Prosthetic joint infections: radionuclide state-of-the-art imaging.

Prosthetic joint replacement surgery is performed with increasing frequency. Overall the incidence of prosthetic joint infection (PJI) and subsequently prosthesis revision failure is estimated to be between 1 and 3%. Differentiating infection from aseptic mechanical loosening, which is the most common cause of prosthetic failure, is especially important because of different types of therapeutic management. Despite a thorough patient history, physical examination, multiple diagnostic tests and complex algorithms, differentiating PJI from aseptic loosening remains challenging. Among imaging modalities, radiographs are neither sensitive nor specific and cross-sectional imaging techniques, such as computed tomography and magnetic resonance imaging, are limited by hardware-induced artefacts. Radionuclide imaging reflects functional rather than anatomical changes and is not hampered by the presence of a metallic joint prosthesis. As a result scintigraphy is currently the modality of choice in the investigation of suspected PJI. Unfortunately, there is no true consensus about the gold standard technique since there are several drawbacks and limitations inherent to each modality. Bone scintigraphy (BS) is sensitive for identifying the failed joint replacement, but cannot differentiate between infection and aseptic loosening. Combined bone/gallium scintigraphy (BS/GS) offers modest improvement over BS alone for diagnosing PJI. However, due to a number of drawbacks, BS/GS has generally been superseded by other techniques but it still may have a role in neutropenic patients. Radiolabelled leucocyte scintigraphy remains the gold standard technique for diagnosing neutrophil-mediated processes. It seems to be that combined in vitro labelled leucocyte/bone marrow scintigraphy (LS/BMS), with an accuracy of about 90%, is currently the imaging modality of choice for diagnosing PJI. There are, however, significant limitations using in vitro labelled leucocytes and considerable effort has been devoted to developing alternative radiotracers, such as radiolabelled HIGs, liposomes, antigranulocyte antibodies and fragments, as well as more investigational tracers such as radiolabelled antibiotics, antimicrobial peptides, bacteriophages and thymidine kinase. On the other hand, positron emission tomography (PET) is still growing in the field of PJI imaging with radiotracers such as (18)F-fluorodeoxyglucose (FDG), (18)F-FDG white blood cells and (18)F-fluoride. But unfortunately this superb tomographic technique will only receive full acceptance when specific PET uptake patterns can be successfully developed. The emergence of hybrid modality imaging using integrated single photon emission computed tomography (SPECT) and PET with computed tomography (SPECT/CT and PET/CT) may also have a contributing role for more accurate assessment of joint replacement complications, especially combined with new radiotracers such as (68)Ga and (64)Cu. Finally, in searching for infection-specific tracers, currently there is no such diagnostic agent available.

Multi-modality imaging of transient osteoporosis of the hip.

Transient osteoporosis of the hip (TOH), also referred to as bone marrow edema syndrome (BMES) of the femoral head and neck, is an uncommon and therefore underdiagnosed benign skeletal disorder, affecting primarily women, particularly in their last trimester of pregnancy, and middle-aged men. The disease is characterized by self-limiting hip pain and radiographically evident osteopenia, but these radiographic findings can sometimes be delayed. In the early phase, the main diagnostic dilemma lies in differentiating TOH from osteonecrosis of the femoral head (ONFH). Conventional radiographs, Tc-99m bone scans (multiphase, SPECT or SPECT/CT) and MRI scans from 10 male patients with 12 TOH episodes were retrospectively and independently reviewed by two nuclear medicine physicians and a musculoskeletal radiologist. The purpose was to identify a typical imaging pattern, and secondly, to reliably distinguish TOH from ONFH. In the early phase of TOH, conventional radiography of the hip could not sufficiently detect focal osteopenia. But in all 10 patients (mean age 45 years, range, 34-62), bone scans and MRI scans demonstrated a similar pattern of diffuse hyperaemia, bony uptake, and bone marrow edema in the femoral head and neck, extending to and ending with a sharp demarcation at the intertrochanteric region. Additionally, neither SPECT nor SPECT/CT nor MRI revealed any cold area or crescent-shaped subchondral defect in the femoral head, indicating ONFH. In some cases there was a joint effusion in varying degree. In 9 patients, an uneventful recovery was eventually observed. Scintigraphically diffuse hyperaemic and/or homogeneous osseous uptake in femoral head and neck extending to the intertrochanteric region, as well as the recently introduced term transient bone marrow edema syndrome (BMES) of the hip on MRI, are probably both expressions of the same pathophysiological mechanism, and pathognomonic for TOH. Hopefully, recognizing this highly specific imaging pattern will exclude in the future more aggressive skeletal diseases like ONFH, severe arthritis, osteomyelitis or even malignancy.

Hybrid imaging of complicating osteomyelitis in the peripheral skeleton.

Diagnosing complicating osteomyelitis (COM) is clinically challenging. Laboratory tests are of limited utility, and other than isolation of the offending organism, diagnostic imaging tests are of paramount importance. Nuclear Medicine techniques play an important role in noninvasive evaluation of osteomyelitis, using both single-photon emission tomography (SPECT) and positron emission tomography (PET) radiopharmaceuticals. It is well-known that those conventional imaging modalities are not performing well in the distinction between soft-tissue and deep bone infection due to the lack of anatomical information. These difficulties have been overcome, to a great extent, with the introduction of in-line SPECT-CT and PET-CT systems which have revolutionized the field of diagnostic medical imaging. Hybrid imaging is especially useful in sites of suspected COM with underlying structural bone alterations. The first clinical studies with these integrated hybrid machines in the field of COM, including metallic implants imaging, are highly promising. In summary, WBC/AGA SPECT-CT and FDG-PET-CT seem to be the most accurate hybrid imaging modality for COM of the peripheral bone. However, there are still false positives, especially in aseptic tibial nonunions and/or metallic implants, as well as in the immediate postoperative setting. Furthermore, there is a lack of well-designed large multicentre prospective studies. Hopefully, in the future, the complementary use of morphological and functional hybrid imaging modalities may overcome some of the challenges faced in the assessment of COM.

Expanding role of 18F-fluoro-D-deoxyglucose PET and PET/CT in spinal infections.

(18)F-fluoro-D -deoxyglucose positron emission tomography ([(18)F]-FDG PET) is successfully employed as a molecular imaging technique in oncology, and has become a promising imaging modality in the field of infection. The non-invasive diagnosis of spinal infections (SI) has been a challenge for physicians for many years. Morphological imaging modalities such as conventional radiography, computed tomography (CT), and magnetic resonance imaging (MRI) are techniques frequently used in patients with SI. However, these methods are sometimes non-specific, and difficulties in differentiating infectious from degenerative end-plate abnormalities or postoperative changes can occur. Moreover, in contrast to CT and MRI, FDG uptake in PET is not hampered by metallic implant-associated artifacts. Conventional radionuclide imaging tests, such as bone scintigraphy, labeled leukocyte, and gallium scanning, suffer from relatively poor spatial resolution and lack sensitivity, specificity, or both. Initial data show that [(18)F]-FDG PET is an emerging imaging technique for diagnosing SI. [(18)F]-FDG PET appears to be especially helpful in those cases in which MRI cannot be performed or is non-diagnostic, and as an adjunct in patients in whom the diagnosis is inconclusive. The article reviews the currently available literature on [(18)F]-FDG PET and PET/CT in the diagnosis of SI.

Myocardial perfusion imaging in the elderly: a review.

Coronary artery disease is a major cause of morbidity and mortality in the elderly population. As a result of ageing of the population and better medical, interventional and surgical treatment of patients with coronary artery disease, more and more elderly patients are referred to the cardiology department for diagnostic work-up. Stress testing, in combination with myocardial perfusion imaging, is routinely used in elderly patients, a population in which the diagnosis of significant coronary artery disease is often challenging because of atypical symptomatology. Since the introduction of technetium-99m ligands for myocardial perfusion imaging, it is possible to perform electrocardiogram-gated perfusion imaging. This not only improves the specificity of the test for coronary artery disease detection, but also enables the simultaneous assessment of left ventricular functional parameters. This article briefly overviews the possible stress modalities, diagnostic accuracy and prognostic value of myocardial perfusion imaging in elderly patients.

188Re-HDD/lipiodol therapy for hepatocellular carcinoma: a phase I clinical trial.

UNLABELLED: The aim of this study was to investigate the pharmacokinetics, organ dosimetry, and toxicity after the intraarterial administration of (188)Re-labeled 4-hexadecyl-1,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol/lipiodol ((188)Re-HDD/lipiodol) for palliative treatment of hepatocellular carcinoma (HCC). A secondary objective was to document the response. METHODS: A mean activity of 3.60 GBq (188)Re-HDD/lipiodol (range, 1.86-4.14 GBq) was administered to 11 patients (16 treatment sessions) via a transfemoral catheter. The pharmacokinetic and dosimetric data were collected by means of venous blood samples, urine collections, and 4 or 5 gamma-scintigraphies over 76 h. Absorbed doses to the various organs were calculated according to the MIRD formalism, using the MIRDOSE3.1 software. The toxicity was assessed until 6 wk after administration by means of the Common Toxicity Criteria scale. The response was evaluated on MRI and by monitoring of the tumor marker. RESULTS: A fast blood clearance of the injected activity was observed with a calculated effective half-life of 7.6 +/- 2.2 h (+/-SD) in blood. The predominant elimination of the activity was through urinary excretion with a mean renal clearance of 44.1% +/- 11.7% (+/-SD) of the injected activity within the 76 h after administration. Fecal elimination was negligible. The calculated whole-body effective half-life was 14.3 +/- 0.9 h (+/-SD). The absorbed dose to the liver tissue, the lungs, the kidneys, and the thyroid was 4.5 +/- 1.9, 4.1 +/- 1.2, 0.9 +/- 0.7, and 0.3 +/- 0.1 Gy, respectively. Treatment was well tolerated, except in 2 patients. One Child B patient experienced a worsening of his liver dysfunction (hyperbilirubinemia) and another patient experienced dyspnea and coughing. Response assessment on MRI showed 1 case of partial response, disease stabilization in 11 treatments, and progressive disease in 1 treatment. In 5 of 8 treatment sessions with an initially elevated alpha-fetoprotein, a reduction (range, 19%-90%) was observed 6 wk later. CONCLUSION: After the intraarterial administration of 3.60 GBq (188)Re-HDD/lipiodol, a fast clearance of the activity appearing in the blood is observed and the predominant elimination is through urinary excretion. The tolerance as well as the preliminary response rates of the present phase I study are encouraging.

Radiolabeled lipiodol therapy for hepatocellular carcinoma in patients awaiting liver transplantation: pathology of the explant livers and clinical outcome.

BACKGROUND: Liver transplantation has become an important curative treatment option for hepatocellular carcinoma (HCC). Criteria for transplantation are strict and, therefore, it is crucial that patients awaiting transplantation do not suffer disease progression. One of the therapeutic options to achieve disease stabilization is neoadjuvant radiolabeled lipiodol treatment. This study aimed to document the dropout rate on the waiting list, the pathological findings on the explant livers, and the long-term outcome of patients treated with radionuclide therapy while awaiting transplantation. METHODS: Patients eligible for transplantation were treated with 2.1 GBq (131)I-lipiodol or 4.1 GBq (188)Re-HDD/lipiodol by transfemoral catheterization of the hepatic arteries. Tumor necrosis was assessed in the explant livers and follow-up data, such as dropout from the waiting list, recurrence, and survival following transplantation were retrospectively documented. RESULTS: In 5 of 22 explants, necrosis exceeded 90%. Two patients died while on the waiting list (10%) and 4 of 20 transplanted patients (20%) suffered recurrent disease. The overall recurrence-free survival was 19.7 months (range, 1.75-56), with a mean follow-up of 20.1 months. CONCLUSION: Our data support the evaluation on larger patient numbers to confirm the benefit of radiolabeled lipiodol in candidates for liver transplantation who are suffering from HCC.

Biologic dosimetry of 188Re-HDD/lipiodol versus 131I-lipiodol therapy in patients with hepatocellular carcinoma.

UNLABELLED: One approach to treatment of primary hepatocellular carcinoma (HCC) is intraarterial injection of (131)I-lipiodol. Although clinical results have been positive, the therapy can be improved by using (188)Re instead of (131)I as the radionuclide. (188)Re is a high-energy beta-emitter, has a shorter half-life than (131)I, and has only low-intensity gamma-rays in its decay. The present study compared the cytotoxic effect of the radionuclide therapy in HCC patients treated with (131)I-lipiodol and (188)Re-4-hexadecyl 2,2,9,9-tetramethyl-4,7-diaza-1,10-decanethiol (HDD)/lipiodol. To this end, dicentric chromosomes (DCs) were scored in metaphase spreads of peripheral blood cultures. The equivalent total-body dose was deduced from the DC yields using an in vitro dose-response curve. METHODS: Twenty (131)I-lipiodol treatments and 11 (188)Re-HDD/lipiodol treatments were performed on, respectively, 16 and 7 patients with inoperable HCC. Patients received a mean activity of 1.89 GBq of (131)I-lipiodol or 3.56 GBq of (188)Re-HDD/lipiodol into the liver artery by catheterization. For each patient, a blood sample was taken during the week before therapy. A blood sample was also taken 7 and 14 d after administration for the patients treated with (131)I-lipiodol and 1 or 2 d after administration for the patients treated with (188)Re-HDD/lipiodol. RESULTS: The mean DC yield of (188)Re-HDD/lipiodol therapy (0.087 DCs per cell) was significantly lower than that of (131)I-lipiodol therapy (0.144 DCs per cell) for the administered activities. Corresponding equivalent total-body doses were 1.04 Gy for (188)Re-HDD/lipiodol and 1.46 Gy for (131)I-lipiodol. Data analysis showed that, in comparison with (131)I-lipidol, (188)Re-HDD/lipiodol yielded a smaller cytotoxic effect and a lower radiation exposure for an expected higher tumor-killing effect. CONCLUSION: (188)Re is a valuable alternative for (131)I in the treatment of HCC with radiolabeled lipiodol, and a dose escalation study for (188)Re-HDD/lipiodol therapy is warranted.

99mTc ciprofloxacin imaging for the diagnosis of infection in the postoperative spine.

BACKGROUND: The non-invasive assessment of postoperative spinal infections can pose a substantial diagnostic challenge, especially in the presence of orthopaedic devices. In contrast to white blood cell scanning, which is of limited use in the spine, the low uptake of 99mTc ciprofloxacin into normal bone marrow, combined with its claimed bacterial specificity, makes it, theoretically, an ideal candidate for evaluating postoperative spinal infections. AIM: This study aimed to evaluate 99mTc ciprofloxacin planar and single photon emission tomography (SPET) imaging in relation to microbiological diagnosis in the postoperative spine. METHODS: Only patients with a microbiologically confirmed diagnosis were included in this analysis. Planar imaging was performed at 1, 3 and 24 h, and SPET was performed at 3 h post-injection of 370 MBq 99mTc ciprofloxacin. Images were scored by two independent, certified, nuclear medicine physicians, blinded for the final diagnosis. RESULTS: Within the first 22 consecutive patients with microbiological diagnosis, there were nine deep infections. Sensitivity, specificity and accuracy at visual scoring were, respectively, 67%, 77%, 73% (1 h), 78%, 69%, 73% (3 h), and 56%, 92%, 77% (24 h) for planar imaging, and 100%, 54%, and 73% for SPET. CONCLUSION: In contrast to white blood cell scanning, SPET with Tc ciprofloxacin is sensitive in evaluating infections in the postoperative spine. Sensitivity is higher for SPET than for planar imaging. However, the results presented prove that its specificity is limited, especially in patients who have recently (< 6 months) undergone surgery. Taken this limitation into account, we advise planar and SPET imaging at 3 h post-injection and at an interval of at least 6 months after surgery to minimize the chance for false positives.

SPECT/CT of osteitis condensans ilii: one-stop shop imaging.

A 16-year-old, nonpregnant, healthy, and sportive teenager suffers from intermittent low back pain. Pelvic x-ray complemented by bone-SPECT/CT demonstrated an uncommon benign condition called osteitis condensans ilii. In the early phase, it is of paramount importance to distinguish osteitis condensans ilii from sacroiliitis or ankylosing spondylitis. This case report highlights the incremental value of performing one-stop shop hybrid SPECT/low-dose CT bone imaging in diagnosing and managing this rare benign skeletal condition.

Clinical trial of specific imaging of infections.

OBJECTIVE: For several decades Ga citrate, technetium-99m ((99m)Tc) or (111)In-labelled leukocytes have been used for imaging the inflammatory process. Unfortunately, these radiopharmaceuticals are not infection-specific markers. In preclinical settings, radiolabelled antimicrobial peptides (AMPs), such as UBI 29-41 seem to be highly infection-specific and even high doses of these peptides have shown neither toxicity nor side effects in animals. METHODS: In this study we present data of a recent clinical trial carried out with the (99m)Tc labelled antimicrobial peptide UBI 29-41 ((99m)Tc-UBI 29-41) regarding its sensitivity, specificity, and accuracy in detecting various types of infections in 148 patients. The outcome of the trial with (99m)Tc-UBI 29-41 is compared with that of five other trials. RESULTS: Preparation of (99m)Tc-UBI 29-41 as a kit formulation is an easy, rapid, and reproducible process, and the tracer is very well tolerated by patients. The radiopharmaceutical has proven to be very stable and after injection into patients the biodistribution (renal clearance) and dosimetry seem to be favourable over other infection imaging radiopharmaceuticals. In this preliminary human study, patients with fever of unknown origin, osteomyelitis, diabetic foot, prosthesis infection, septic arthritis, or bacteraemia were successfully imaged with (99m)Tc-UBI 29-41 scintigraphy. CONCLUSION: (99m)Tc-UBI 29-41 is a promising agent for the specific detection of infections in humans because of its high sensitivity (96.3%), specificity (94.1%), and accuracy (95.3%) with high positive predictive (95.1%) and negative predictive values (95.5%).

Future diagnostic agents.

Timely and specific diagnosis of infectious diseases can be clinically challenging but essential for the patient's outcome. Laboratory tests, such as a blood culture or urine specimen, can detect the responsible micro-organism but cannot discriminate between sterile inflammatory disease and truly infectious disease. Imaging tests, like scintigraphic techniques, can pinpoint the infection in the body. There are a number of clinical scintigraphic tests from which to choose, and no single test is optimal for the various presentations of clinical infectious disease. The currently available radiopharmaceuticals often are not capable of distinguishing between sterile inflammation, and bacterial or fungal infections. Neutrophil-mediated processes, characteristic for both inflammatory and infectious processes, can be targeted in situ by radiolabeled leukocytes, antibodies or fragments, or even by cytokines and (18)F-fluorodeoxyglucose. Unfortunately those techniques are not infection-specific markers, and ongoing research is in progress to tackle this problem. The most promising option in this respect is directly targeting bacteria or fungi with radiolabeled antibiotics or antimicrobial peptides. These theoretically highly infection-specific radiopharmaceuticals could be used for monitoring the success of antimicrobial therapy of infectious disease. Although results from preclinical experiments and pilot studies in patients are promising, radiolabeled anti-infective agents are not currently in routine clinical use and studies are continuing to prove their effectiveness for diagnostic imaging of infections in the future.

F-18 FDG PET/CT in the diagnosis of fever of unknown origin.

METHODS: The utility of Fluorine-18 fluorodeoxyglucose positron emission tomography/CT in identifying the causal source was assessed in this retrospective study. A total of 68 patients (33 men, 35 women; age range, 23-91 years) with fever of unknown origin (FUO) underwent a positron emission tomography/computed tomography (PET/CT) scan. PET/CT was considered helpful when abnormal results allowed an accurate diagnosis, based on histopathology, microbiologic assays, or clinical and imaging follow-up. RESULTS: PET/CT demonstrated suspected pathologic foci of Fluorine-18 fluorodeoxyglucose (F-18 FDG) uptake in 41 patients (60%), in 38 of these 41 patients (93%) F-18 FDG PET/CT helped in identifying the causal source, including infection in 25 patients, inflammation in 11 patients, a benign neoplasm in 1 patient, and in 1 patient rejection of a pancreas transplant. In 27 negative F-18 FDG PET/CT studies, no focal pathologic disease was diagnosed in the follow-up. In 6 of these 27 patients, a systemic disease without a focal manifestation was the cause for FUO. In the remaining 21 patients, fever and other signs subsided during follow-up. CONCLUSION: Overall 56% of the F-18 FDG PET/CT studies contributed in the identification of the source in patients with FUO, and elevated erythrocyte sedimentation rate and C-reactive protein (positive predictive value 93%). When systemic diseases are excluded F18-FDG PET/CT has a high negative predictive value for focal etiologies of FUO (negative predictive value 100%).

FDG hepatic superscan caused by massive breast cancer invasion.

A 46-year-old woman who was treated in the past for locally advanced breast cancer, presented with signs of acute liver failure. FDG PET revealed a massive hot liver with increased activity without any pathologic FDG uptake elsewhere in the body. Therefore, the term hepatic superscan was chosen because intense diffuse hepatic FDG uptake was seen in combination with a surprisingly low cardiac and in minor degree of low brain uptake, similar to the superscan pattern encountered in conventional skeletal scintigraphy. This very unusual finding was the indicator of extensive hepatic involvement caused by breast cancer.

Subcutaneous metastasis from an occult esophageal cancer detected by PET-CT.

We describe a unique case of an occult esophageal cancer patient without any significant symptomatology, which initially presented with a subcutaneous metastasis in the thigh. Eventually, FDG PET-CT unmasked the primary tumor of unknown origin.

Radionuclide imaging of spinal infections.

BACKGROUND: The diagnosis of spinal infection, with or without implants, has been a challenge for physicians for many years. Spinal infections are now being recognised more frequently, owing to aging of the population and the increasing use of spinal-fusion surgery. DISCUSSION: The diagnosis in many cases is delayed, and this may result in permanent neurological damage or even death. Laboratory evidence of infection is variable. Conventional radiography and radionuclide bone imaging lack both sensitivity and specificity. Neither in vitro labelled leucocyte scintigraphy nor 99mTc-anti-granulocyte antibody scintigraphy is especially useful, because of the frequency with which spinal infection presents as a non-specific photopenic area on these tests. Sequential bone/gallium imaging and 67Ga-SPECT are currently the radionuclide procedures of choice for spinal osteomyelitis, but these tests lack specificity, suffer from poor spatial resolution and require several days to complete. [18F]Fluoro-2-deoxy-D-glucose (FDG) PET is a promising technique for diagnosing spinal infection, and has several potential advantages over conventional radionuclide tests. RESULTS: The study is sensitive and is completed in a single session, and image quality is superior to that obtained with single-photon emitting tracers. The specificity of FDG-PET may also be superior to that of conventional tracers because degenerative bone disease and fractures usually do not produce intense FDG uptake; moreover, spinal implants do not affect FDG imaging. However, FDG-PET images have to be read with caution in patients with instrumented spinal-fusion surgery since non-specific accumulation of FDG around the fusion material is not uncommon. CONCLUSION: In the future, PET-CT will likely provide more precise localisation of abnormalities. FDG-PET may prove to be useful for monitoring response to treatment in patients with spinal osteomyelitis. Other tracers for diagnosing spinal osteomyelitis are also under investigation, including radiolabelled antibiotics, such as 99mTc-ciprofloxacin, and radiolabelled streptavidin-biotin complex. Antimicrobial peptides display preferential binding to microorganisms over human cells and perhaps new radiopharmaceuticals will be recruited from the array of human antimicrobial peptides/proteins. In experiments with Tc-ubiquicidin-derived peptides, radioactivity at the site of infection correlated well with the number of viable bacteria present. Finally, radiolabelled antifungal tracers could potentially distinguish fungal from bacterial infections.