptic lesions. Ann Inter Med, 1973 ; 79: 403.

4.

Hopkins GB, Kan M, Mende Gw. Early 67Ga scintigraphy for the localization of abdominal abscesses. 1 Nucl Med, 1975; 16: 990.

5.

De Meester TR, Colomb HM, Kirchner P et al. The role of . ga lliul1l-67 scanning in the cl inical staging and preoperative evaluation of patients with carcinoma of the lung. Ann Thorac Surg, 1979; 28: 411.

22.

Sohn MH, Jones Bl, Whiting IH. Distribution of gallium-67 in normal and hypostransferrinemi c tumor-bearing mice. I Nucl Med, 1993; 34: 2135.

23.

Palestro C . The Current Role of Gallium Imaging in Infection. Semin Nucl Med, 1994; 14: 128.

24.

Bekerman C, Bitran J. Gallium-67 scan ning in the c linical evaluation of human immunodeficiency virus infection Indications and limitations. Semin Nucl Med, 1988; 18: 273.

25.

Datz FL, in Handbooks in Radiology Nuclear Medicine. Datz FL (ed), Year Book Medical Publishers Inc., Chicago, 1988; p. 175.

26.

Saha GH, in Fundamentals of Nuclear Pharmacy, Saha GH (ed), Springer-Verlag, New York, 1992; p. 29 1.

27.

Tsan MF. Mechanism of Ga lliu l1l-67 accumulation in inflammatory lesions . 1 Nucl Med, 1985; 26 : 88.

28.

Weiner R, Hoffer PB , Thakur ML. Lactoferrin : its role as a 67Ga binding protein in polymorphonuclear leucocytes. I Nucl Med, 1981; 22: 32.

29.

GOI'enberg M, Groshar D , Eve n-Sapir E et al. Ga-67 uptake unsuppressed by leucopenia and intense antibiotic therapy. Clin Nucl Med, 1992; 17: 97 .

30.

Hoffer PB. Gallium: Mechanisms. I Nucl Med, 1980; 21: 282.

31.

Swartzendruber DC, Nelson B, Hayes RL. Gallium-67 localization in lysoso mal-like granules of leukaemic and nonleukaemic Illurine tissues . JNCI, 1971 ; 46: 941 .

6.

Levenson SM, Warren RD, Richman SD et al. Abnormal pulmonary Gallium-67 accumulation in P. carinii pneumonia. Radio logy, 1976; 119: 395.

7.

Lisbona R, Rosenthall L. Observations on the sequential use of 99mTc phosphate complex and 67Ga imaging in osteomyelitis cellu li tis and septic arthritis. Radiology, 1977; 123: 123 .

8.

Thadepalli H, Rambhatla K, Mishkin FS et al. Correlation of microbiologic findings and Ga-67 scans in patients with pulmonary infections. Chest, 1977 ; 72: 442 .

9.

Andrews GA, Hubner KP, Greoulaw RH. Ga-67 citrate imaging in malignant lymphoma: final report of cooperative group. J Nucl Med, 1978; 19: 1013.

10.

Bekerman C, Port RB , Pang E . Scintigraphic evaluation of chi ldhood malignancies by 67Ga-citrate. Radiology, 1978; 127: 719.

32.

Hayes RL, Carlon IE. A study of macromolecular binding of 67Ga in normal and malignant animal tissue. Cancer Res , 1973; 33: 3265.

11.

Siemsen JK, Grebe SF, Waxman AD. The use of Gallium-67 in pu lmonary disorders. Semin Nucl Med, 1978; 8: 235.

33.

Hoffer PB, Bekerman C, Henkin RE (eds) . Gallium-67 imaging. Wiley, New York, 1978; p. 23.

12.

Reingold OJ, Tedesco FJ, Block FE et al. Gallium-67 citrate scintiscanning in active inflammatory bowel disease. Dig Dis Sci , 1979 ; 24: 363.

34.

Datz FL. Handbooks in Radiology, Nuclear Med icine Year Book, Medical Publishers fnc., Chicago, 1988; p. 177.

35.

McAfee JG, Subramanian G. Radioactive agents for imaging, in Clinical Radionuclide Imaging, Freeman LM. (ed), Gru ne and Stratton Inc., New York, 1984; p. 55.

36.

Treves ST, Kirkpatrick lA, Bone in Ped iatric Nuclear Med icine, Treves ST (ed),Spring- Veriang, 1985; p. 2.

37.

Kereiakes JG, Seltzer RA, Blackburn B et al. Radiol1uclide doses to infants and children: A plan for a sta ndard child. Health Phys, 1965; II: 999.

38.

Thomas SR, Gelfand MJ, Kereiakes JG et al. Dose to the metaphyseal growth comp lexes in children und ergoin g Tc99m-EHDP bone scans . Radiology, 1978; 126: 193.

13.

Halpern S, Hagan P. Gallium-67-citrate imaging in neoplastic and inflammatory disease. In Nuclear Medicine Annual 1980, Freeman LM, Weissman HS, (eds), Raven Press, New York, 1980; p. 219 .

14.

Boxen I, and Ballinger JR. Nuc lear medicine detection of inflammation and infection. Curr Opin Radiol, 1991 ; 3: 840.

15.

Saha GH, in Fundamentals of Nuclear Pharmacy. Saha GH (ed). Springer-Verlag, New York, 1992; p. 49.

16.

Mettler FA, Guiberteau MI. Essential of Nuclear Medicine Imaging W.B. Saunders company, Philadelphia, 1991 ; p.253.

17.

Hoffer PB , Bekerman C, Henkin RE (eds). Gal lium-67 Imaging. W iley, New York,1978; p. 3.

39.

Anderson KC, Leonard RCF, CaneJlos GP et al. High-dose Gallium imaging in lymphoma. Am J Med, 1993; 75: 327.

18.

Hartman RF, Hayes RL. The binding of Gallium by blood serum. J Pharmacol Exp Ther, 1969; 168: 193 .

40.

19.

Neuman RD , Hoffer PB. Gallium scintigraphy for detection of inflammation and tumors in Clinical Radionuclide Imaging Freeman L.M (ed), Grune and Stratton inc., New York, 1984; p. 1319.

Front D, Israel O. The role of Ga-67 scintigraphy in evaluating the results of therapy of lymphoma patients. Semin Nucl Med, 1995; 25: 60.

41.

Brachman MB, Ramanna L, Tanasescu DE et al. Gallium tumor scanning: How many days between injection and imaging? [Abstract]. J Nucl Med , 1986; 27: 1030.

42.

Siemsen JK, Grebe SF, Sargent EN et al. Gallium-67 scintigraphy of pulmonary diseases as a complement to radiography. Radiology, 1976; 118: 371.

43.

Bekerman C, Hoffer PB, Bitran JD et al. Gallium-67 citrate imaging studies of the lung. Sem Nucl Med, 1980; 10: 286.

20.

Hara T. On the binding of Gallium to transferrin. Int J Nucl Med BioI, 1974; I: 152.

21.

Larson SM, Allen DR, Rasey JS et al. Kinetics of binding of carrier free Ga-67 to human transferrin. J Nucl Med, 1978; 19: 1245 .

43

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

44.

Kataoka M, Kawamura M, Itoh H et a1. Ga-67 citrate scintigraphy for the early detection of radiation pneumonitis . Clin Nucl Med, 1992; 17: 27.

45.

Edwards CL, Hayes RL, Nelson B. The "normal" Ga67 photoscan. (abstr). J Nucl Med, 1972; 13: 428.

46.

Larson SM, Milder MS, Johnston GS. Interpretation of Ga67 photoscan . J Nucl Med, 1973 ; 14: 208.

47.

Handmaker H, O'Mara RE : 67Ga imaging in pediatrics. J Nue! Med, 1977; 18: 1057.

48.

Johnson PM, Berdon WE, Baker DH, et a1. Thymic uptake of Gallium-67 citrate in a healthy 4-year-old boy. Pediatr Radiol, 1978; 7: 243.

49.

Harris EW, Rakow J.I, Weiner M et al. Thallium-201 scintigraphy for assess ment of a Gallium-67-avid mediastinal mass following therapy for Hodgink's Disease. J Nucl Med, 1993; 34: 1326.

50.

Drossman SR, Schiff RG, Kronfeld GD et al. Lymphoma of the mediastinum and neck: Evaluation with Ga-67 imaging and CT Correlatation . Radiol, 1990; 174: 17 L

51.

Peylan-Ramu N, Haddy TB, Jones E et al. High frequency of benign mediastinal uptake of Gallium-67 after completion of chemotherapy in children with high-grade non-Hodgkin's lymphoma. J Clin On col, 1989; 7: 1800.

64.

AI-Sheikh W, Sfakianakis GN, Mnaymneh Wet al. Subacute and chronic bone infection s: Diagnosis using In-Ill, Ga-67 and Tc-99m MDP bone scintigraphy, and radiography. Radiology, 1985; 155: 501.

65.

Magnuson JE, Brown ML, Hauser MF et al. Orthopedic prosthesis infection . In-Ill labeled leucocyte scintigraphy in suspected orthopedic prosthesis infection , comparison with other imaging modalities. Radiology, 1988; 168: 235 .

66.

Johnson JA, Christi I MJ, Sandler MP et a!. Detection of occult infection following total joint arthrop lasty using sequential technetium 99m-HDP bone scintigraphy and Indium-III-WBC imaging. 1 Nucl Med, ] 988 ; 29: ] 347.

67.

McDougall IR, Goodwin DA. GalLium sca n vs indium-IIIlabeled oxyquinoline WBC scan . Arch Inter Med, 1982; 142: 1406.

68.

Propst-Proctor SL, Dillingham MF, McDougal IR et al. The white blood cell scan in orthopaedics. CORP, 1982; 168: 157.

69.

Lisbona R, Derbekyan V, Novales-Diaz J et al. Gallium-67 scintigraphy in tuberculous and nontuberculous spondiliti s. J Nuci Med , 1993 ; 34: 853.

70.

Modic MT, Feiglin DH, Piraino DW et a!. Vertebral osteomyelitis: Assessment using MR. Radiology, 1985 ; 157 : 157.

71.

Alazraki N, Fierer J, Resnick D. Chronic osteomyelitis: monitoring by 99mTc-phosphate and 67Ga-citrate imaging. AJR, 1985; 195: 767.

52.

Donahue DM, Leonard JC, Bassnadjian GP et al. Thymic Gallium-67 locali zation in pediatric patients on chemotherapy. Concise communication . 1 Nucl Med, 1981; 22: 1043.

72.

53.

Woolfenden JM, Carrasquillo JA, Larson SM et al. Acquired immunodeficiency sy ndrome : Ga-67 imaging. Radiology, 1987; 162: 383 .

Wiseman J, Rouleau J, Rigo P et al. Gallium-67 myocardial imaging for the detection of bacterial endocarditi s. Radiology, 1976; 120: 135.

73.

Robinson JA, 0' Connell 1, Henkin RE et al. Gallium-67 imaging in cardiomyopathy. Ann Intern Med, 1979; 90: 198.

74.

O'Connell 1, Robinson lA, Henkin RE et al. Gallium citrate scanning for noninvasive detection of inflammation in pericardial diseases . Am J Cardiol , 1980; 46: 879.

54.

Ze man RK, Ryerson TW. The value of bowel preparation in Ga-67 citrate scanning. Concise communication. J Nucl Med, 1977; 18: 886.

55.

Schanwecker DS. The scintigraphic diagnosis of osteomyelitis. AJR, L992 ; 158: 9.

75.

56.

Harcke HT. Bone imaging in infants and children. A review. J Nucl Med, 1978; 19: 324.

Taillefer R, Dionne D. Gallium-67 uptake by the heart. Semin Nucl Med, 1993; 13: 176.

76.

57.

Sullivan DC, Rosenfield NS, Ogden J et al. Problems in the scintigraphic detection of osteomyelitis in children . Rad iology, 1980; 135: 731.

Morguet AJ, Munz DL, Kreuzer H et al. Scintigraphic detection of inflammatory heart disease. Eur J Nucl Med, 1994; 21 : 666 .

77.

Camargo PR, Mazzieri R, Snitcowsky R et a l. Correlation between gallium-67 imaging and endomyocard ial biopsy in children with severe dilated cardiomyopathy. Int J Cardiol, 1990; 28: 293.

78.

Lanfrachi J, Sachs RN, Beaudet B et al. Exploration des myocardiopathies dilatees par la scintigraphie myocardique au gallium-67. Ann Med Interne, 1989; 140: 486 .

79.

Melvin ET, Berger M , Lutzker LG et al. Noninvasive methods for detection of valve vegetations in infective endocarditis. Am J Cardiol, 1981 ; 47: 271.

80.

Desai SP, Yuille DL. The un suspected complications of bacterial endocarditis imaged by Gallium-67 sca nnin g. J Nucl Med, 1993; 34: 955.

81.

Bufalino VJ, Robinson JA, Henkin Ret a!. Gallium -67 sca nning : "new diagnostic approach to the post-pericardiotomy syndrome. Am heart J, 1983; 106: 11 38.

82.

Huikuri HV, Ikaheimo MJ, Airaksinen J et al. Prevalence and significance of Gallium-67 uptake in the heart after openheart surgery. Am J Cardiol , 1988; 61: 405.

83.

Chandramouly MD, Cao H, Cochavi S. Gallium scintigraphy in hemodialysis access graft infection. Clin Nucl Med, 1993; 18: ISS.

58.

Ash 1M, Gilday DL. The futility of bone scanning in neonatal osteomyelitis. Concise communication. J Nue! Med, 1980; 21: 417 .

59.

Chandler lR, Malignant external otitis . Further considerations. Ann Otol Rhinol Laryngol, 1977; 86: 417.

60.

Malamitsi J, Maragoudakis P, Papafragou K et al. Preliminary results on scintigraphic evaluation of malignant external otitis . Eur J Nucl Med, 1993; 20: 511.

61.

Rosenthall L , Lisbona R, Hermandez M et al. Tc-99m PP, and Ga67 imaging following insertion of orthopedic devices. Radiology, 1979; 133: 717.

62.

Merkel KD, Brown ML, Dewanjee MK et al. Comparison of indium labeled-leucocyte imaging with sequential technetium-67Ga scanning in the diagnosis of low grade musculoskeletal sepsis. J Bone Joint Surg, 1985; 67: 465 .

63.

Merkel KD, Fitzgerald RH Jr, Brown ML. Scintigraphic examination of total hip arthroplasty: Comparison of indium with technetium-67Ga in the loose and infected canine arthroplasty. In: The Hip Proceedings of the Twelth Open Scientific Meeting of the Hip Society, Welch RB (ed), Atlanta, GA, 1984; p. 163.

44

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

84.

Thi vo ll e P, Varenue L, Heyden Y et al. Gallium-67 citrate whole body scannin g for th e locali zation of infected vascular sy nthetic g rafts. C lin Nucl Med, 1985; 10: 330.

105. Adams BK, Med M, Crosier 1H. Bone and Gallium sci ntigraphy in Po lyostic actino mycos is of the upper limb. Clin Nucl Med , 1994; 19: 254.

85.

Hopkins GB, Mende Cw. Gallium-67 and subphrenic abscesses. Is delayed scintigraphy necessary ? J Nucl Med, 1975; 16: 609.

106. Brago FJ, Araujo EB, Camargo EE et al. Gallium scin ti graphy in Hansen's disease. E ur 1 N ucl Med, 1991; 18: 866.

86.

Goldenberg DJ , Russel CD, Mihas AA et al. Value of Gallium-67 citrate scanning in Crohn's di sease: Co nci se communication. J Nucl Med, 1979 ; 20: 215.

107. Mouratidis B, Lomas FE. Gallium-67 scintigraphy in bordeline lepromatous leprosy. A ustralas-Radiol, 1993 ; 37 : 270. 108. Fausi AS . The hum an immunodefic iency vi rus Infectivity and mechanism of pathogenesis . Science, 1989; 239 : 6 17.

87.

Lebouthillier G, Lette J, Morais J et al. 67Ga-67 imaging in primary and seco ndary psoas abscess . Clin Nucl Med,1993; 18: 637 .

109. Hopewell PC, Luce 1M. Pulmon ary involvement in the acquired immunodeficiency sy ndrom e. Chest, 1985 ; 87: 104.

88.

Henderson RW, Telfe r N, Siemsen JK et al. Gallium scin tigrap hy in psoas musc le inflammation (letter) . ] N ucl Med, 1980; 2 1: 897 .

110. Pitchen ik AE, Fertel D, Bloch AB. Mycobacterial diseas: Epidemi ology, diagnosis, treatment and prevention. Clin Chest Med, 1988; 9: 425.

89.

McCuskey WHo Psoas abscess demonstration with SPECT and CT. Clin Nucl Med, 1993; 8: 613 .

90.

Hagasi T, Nakayami Y. Clinical evaluation of 67Ga-citrate scannin g. J N ucl Med, 1972; 13: 196.

111. Wallace 1M. Pulmon ary infection in hum an imlllunodeficiency disease. Viral pulmonary infections. Sem Respir Infect, 1989; 4: 147.

91.

Kao CH, Wang S1 , Liao SQ et al. Usefuln ess of gallium-67c itrate scans in patients with acute di sseminated tuberculosis a nd co mpariso n with chest x-rays . ] Nucl Med, 1993; 34: 191 8.

92.

Ya ng SO, Lee Yr, Chun g DH et al. Detection of ex trapulmonary tuberculosis with ga llium-67 scan and computed tomography. J Nucl Med, 1992; 33: 2 118.

93.

Fedullo PF, Moser KH, Harrell 1H et al. Gallium scannin g in the diagnosis of smea r negativ e pulmonary tuberculosis. Am Rev Respir Dis, 1982 ; 125 (S uppl. : 172).

94.

Wa lsh TJ, Bekerm an C, Chausow A et al. The value of gallium-67 scanning in pulmonary tuberculosis. Am Rev Resp dis, 1985; 132: 746 .

112. Greenson JK, Belitsos PC, Yardley et al. AIDS enteropathy: Occ ult infecti ons and duodenal mucosal alterati ons in chroni c diarrhea. Ann Intern Med , 199 1; 114: 366. 113. Price RW, Brew B. Manage ment of the neurologic compli cations of HIV-I infect ion and AIDS . In The Med ical Management of AIDS , Sande MA, Vo lberding PA (eds), Saunders Company, Phil adelphia, J990; p. 161. 114. Krieger AE, Holland GN. Occul ar in vo lvement in AIDS . Eye, 1988; 2: 496. 115. Scalde n DT, Zon LI, Groop man 1E. Pathop hysio logy and management of HIV associated hematolog ic disorders. B lood, 1989; 74: 1455 . 116. Levi ne AM. Lymphoma in acq uired immunodeficiency sy ndrome. Semin Oncol, 1990; 17: 104.

95.

G rieff M, L isbona R. Detection of mili ary tubercolosis by 67Ga scinti graph y. C lin Nucl Med, 1991; 16: 9 10.

96.

Pettengell K , Garb M , Houlder A et al. Radiolluclide scinti graphy in tuberculous. Enteri tis Gastrointes t Radiol, 1990; I S: 148 .

97.

Sfakianakis GN , AI-Sheikh W, Heal A et al. Compari so n of scintigraphy with In-Ill leucocytes and Ga-67 in the diagnosis of occult sepsis. 1 Nucl Med, 1982; 23: 6 18.

98.

Armbu ster TG , Georgen TG, Resnick D et al. Ut ility of bone scannin g in di sseminated coccidioidomycosis. 1 N ucl Med, 1977 ; 18: 450.

99.

Standalnik RC, Go ldstein E. Diagnostic va lue of Gallium and bone sca ns in evaluation of ex trapulmon ary coccidioidomycos is. Am Rev Resp Dis, 1980; 14: 149.

120. Munoz A, Schroger L, Bacellow H et al. Trends in the incidellCe of outcomes defining acquired immunodeficiency sy ndrome (AIDS) in the mul ticenter AIDS Co hort Study : 19851991. A m J Epide miol, 1993 ; 137: 423 .

100. Ok uyama S, Sato T,Sasaki M. Deliniation of aspergilloma and granulom a with radiogallium and radiostrontium. Sci Rep Res Inst Tohoku Univ. [Med), 1981 ; 28 : 1.

121. L ucas SB, Hounnon A, Peacock C et al. The mortality and pathology of HIV infection in a west African city. AIDS , 1993 ;7: 1569.

101. Rao GM, Guruprakash GH, B has kar G. Localization of Gallium-67 in aspergelloma (letter) J Nucl Med, 1979; 20: 900.

122. Murray JF, Felton CP, Garay SM et a l. Pulmonary complications of acquired immunodeficiency synd rome: a report of a National Heart, Lung and Blood Institute Workshop. N Engl 1 Med, 1984; 3 10: 1682.

102. Thadepalli H, Salem FA, Mandai AK et al. Pulmonary mycetoma due to Cocc idioides immiti s. Chest, 1978; 71: 429. 103. Firat Dayanikli B, Weissman AF, Wahl RL. Successful Gallium-67 imaging of North Ameri ca n pulmonary blastomycosis. ] Nucl Med, 1993; 34: 958 . 104. Brago F.J, Araujo EB , Camargo EE et al. Scintigraphic evaluation of my cetoma. Nucl Med Co mlllunication, 1993; 14: 814.

117. Krown SE, Metroka C, Wernz J. Kapos i's sarcoma in acquired immune defici ency sy ndrome: A proposal for uni form evaluation, response and staging cri teria. J Clin Oncol, 1989 ; 7: 120 J. 118. Ganz WI, Serafini AN . The diagnostic role of Nucl ear Med icine in the acquired immun odeficiency sy ndrome. J Nucl Med, 1989; 30: 1935. 119. Hoover DR, Saah AJ, Bacell ow H. Clini cal manifestations of AIDS in the era pneumocystis propbylaxis . N Engl J Med, 1993; 329: 1922.

123. Barron 1P, Birnbaum NS , Sharel B et al. PneuI1locystis carinii pneumonia studied by Gallium-67 scann ing. Rad iology, J985; 154: 791. 124. Kramer AE, Sanger JJ, Garay SM et a l. GalliuI1l-67 scans of the chest in patients with acquired illlmunodeficiency syndrom e. 1 Nucl Med, 1987; 28: 1107.

45

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

125. M ill J. Pneumocy sti s carinii and Toxo plasma gondii infection s in patients with AIDS. Rev Infect Dis, 1986; 8: 100 I.

126. Tow TWY, Rosen MJ , Teirstein AS. Normal chest roentgenogram as a prognostic factor in Pneumocystis carinii pneumo nia st udied by Gallium-67 scanning. Radiology, 1985; 154: 791.

127. Kram er EL, Sanger JJ, Ga ray SM e t al. D iagnostic implications of Ga-67 chest sca nn patterns in human immunodeficienc y virus-seropositive patients. Radiology, 1989; 170: 671.

128. Ganz WI , Ace W, Serafini AN. The diagnosti c us es of Nuclear Medicine in AIDS . In 32nd Proceedings of the So utheastern C hapter of the Society of Nuclear Medicine, Decision making in c linical N ucl ear Medicine XVII, 1991; p. I.

129. Tupl er RH , T urbin er EH . Scintigraphic di stribution of Pneumocyst is carinii pne umonia in AIDS treated with prophylactic inhaled pentamidine. Clin Nucl Med, 1991; 16: 772.

130. Bitra n J, Bekerman C, Weinstein R et al. Patterns of gallium67 scintig raphy in patients with acquired immunodefi c iency syndrome and AIDS re lated complex. J Nucl Med, 1987; 28: 1103.

131. Shelhamer JH, Og uiben e FP, Macher AM et al. Persistence of pneumonitis carinii lung tissue of acquired immunodefici ency sy ndrome patients treated for pneumocystis pneumonitis. Am Rev Resp D is, 1987; 130: 1161.

132. De Lorenzo JL, Mag uire GP, Worser GP et al. Persi stence of pneumonitis carinii pneumonia in the acquired immunodefi ciency sy ndrome : evalu ation of therapy by follow up transbronchial lun g biopsy. Chest, 1985 ; 88: 79 .

142. Daley CL, Small PM, Schecter GF et al. An outbreak of tuberculosis with acce lerated progression among persons infec ted with the human immunodeficiency virus - an analysis usi ng restriction fragment le ngth polymorphisms. N Engl J Med, 1992; 326: 23 I.

143. F ischl MA, U ttamchadani RB, Daikos GL et al. An outbreak of tuberculosis caused by multipl e drug res ista nt tubercle bacillii among patients with H IV infection. A nn Inter Med, 1992; 117: 77.

144. Ed lin BR, Tokars JI, Grieco MH et al. An o utbreak of multidrug-resistant tuberc ulo sis among hosp itali zed patients with th e acquired immunodefi ciency sy ndrome. N Eng l J Med, 1992 ; 326: 1514.

145. F isc hl MA, Daikos GL, Uttamchadani RB et al. C linical presentation and outcome of patients with HIV infecti o n and tuberculo sis caused by multipl e- res istant bacillii. A nn Inter Med, 1992; 117: 184.

146. Barber TW, Craven DF, McCabe WR. Bacteremi a due to mycobacterium tuberculosis in patients with human immunodeficiency virus infection . Medicine, 1990; 69: 375.

147. C hai sso n RE, Moore RD , Richman DD et al. Incidence and natural hi story of Mycobacterium avium co mpl ex infection s in patients with advanced HIV disease treated with ridovudi ne. Am Rev Resp Dis, 1991 ; 146: 285 .

148. Nightgale SD, Byrd LT, Southern PM et al. Incidence of Mycobacterium avium [ntracellulare co mpl ex bacteremia in human immunodefi c iency virus-positive patients. J lnf Dis, 1992; 165: 1082.

149. Haw kin s CC, Go ld JWM, Whimbey E et al. Mycobacterium avium complex infection s in patients w ith the acquired immunodeficiency sy ndrom e. Ann. Inte r. Med. , 1986; 105: 184.

133. Z uckier LS , Ongseng F, Goldfarb CR . Lymphocytic intersti-

150. Lee VW, Rosen MP, Baum A et al. AIDS related Kaposi sar-

tial pneumonitis: a cause of pulmonary Gallium-67 uptake in Child with acq uired immunodeficiency sy ndrom e . J Nucl Med, 1988; 29: 707.

coma: finding in thallium -20J scintig raph y. Am J Roentge nol , 1988; 151: 1233 .

134. CDC Classification sys tem for human immunodefici ency virus (H[V) infection in children und er 13 years of age. MMWR, 1987;36 :225.

135. Jos hi VV, O leske JM, Minnerfor AB et al. Pathology of suspected acq uired immune defici ency sy ndrome in children: a study of eight cases . Pediat Pathol, 1984; 2: 71.

136. S uster B, Akerman M, O renste in M et al. Pulmonary mani festation of AIDS: Review of 106 episodes. Radiology, 1986; 16 1: 87 .

137. Stover DE, White DA, Romano PA et al. Spectrum of pulmo nary di seases associated with the acquired immune deficiency sy ndrom e. Am J Med, 1985 ; 78: 429.

138. Ganz WI, Serafini AN, G anz SS et al. Diagnostic pattern of Ga-67 uptake in lymphocytic Interstitial Pneumonitis (A bstract) J Nucl Med, 1988; 29: 887.

139. Ganz WI, Cohe n D, Mallin et al. Gallium scintigraphic pat-

151. Edwards CL, Hayes RL. Scanning ma li g nant neop las ms with ga l1ium-67. JAMA, 1970; 212: 11 82.

152. A lazraki NP. Usefulness of ga llium imag in g in the evaluation of lun g cancer. Crit Rev Diagn Imag, 1980; 13: 249.

153. Teates CD, Bray ST, Williamson BR. Tumor detection with 67Ga citrate: A literature survey ( 1970-1978). C lin Nucl Med, 1978 ; 3: 456.

154. [to Y, O kuyam a S, Awono T et al : D iagnostic evaluation of 67Ga scanning in lun g cancer and other diseases. Radiology, L971 ; 101: 355.

155. Alazraki NP, Ramsdell JW, Taylor A et a l. Reliability of ga llium scan, chest radiography co mpared to medi ano scopy for evaluatiing mediastinal spread in lun g ca ncer. Am Rev Respir Dis, 1978; 117: 415.

156. De Meester TR, Bekerman C, Joseph JG et al. Ga llium-67 scanning for carcinoma of the lung. J T horac Cardiovasc Surg, 1976; 72: 699.

tern in lung CMV infection s (abstract). J Nucl Med, 1994; 35 : 133 .

157. Muhe von E. Scintigraphic demonstration of bronchial carc i-

140. Johnson MP, Chaisso n RE. Tuberculosis and HIV D isease. In

158. Hjelms E, Dyrbye M. Ga-67 scinti graphy in mali g nant lesions of the lung. Scand J Respir Dis, 1974; 55: 1.

AIDS C linical Review 1993/1994, Voldering PA, Jacobson MA, (eds) Marce l Dekker New York, 1994; p 73 .

141. T heu er CP, Hopewell PC, E lias D et al. H uman immunodeficienc y virus infection in tuberculosis patients. J Infect Dis, 1990 ; 162: 8.

46

noma using Ga-67 citrate. Thorax C hir, 197 1; 10: 440 .

159. Rahgeb AM, Elgazza r A-HH, Ibrahim AK et al. A com parative study between planar Ga-67 , T I-20 I images, chest x- ray CT in inoperabl e non -small cell carcinoma of the Lun g. C lin Nucl Med, 1995; 20: 426.

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

160. Hi gashi T, Wakao H, Nakamura A. Quantitative Ga-67 scannin g for predi cti ve value in primary lung carcinoma. J Nucl Med, 1980; 21: 628.

180. Wylie BR, SOllthee AE, Joshua DE et al. Ga llium scanning in the man agement of media stinal Hodgkin' s disease. Eu r 1 Haematol , 1989; 42: 344.

161. Langhammer H, G laubitt G, G rebe SF. Ga-67 for tumor sca nnin g . J Nucl Med; 1972; 13 : 25.

181. Front D, Ben-Haim S, Israel 0 et al. Lymphomas predictive val ue of Ga-67 sc intigraph y after treatment. Radiology, 1992 ; 182: 359.

162. Van del' Schoot JB , Gruen AS , Dejong J. Ga-67 scintigraphy in lun g di seases . Thorax, 1976; 27: 543 . 163. Abdel-Oayem HM , Scott A, M acapinlac H et al. Tracer imaging in lung Ca nce r. Eur J Nucl Med, 1994; 2 1: 57. 164. Kataoka M . Gall ium-67 citrate imaging for th e assessment of radi ation pneumonitis. Ann Nucl Med, J989 ; 3: 73 . 165. Richman SO, Levenso n SM, Bunn PA et al. Ga-67 accumulation in pulmonary les ion s associated with bleomycin tox icity. Can cer, 1975; 36: 1966. 166. Bohediewicz PJ. Visualisation of Microscopic Metastatic Hepatoma to Lung on Gallium scintigraphy. C lin Nucl Med , 1992; 17: 384. 167. SOllthee AE, Kaplan WO, Iochedson MS et al. Gallium imaging in metastati c and rec urre nt soft. ti ss ue sarcoma. 1 Nucl Med, 1992; 33: 1594.

182. Front D, Israel O. Nuclear Medi cine in monitorin g response to cancer treatment. J Nucl Med, 1989; 30: 1731. 183. Bar-S halom R, Israel 0 , Epe lbaum Ret al. Ga llium-67 sci ntigraphy in Lymphoma with bone in vo lve me nt. J Nucl Med, 1995; 36: 446. 184. Fox K, S ilfen D , Alavi A. App li cations of ga lliul1l-67 sci ntigraphy in th e manageme nt of patients with mali gnant lymphoma. J Nucl Med, 199 1; 32: 2299. 185. White LM, Gray BG, Ic hi se M et al. Sc intigraphi c flare in skeletal lymphoma. CI Nucl Med, 1993 ; 19: 66 1. 186. Kasales CJ, Langer JE, Yo un g CT et a1. Residual mass after treatment of primary cervical lymphoma: utility of gallium67 and MRI. Abdom Imagin g, 1994; 19: 274. 187. Canell os GP. Res idual di sease in lymph oma may not be residual di sease (editorial). 1 Clin O ncol , 1988; 6 : 93 1.

168. How man-Gil s R, Stevens M, Begin M. Role of gallium-67 in management of paedi atri c solid tumors. Aus Paediatr J, 1982; 18: 120.

188. Bekerman C, Hoffer PB, Bitran 10. The role of Ga llium-67 in the clini cal evalu ati on of cancer. Semin N ucl Med, 1984; 14: 296.

169. Tumeh SS, Rose nthal OS, Kapl an WD et al. Ly mphoma : Evalu ation with Ga-67 SPECT. Radiology, 1987; 164: 111.

189. Weeks JC, Yeap BY, Canellos GP et al. Va lue of fo llow up procedures in patients with large-cell lymphoma who achi eve a complete remi ss ion. Clin Oncol, 199 1; 9: 11 96.

170. Chen OCP, H un g G , Levine A et al. Correl ation of galliulll uptake and degree of malignancy in non- Hodgkin' s lymphoma (A bstract) 1 Nucl Med, 1986 ; 27 : 103 I. 171. Israel 0 , Front O. Beni gn Mediastinal and parahilar uptake of ga llium-67 in treated lympho ma. Do we ha ve all the answers? Editorial: 1 Nu cl Med, 1993; 34: 1330. 172. Fro nt D, Bar-Shalmon R, Epelbaum R et al. Early detection of Iympboma reccurence with Gallium-67 scintigraphy. J Nucl Med, 1993; 34: 2 101. 173. Zall ars LE, Nage l JS and Tumeh SS. Three cases demonstrating th e rol e of Ga llium scanning in relap sing Hodgkin's disease and Non-Hodgkin lymphoma. 1 Nucl Med, 1987; 28: 16 11. 174. Front D, Israel 0 , Epelbaum R et al. Ga-67 SPECT before and after treatment of lymphoma. Radiology, 1990; 175: 515. 175. Kaplan WD, Jochelson MS , Herman TS et al. Gallium-67 imaging a predictor of residual tumor viabi lity and clinical outcome in patients with diffuse large-ce ll lymphoma. 1 C lin Oncol, 1990 ; 8: 1966 . 176. Mc laughlin AF, Mayee MA, Greennough R et al. C urrent rol e of ga lliulll sca nnin g in the manage ment of lymphoma. Em J Nuc l Med , 1990; 16: 755.

190. Kaplan WD. Residual mass ancl negati ve ga llium scintigraphy in treated lymphom a: When is the ga ll ium scan realy negative? Editorial J Nucl Med, 1990; 3 1: 369 . 191. Bascom R, Iohns CJ. The natural hi story and management of sarcoido sis. Adv Intern Med, 1986; 3: 2 13. 192. Elias l A, Daniele RP. Systemi c sa rcoidosis. In Textbook of pulmo nary diseases,Baum GL, Wo linsky E,(eds), Boston, Littl e Brown, 1989; p. 663. 193. Alavi A (Guest Editor), Palevsky HI. Ga llium-67-ci trate scanning in th e assessment of disease activity in sarcoidosis (clinicopathological conferences). 1 Nucl Med, 1992; 33: 75 I. 194. Daniele RP, Rossman MD, Kern J A et al. Pathogenesis of sarcoidosis State of the art. Chest, 1986; 89: 174. 195. Thomas PO, Hunninghake GW. C urrent co ncepts of th e pathogenesis of sarcoidosis. Am Rev Resp Dis, 1987; 135 : 747. 196. Costabel U, Zaiss A, Wagner 01 e t al. Value of bronchoalveo lar la vage lymphocyti c sUbpopulations for the diagnosis of sarcoidosis. In Sarcoidosis and other granul omatous di sorders. G rassi C, Rizzato G, Porri E (eds) . Expec ta Med ica, Amsterdam 1988 ; p . 429. 197. Ainslie G, D u Gois RM, Poulter LW. Relation between immunocytological features of bronchoalveolar lavage flui d and clinical indices in sa rcoidosis. T horax , 1989; 44 : 50 I.

177. Kostakogl u L, Yeh SDJ , Portlock C et al. Validation of Galliull1 -67-c itrate Single P ho to n E mi ss ion Co mputed Tomography in biopsy-confirm ed redidual Hodgkin's di sease in the Mediastinum. 1 Nucl Med, 1992; 33: 345.

198. Poulte r LW, Rossi GA, Bjermer L et al. The value of bronchoalveolar lavage in the diagnosis and prognosis of sarcoidosis. E ur Repr Review, 1992; 2: 8; 75.

178. Is rael 0, Fro nt D, Epelbaum R et al. Residual mass and negative ga llium scintigraphy in treated lymphoma. 1 Nucl Med, 1990; 3 I: 365 .

199. Heshiki A, Sanfo rd L, Schatz SL et al. Gallium-67 citrate scanning in patients with pulmonary sarcoidosis. AJR, 1974; 122: 744.

179. Israe l O. Front D, Lam M et al. Gallium -67 imaging in moni torin g lymphoma respo nse to treatment. Cancer, 1988; 61 : 2439 .

200. Bekerman C, Sri don IP, P in sky S. T he ro le of ga llium-67 in the cl inical evaluation of sarcoidosis. Semin Roentgenol, 1985; 20: 400.

47

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

201. Sulavik SB, Spencer RP, Weed DA et al. Reconguition of distinctive patterns of gallium-67 distribution in sarcoidosis. 1 Nucl Med, 1990; 33: 1909.

221. Howard P Jr, Hahn HH, Palmer PL et al. Fever of unknown origin: A prospective study of 100 patients. Tex Med, 1977; 73: 56.

202. Sulavik SB, Palestro CJ, Spencer RP et al. Extrapulmonary si tes of radiogallium accumulation in sarcoidosis. Clin Nucl Med, 1990; 12: 876.

222. Larson EB, Feathrstone Hl, Petersdorf RG. Fever of undetermined origin : Diagnosis and follow up of 105 cases- I970-80. Medicine, 1982; 61: 269.

203. Baughman RP, Fernandez M, Bosken Ch et al. Comparison of Gallium-67 sca nning, bronchoalveolar lavage and serum angiotensin-con verting enzyme levels in pulmonary sarcoidosis predicting response to therapy. Am Rev Respir Dis, 1984; 129: 676.

223. Knockaert DC, Vanneste Ll, Vanneste SB et al. Fever of unknown origin in the 1980s: An update of the diagnostic spectrum. Arch Intern Med, L992; 152: 51.

204. Line BR, Hunninghake GW, Keogh BA et al. Gallium scanning to stage the alveolitis of sarcoidosis: correlation with clinical studies, pulmonary function studies and broncho-alveolar lavage. Am Rev Respir Dis, 1981; 123: 440. 205. Niden AH, Mishkin FS, Salem F et al. Prognostic significance of gallium ling scan in sarcoidosis. Ann NY Acad Sci, 1986; 465: 435. 206. Myslivecek M, Husak V, Kolek V et al. Absolute quantitation of gallium-67 citrate accumulation in the lungs and its importance for the evaluation of disease activity in pulmonary sarcoidosis . Eur 1 Nucl Med, 1992; 19: 1016. 207. Ramsay SC, Yeates MG, Burke W Ml et al. Quantitative pul mon ary gallium scanning in interstitial lung disease. Eur 1 Nucl Med, 1992; 19: 80. 208. Bourguet P, Delaval P, Nicol L et al. Absolute quantitation of pulmonary gallium-67 uptake in sarcoidosis. Sarcoidosis, 1985; 2: 70. 209. Bourguet P, Delaval P, Herry lY. Direct quantitation of thoracic gallium-67 uptake in sarcoidosis. J Nucl Med, 1986; 27: 1550. 210. Petersdorf RG, Beeson P. Fever of unexplained origin. Report of 100 cases . Medicine, 1961; 40: I. 211. Durak DT, Street AC. Fever of unknown origin-reexamined and redefined. Curr Clin Top Infect Dis, 1991; 11: 35. 212. Petersdo rf RG. Fever of unknown origin. An old friend revisited. (Editorial). Arch ofIntern Med, 1992; 152: 21. 213. Dale DC. The febrile patient. In Textbook of Medicine, Wyngaarden lB , Smith LS lr, Bennet JC (eds) . WB Saunders Company, Philadelphia, 1992; p. 1567. 214. Gelfand JA, Wolff SM. Fever of U nknown Origin. In Principles and Practice of infectious Diseases, Mandell JE, Bennett JE, Dolin R (eds), Churchill Livingstone, New York, 1995; p. 536. 215. McClung Hl. Prolonged fever of unknown origin in children. Am 1 Dis Child, 1972; 124: 544. 216. Pizzo PA, Lovejog FH, Smith DH. Prolonged fever in children . Review of 100 cases. Pediatrics, 1975; 55: 486 . 217. Lohr lA, Hendley 10. Prolonged fever of unknown origin: A record of experiences with 54 childhood patients . Clin Pediatr, 1977; 16: 768 .

224. Aduan R, Fauci A, Dale D et al. Prolonged fever of unknown origin. Clin Res, 1978; 26: 558A . 225. Brusch JI, Weinstein L. Fever of unknown origin. Med Clin North Am, 1988; 72: 1247. 226. Kazanjian PH. Fever of unknown origin : Review of 86 patients treated in community hospitals. Clin Infec Diseases, 1992; 15: 968. 227. Knockaert DC, Vanneste Ll, Boddaers Hl. Recurrent of episodic fever of unknown origin. Review of 45 cases and survey of the literature. Medicine, 1993; 72: 184. 228. Wolff SM, Fauci AS, Dale DC. Unusual etiologies of fever and their evaluation . Annu Rev Med, 1975; 26: 277. 229. Jocoby GA, Swartz MN. Fever of undetermin ed origin. N Engl 1 Med, 1973; 289: 1407 . 230. Knochaert DC. Fever of unknown origin , a literature survey. Acta Clin Belg, 1992; 47: 42. 231. Knochaert DC, Mortelman SA, De Roo MC et al. Clinical value of Gallium-67 scintigraphy in Evaluation of Fever of Unknown Origin. Clin Infect Dis, 1994; 18: 160 I. 232. Harvey WC, Podoloff DA, Kopp DT. 67-Gallium in 68 consecutive infection searches. 1 Nucl Med, 1975 ; 16: 2. 233. Biello DP, Levitt RG , Melson GL. The roles of gallium-67 scintigraphy, ultrasonography and computed tomography in the detection of abdominal abscesses. Semin Nucl Med, 1979; 9: 58 . 234. Moil' C, Robins RE. Role of ultrasonography, gallium scanning and computed tomography in the diagnosis of intraabdominal abscess. Am 1 Surg, 1982; 143: 582. 235. Nolla-Sole 1M, Mateo-Soria L, Rozadilla-Sacanell A et al. Role of technetium-99m diphosphonate and gallium-67 citrate bone scanning in the early diagnosis of infections spo ndylodiscitis. A comparative study. Ann Rheum Dis, 1992; 51: 665. 236. Gugliardi PD, Hoffer PB, Rosenfield AT. Correlative imaging in abdominal infection : an algorithmic approach using nuclear meciicine, ultrasound, and computed tomography. Semin Nucl Med, 1988; 18: 320. 237. Hoffer PB, Bekennan C, Henkin RE (eds). Galliulll-67 imaging. 10hn Wiley, New York, 1978; p. 90. 238. Larso n EB, Featherstone Hl, Petersdorf RG . Fever of undetermined origin: ciiagnosis and follow-up of 105 cases. 19701980. Medicine, 1982 ; 61: 269.

218. Shoen RP, Van Ommen RA. Fever of obscure origin. Am 1 Med, 1963; 34: 486.

239. Mc Neil Bl, Sanders R, Alderson PO et al. A prospective study of computed tomography, ultrasound and gallium imaging in patients with fever. Radiology, 1981 ; 139: 647.

219. Deal WB. Fever of unknown origin. Postgrad Med, 1972; 50: 182.

240. Habibian MR, Staab EV, Matthews HA. Gallium citrate Ga67 scans in febrile patients . lAMA , 1975 ; 233: 1073.

220. Frayha R, Uwaydah M. Fever of unknown origin. Lab Med 1, 1973; 26 : 49.

241. Kissim MW, Williamson RCN. Gallium-67 scannin g in pyrex.ia of unknown origin . Br Med 1, 1979; 2: 1330.

48

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

10. LIST OF ILLUSTRATIONS AND CASES Figures

Page

Fig. 1

Normal

3

Fig. 2

Increased renal activity (pyelonephritis)

3

Fig. 3

Normal

4

Fig. 4

Case of cirrhosis

4

Fig. 5

Normal (thorax)

6

Fig. 6 Fig. 7 Fig. 8

A-B Normal (abdomen), drug induced interstitial pneumonitis A-D Normal (breasts). Normal (nipples) A-C 3 cases of normal patterns (abdomen-colon)

6 7 8

Fig. 9

Normal whole-body (large joints, extremities, lacrimal glands, nasopharynx)

8

Fig. 10

Normal (nasopharynx)

8

Fig. 11 A-E 5 additional normal cases

9

Fig. 12 A-E Post traumatic osteomyelitis

10

Fig.13 A-B Sarcoilitis melitensis

11

Fig. 14 A-C Septic arthritis

11

Fig. 15 A-D Osteomyelitis, cellulitis

12

Fig. 16 A-E Infection of hip arthroplasty

13

Fig. 17 A-D Vertebral osteomyelitis

13

Fig. 18 A-C Post-therapy active osteomyelitis

14

Fig. 19 A-I Amputation, osteomyelitis (before and after treatment)

14- 15

Fig. 20 A-D Malignant external otitis (before and after treatment)

15

Fig. 21 A-B Myocarditis

16

Fig. 22 A-B Graft infection

17

Fig. 23 A-B Intrahepatic abscess

17

Fig. 24 A-B Lung and skin tuberculosis

18

Fig. 25 A-C Miliary tuberculosis

19

Fig. 26

AIDS-PCP

20

Fig. 27

AIDS-PCP

20

Fig. 28

AIDS-PCP during treatment

21

Fig. 29

Lymphocytic interstitial pneumonitis (LIP)

21

49

GALLIUM IMAGING IN CURRENT CLINICAL PRACTICE

Page

Figures Fig. 30

AIDS -CMV-PCP

22

Fig. 31

AIDS -TBC

22

Fig. 32

AIDS-MAC

23

Fig. 33

AIDS-MAC-CMV

23

Fig. 34 A-C Lung cancer

25

Fig. 35 A-F Skeletal metastases in lung cancer

25

Fig. 36 A-B Hepatoma

27

Fig. 37 A-D Case of a soft tissue sarcoma (fibrosarcoma)

27

Fig. 38

Hodgkin's disease

27

Fig. 39

Lymphoma

27

Fig. 40 A-H Lymphoma

28-29

Fig. 41 A-B Sarcoidosis (lambda sign)

30

Fig. 42

Sarcoidosis (panda pattern)

30

Fig. 43

Sarcoidosis (lambda and panda patterns)

31

Fig. 44 A-B Sarcoidosis (lambda and panda patterns)

31

Fig. 45 A-B Sarcoidosis (diffuse lung uptake)

31

Fig. 46 A-B Sarcoidosis (before and after treatment)

32

Fig. 47 A-B Sarcoidosis (before and after treatment)

32

Fig. 48 A-F Sarcoidosis (follow up)

33

Fig. 49 A-N Several cases of active sarcoidosis

34-35

Fig. 50 A-C Rheumatoid arthritis-interstitial pneumonitis

36

Fig. 51

36

Adult Respiratory Distress Syndrome (ARDS)

Fig. 52 A-C Drug induced interstitial pneumonitis

37

Fig. 53

37

Idiopathic active interstitial pneumonitis

Fig. 54 A-B Inactive idiopathic interstitial pneumonitis

37

Fig. 55 A-B Fever of Unknown Origin (FUO) (T-Lymphoma)

38

Fig. 56

FUO in AIDS patient (lymphoma)

39

Fig. 57

FUO (non-Hodgkin's lymphoma)

39

Fig. 58 A-B FUO. (sarcoidosis)

40

Fig. 59

41

50

FUO

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