Withdrawal of indium-111: implications for white-cell imaging. The nuclear medicine community must act Ranju T. Dhawana and Adrien M. Petersb Nuclear Medicine Communications 2014, 35:789–791 a

St Mary’s Hospital, Imperial College NHS Healthcare Trust, London and Brighton Sussex Medical School, UK


Correspondence to Adrien M. Peters, MA, MD, DSc, FMedSci, Audrey Emerton Building, Brighton Sussex Medical School, Eastern Road, Brighton BN2 5BE, UK Tel: + 44 1273 523360; fax: + 44 1273 523366; e-mail: [email protected] Received 19 December 2013 Accepted 17 March 2014

The recent withdrawal by GE Healthcare of indium-111 (111In) products is disappointing. It is driven by an economic imperative prompted by the perception of industry that medical demand for this radionuclide is waning and that 99mTc-HMPAO is an easily available favourable like-for-like replacement for white cell labelling. GE Healthcare has recently relocated its UK manufacturing base to Arlington Heights, USA, mandating quality control procedures to be instituted before the facility can supply 111In products to the UK and Europe. Presumably, these are considered logistically arduous to undertake for resuming supply of a product seen as a diminishing priority by industry. We believe this reflects a retrograde step. Although 111In is not an everyday bread-and-butter isotope, it is an important radionuclide for cell and protein labelling for a variety of applications, many of which are researchrelated – for example, evaluation of blood cell kinetics and pathophysiology of lymphoedema. More disappointing, however, are the reasons for the dwindling use of the radionuclide and consequent lack of initiative from the scientific community to intervene and negotiate with industry on this important issue. The diminishing overall use of 111In reflects three trends in nuclear medicine; first, less prospective research activity in general; second, an increasing interest in the development of PET radiopharmaceuticals; and third, a move towards the exclusive use of 99mTc-HMPAO for labelling leucocytes for imaging infection and inflammation. It is this last-mentioned trend on which this editorial focusses. While doing so, we recognize the potential value and use of 18F-FDG PET/computed tomography (CT) in inflammation imaging, but that is a separate discussion. Many nuclear medicine departments have over the past few years abandoned 111In for labelling leucocytes in favour of 99mTc-HMPAO, embracing the latter as the more convenient agent, boasting superior physical and imaging characteristics. We believe this move stems from an oversimplified interpretation of the kinetic basis of infection imaging and the flawed assumption that 99m Tc-HMPAO and 111In are interchangeable as leucocyte labels, differing only in physical characteristics. In contrast, we believe that with the exception of 0143-3636 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

inflammatory bowel disease (IBD), for which 99m Tc-HMPAO is clearly the preferred label, 111In should in general continue to be used for imaging infection and inflammation using labelled leucocytes. In reaching this conclusion, several important physiological and physical considerations need to be considered. A key physiological variable is the rate of localization of granulocytes in inflammatory foci. We stress ‘granulocytes’ as these are the effective ingredients in a white cell preparation using current routine methodology. Granulocytes leave blood exponentially with a half time of about 7 h, corresponding to a rate constant of 0.1/h [1,2]. It therefore follows that granulocytes accumulate in enclosed inflammatory foci with the same rate constant, implying that accumulation is not complete until about 24 h after injection. Orthopaedic infection, especially involving prosthetic joints (probably now the most common clinical indication for a leucocyte scan), is usually relatively long-standing and therefore generally associated with a mixed leucocyte infiltrate, including mononuclears, and a relatively subacute inflammatory response. These pathophysiological considerations mandate the use of delayed (24 h) imaging to allow for maximum granulocyte accumulation. Imaging at 24 h with 99mTc is less helpful not only because of the physical limitation of a short half-life but, pertinently, also because once a 99mTc-labelled granulocyte has migrated into an inflammatory focus and been engulfed by a local macrophage the radionuclide is lost to the circulation because of unstable intracellular binding [2]. 111In, in contrast, remains firmly macrophage-bound [1,3] and, through its long half-life, lends itself to delayed imaging. A further consideration in orthopaedic infections is the desirability for template marrow imaging to distinguish between physiological and pathological isotope signals, especially in bone that has been surgically violated with consequent alterations in marrow distribution. The simultaneous (rather than sequential) use of 99m Tc-nanocolloid and 24 h 111In-labelled leucocyte imaging presents an elegant method for accomplishing this in one sitting [4–7]. The simultaneous dual-isotoperendered detailed SPECT/CT maps generated can be compared favourably without the potential for any variation from spatial orientation on sequential imaging. DOI: 10.1097/MNM.0000000000000138

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The situation is different in IBD in which a long physical half-life or dissociation of the label are not critical factors. Migrating granulocytes rapidly pass through the bowel wall and enter the bowel lumen without undergoing macrophage engulfment [8]. Here, in fact, an earlier window of visualization requires better physical image characteristics to distinguish temporally (and spatially) between granulocytes in bowel wall and intraluminal granulocytes undergoing distal luminal transit. Therefore, 99mTc-HMPAO is ideally suited to this circumstance and facilitates a rapid diagnosis. Indeed, it is tailor-made for IBD. The kinetic situation is somewhat more complex in complicated IBD when pus collects and drains, or fistulates; therefore, imaging protocols must be designed to address the diagnostic question. The disadvantage of 99mTc-HMPAO in these settings is the appearance of nonspecific activity in bile, urine, and intestines, which often complicates image interpretation for detection of a communicating abscess. This is unfortunate because nowadays the only abdominal abscesses beyond the eyes of the radiologist are generally communicating abscesses because of their spontaneous decompression. In contrast, 111In performs very well in cases of communicating abscesses [9]. The vast majority of circulating granulocytes are neutrophils. Although they make up a small proportion of circulating granulocytes, eosinophils can now be isolated in almost pure form through magnetic bead technology. In this technique, a purified granulocyte preparation containing magnetic beads bearing specific antineutrophilic antibodies is placed in a column within a magnetic field. Having attached to the neutrophils, the beads are ‘pulled out’ from the cell population by the magnetic force, leaving the eosinophils to be collected in the eluate. In other words, the neutrophils are positively selected while the eosinophils are negatively selected. The viability of cells is questionable following positive selection because of the effects of antibody binding. The technique is therefore well suited to eosinophils and has opened the way for new studies on eosinophil kinetics, which, it turns out, are significantly different from neutrophil kinetics [10]. For example, eosinophils have a longer intravascular lifespan and a lower 45-min blood recovery compared with neutrophils. They also repeatedly recirculate between blood and, as yet, unidentified tissues [10], giving the blood recovery profile a sawtoothed appearance. Importantly, relevant to the choice of leucocyte label for infection imaging, it has also emerged that 99mTc-HMPAO is highly selective for eosinophils. First shown by Puncher and Blower [11] using an autoradiographic approach, this selectivity can now be more accurately quantified using purified cell populations. Thus, in the presence of equal numbers of eosinophils and neutrophils, 20-fold more 99mTc-HMPAO activity labels eosinophils compared with neutrophils [12]. The contribution of eosinophils to an inflammatory infiltrate is

therefore another variable potentially affecting the choice between 111In and 99mTc-HMPAO for leucocyte scanning. It has been the long-standing clinical impression of the authors that 99mTc-HMPAO-labelled leucocytes give a disproportionately higher target-to-background bowel signal in IBD compared with 111In-labelled leucocytes, even allowing for differences in photon flux. Bone marrow also appears more prominent with 99mTc-HMPAO. As in mucosal inflammation in general, eosinophils are important players in IBD [13,14]; thus, this impression would be explained by the selectivity of 99mTc-HMPAO for eosinophils. The strong bone marrow signal also provides a clue to the site through which blood eosinophils recirculate. In contrast, this selectivity of 99m Tc-HMPAO for eosinophils does not help in imaging of orthopaedic infection, as these granulocytes are not important in such infections. The larger paradox here is that, although the physics and physiology of 99mTc-HMPAO leucocyte imaging are suited to IBD imaging, its clinical use in the IBD context is diminishing. Refinement of MRI techniques of the small bowel, application of terminal ileal intubation at colonoscopy, and use of capsule endoscopy have meant that there are fewer diagnostic conundra requiring white cell imaging in IBD. In contrast, in the evaluation of orthopaedic infection pertaining to postsurgical/prosthetic sites, conventional imaging (CT/MRI) is relatively less informative and nuclear medicine offers an important trouble-shooting test. In our view, the optimal approach to imaging such orthopaedic infection (in the postoperative/prosthetic field) is dual isotope imaging with 111In-leucocytes and 99mTc-nanocolloid [4–7]. 111 In-leucocytes are kinetically suited to this evaluation, whereas the addition of SPECT-CT can embellish the technique with structural detail that enables more exact comparisons of the white cell/marrow distribution to map the discordance with greater confidence. Although there are no robust head-to-head comparisons in the literature on 99mTc-HMPAO compared with 111In/marrow in the postoperative/prosthetic infection cohort (and perhaps these are needed), there is no sound physiological premise for a like-for-like replacement of 111In with 99m Tc-HMPAO in this patient cohort. A final reflection is that, although the withdrawal of 111In is regrettable, the linked withdrawal of 111In-oxine is perhaps not. In the authors’ view (albeit controversial), oxine is more toxic to cells compared with tropolone [15,16], and with regard to labelling efficiency tropolone is probably less sensitive to plasma in the labelling medium compared with oxine. Because 111In and oxine are already complexed in the delivered product, the concentration of oxine in the medium in which the cells are suspended for labelling cannot be controlled, and increases (μg/MBq) as the 111In decays during the period since shipment. In contrast, 111In and tropolone solution

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In withdrawal Dhawan and Peters 791

are added separately. Platelets indeed seem to benefit from labelling with 111In-tropolonate, showing higher recovery, longer survival, and less early liver uptake (a marker of ‘collection injury’) compared with platelets labelled with 111In-oxinate [17]. Although we are not aware of any direct in-vivo comparisons with respect to leucocytes, from long personal experience, we believe tropolone is superior to oxine for cell labelling in general. Therefore, maintenance of the supply of 111In-chloride is more critical than the supply of the 111In-oxine complex. The current situation with the withdrawal of 111In product lines by GE Healthcare, however, makes the availability of this valuable clinical imaging test vulnerable to the inherent risks of having a single port of call in a sole monopoly supplier. The consequent lack of resilience that may arise in this context needs to be addressed. GE Healthcare has a long-standing constructive partnership with the nuclear medicine community in the UK and Europe. Along with other key industrial partners, GE Healthcare benefits from the European clinical market while the imaging sector and our patients benefit from the innovations that industry brings to clinical practice. Key decisions of this nature, which have a bearing on clinical practice and the availability of tests, should engage a stakeholder consultation process and not simply be dictated by narrow focus on the economics of a single product line. For its part, the nuclear medicine community in the UK and Europe must reflect on the flawed perception in some quarters (which has some bearing on the decision by industry) that 99mTc-leucocytes are a like-for-like replacement for 111In-leucocytes in orthopaedic infections. Indeed, as discussed in this article, they are not. Therefore, as stakeholders, the EANM and BNMS must open dialogue with our industrial partners to redress this situation. The quality control procedures to certify Arlington Heights, USA, for supply to the Europe/UK may be logistically demanding but should not absolve GE Healthcare from its commitment to the European and British Nuclear Medicine Community.

Acknowledgements Conflicts of interest

There are no conflicts of interest.

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Withdrawal of indium-111: implications for white-cell imaging. The nuclear medicine community must act.

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