Andor W. J. M. Glaudemans

Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis

Background— Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. Methods and Results— Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0–100). Conclusions— Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.

The Use of 18F-FDG-PET/CT for Diagnosis and Treatment Monitoring of Inflammatory and Infectious Diseases

FDG-PET, combined with CT, is nowadays getting more and more relevant for the diagnosis of several infectious and inflammatory diseases and particularly for therapy monitoring. Thus, this paper gives special attention to the role of FDG-PET/CT in the diagnosis and therapy monitoring of infectious and inflammatory diseases. Enough evidence in the literature already exists about the usefulness of FDG-PET/CT in the diagnosis, management, and followup of patients with sarcoidosis, spondylodiscitis, and vasculitis. For other diseases, such as inflammatory bowel diseases, rheumatoid arthritis, autoimmune pancreatitis, and fungal infections, hard evidence is lacking, but studies also point out that FDG-PET/CT could be useful. It is of invaluable importance to have large prospective multicenter studies in this field to provide clear answers, not only for the status of nuclear medicine in general but also to reduce high costs of treatment.

Accuracy of FDG-PET–CT in the Diagnostic Work-up of Vascular Prosthetic Graft Infection

OBJECTIVES To investigate the diagnostic accuracy of fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) compared with computed tomography (CT) scanning and added value of fused FDG-PET-CT in diagnosing vascular prosthetic graft infection. DESIGN Prospective cohort study with retrospective analysis. MATERIALS Twenty five patients with clinically suspected vascular prosthetic infection underwent CT and FDG-PET scanning. METHODS Two nuclear medicine physicians assessed the FDG-PET scans; all CT scans were assessed by two radiologists. Fused FDG-PET/CT were judged by the radiologist and the nuclear medicine physician. The concordance between CT and FDG-PET and the inter-observer agreement between the different readers were investigated. RESULTS Fifteen patients had a proven infection by culture. Single FDG-PET had the best results (sensitivity 93%, specificity 70%, positive predictive value 82% and negative predictive value 88%). For CT, these values were 56%, 57%, 60% and 58%, respectively. Fused CT and FDG-PET imaging also showed high sensitivity and specificity rates and high positive and negative values. Inter-observer agreement for FDG-PET analysis was excellent (kappa = 1.00) and moderate for CT and fused FDG-PET-CT analysis (0.63 and 0.66, respectively). CONCLUSION FDG-PET scanning showed a better diagnostic accuracy than CT for the detection of vascular prosthetic infection. This study suggests that FDG-PET provides a useful tool in the work-up for diagnosis of vascular prosthetic graft infection.

PET imaging of oestrogen receptors in patients with breast cancer

Oestrogen receptors are overexpressed in around 70% of all breast cancers, and are a target for endocrine therapy. These receptors can be visualised on PET with use of 16α-[(18)F]-fluoro-17β-oestradiol ((18)F-FES) as a tracer. Compared with biopsy, which enables assessment of individual sites, whole-body (18)F-FES-PET enables quantification of oestrogen-receptor expression in all metastases. In several studies, measurement of tumour protein expression in oestrogen receptors by (18)F-FES-PET, concurrent with biopsy, detected oestrogen-receptor-positive tumour lesions with a sensitivity of 84% and specificity of 98%. Roughly 45% of patients with metastatic breast cancer have discordant oestrogen-receptor expression across lesions (ie, (18)F-FES-positive and (18)F-FES-negative metastases). Low tumour (18)F-FES uptake in metastases can predict failure of hormonal therapy in patients with oestrogen-receptor-positive primary tumours. Finally, (18)F-FES-PET has shown that oestrogen-receptor binding capacity changes after intervention with hormonal drugs, but findings need to be confirmed. Factors other than oestrogen-receptor expression, including menopausal status and concomitant therapies, that can affect tumour (18)F-FES uptake must be taken into account.

Nuclear imaging in cardiac amyloidosis

Amyloidosis is a disease characterized by depositions of amyloid in organs and tissues. It can be localized (in just one organ) or systemic. Cardiac amyloidosis is a debilitating disease and can lead to arrhythmias, deterioration of heart function and even sudden death. We reviewed PubMed/Medline, without time constraints, on the different nuclear imaging modalities that are used to visualize myocardial amyloid involvement. Several SPECT tracers have been used for this purpose. The results with these tracers in the evaluation of myocardial amyloidosis and their mechanisms of action are described. Most clinical evidence was found for the use of 123I-MIBG. Myocardial defects in MIBG activity seem to correlate well with impaired cardiac sympathetic nerve endings due to amyloid deposits. 123I-MIBG is an attractive option for objective evaluation of cardiac sympathetic level and may play an important role in the indirect measurement of the effect of amyloid myocardial infiltration. Other, less sensitive, options are 99mTc-aprotinin for imaging amyloid deposits and perhaps 99mTc-labelled phosphate derivatives, especially in the differential diagnosis of the aetiology of cardiac amyloidosis. PET tracers, despite the advantage of absolute quantification and higher resolution, are not yet well evaluated for the study of cardiac amyloidosis. Because of these advantages, there is still the need for further research in this field.

FDG-PET/CT in infections: the imaging method of choice?

In the wake of the United States’ regulations on the use of F-fluorodeoxyglucose (FDG), the Spanish medicines regulatory agency last year stated that the use of FDG with PET, although well established in the areas of cancer, cardiac medicine and neurology, is not yet sufficiently established, within the European Union, in the diagnosis of infectious and inflammatory diseases, and therefore should not be authorised as a diagnostic radiopharmaceutical in these conditions. This position was contested by other EU member states and the dispute was eventually referred to the European Medicines Agency (EMEA). The EMEA Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of FDG outweigh its risks, and that its use should, therefore, be authorised across the EU. The CHMP deemed adequately documented a series of indications for the use of FDG in infectious or inflammatory diseases, namely:

The molecular imaging approach to image infections and inflammation by nuclear medicine techniques.

Inflammatory and infectious diseases are a heterogeneous class of diseases that may be divided into infections, acute inflammation and chronic inflammation. Radiological imaging techniques have, with the exception of functional MRI, high sensitivity but lack in specificity. Nuclear medicine techniques, by contrast, allow the in vivo detection in humans of different physiologic and pathologic phenomena and offer noninvasive tools to detect early pathophysiological changes before anatomical changes occur. In this review, we highlight the role of nuclear medicine in inflammation/infection with emphasis on molecular imaging for in vivo histological characterization of affected tissues for diagnostic purposes and follow-up of therapies. We also describe the clinical indications of all available radiopharmaceuticals in the light of the newly available guidelines.

Bone scintigraphy with (99m)technetium-hydroxymethylene diphosphonate allows early diagnosis of cardiac involvement in patients with transthyretin-derived systemic amyloidosis

Abstract Objective: To assess the usefulness of bone scintigraphy with 99mTechnetium-hydroxymethylene diphosphonate (99mTc-HDP) for the detection of cardiac involvement in a group of patients with ATTR amyloidosis in different phases of disease, to relate the findings to echocardiography, ECG and cardiac biomarkers, and to evaluate different bone scintigraphic techniques and calculation methods for quantification of the cardiac uptake and for correlation with echocardiographic features and cardiac biomarkers. Methods: Forty-one patients underwent clinical examinations, echocardiography, ECG, measurement of cardiac biomarkers and bone scintigraphy (planar imaging and SPECT-CT) and were subsequently subdivided into three groups: (1) carriers of an amyloidogenic TTR mutation, n = 11, (2) proven ATTR amyloidosis without echocardiographically-defined (mean wall thickness >12 mm) cardiac amyloidosis (AC), n = 19, and (3) ATTR amyloidosis with echocardiographically-defined cardiac amyloidosis, n = 11. Planar and SPECT-CT images were analyzed visually according to a routine scoring system (grade 0–3) and semi-quantitatively by heart-to-whole body (H/WB) and heart-to-skull (H/S) ratio on planar images and by a left ventricle-blood pool ratio on SPECT-CT images. Results: All patients with ATTR and echocardiographically-defined AC and none of the carriers showed high cardiac uptake on bone scintigraphy. Furthermore, 8 out of 19 patients with ATTR without echocardiographically-defined AC showed high cardiac uptake. Highest correlations were found between H/S ratio on planar bone scintigraphy with troponin T (r = 0.76, p < 0.0001) and H/WB ratio with left ventricular mass index (r = 0.73, p < 0.0001). Conclusions: Bone scintigraphy with 99mTc-HDP may detect cardiac involvement in patients with ATTR amyloidosis prior to echocardiographic evidence of cardiac involvement. Cardiac uptake on bone scintigraphy correlates with severity of cardiac involvement using echocardiography, ECG and cardiac biomarkers. Visual grading and calculation of H/S ratio on planar imaging are the preferred methods to assess cardiac uptake.

PET/MRI in infectious and inflammatory diseases: will it be a useful improvement?

The knowledge of disease mechanisms and the identification of markers of disease development and progression, and for therapy evaluation, are rapidly expanding. Early diagnosis, possible disease prevention and individual therapy stratification are important goals in health care. Nuclear medicine and radiology are potentially able to satisfy these increasing demands for diagnosis, prevention, pathophysiological understanding and treatment possibilities. An increasing number of biomarkers, drugs, antibodies and peptides, contrast agents and MRI sequences have also been developed for these purposes. Together with this continuing search for the “holy grail” radiopharmaceutical, the use of hybrid imaging is another important development in the field. A recent development in hybrid cameras is the introduction of combined PET and MRI. Despite the intriguing novelty, it is important to evaluate carefully, in a cost–benefit manner, the possible advantages and clinical applications of such an expensive tool.

Can Sequential 18F-FDG PET/CT Replace WBC Imaging in the Diabetic Foot?

White blood cell (WBC) scintigraphy is considered the nuclear medicine imaging gold standard for diagnosing osteomyelitis in the diabetic foot. Recent papers have suggested that the use of 18F-FDG PET/CT produces similar diagnostic accuracy, but clear interpretation criteria have not yet been established. Our aim was to evaluate the role of sequential 18F-FDG PET/CT in patients with a high suspicion of osteomyelitis to define objective interpretation criteria to be compared with WBC scintigraphy. Methods: Thirteen patients whom clinicians considered positive for osteomyelitis (7 with ulcers, 6 with exposed bone) were enrolled. The patients underwent 99mTc-exametazime WBC scintigraphy with acquisition times of 30 min, 3 h, and 20 h and sequential 18F-FDG PET/CT with acquisition times of 10 min, 1 h, and 2 h. A biopsy or tissue culture was performed for final diagnosis. Several interpretation criteria (qualitative and quantitative) were tested. Results: At final biopsy, 7 patients had osteomyelitis, 2 had soft-tissue infection without osteomyelitis, and 4 had no infection. The best interpretation criterion for osteomyelitis with WBC scintigraphy was a target-to-background (T/B) ratio greater than 2.0 at 20 h and increasing with time. A T/B ratio greater than 2.0 at 20 h but stable or decreasing with time was suggestive of soft-tissue infection. A T/B ratio of no more than 2.0 at 20 h excluded an infection. Thus, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for osteomyelitis were 86%, 100%, 100%, 86%, and 92%, respectively. For 18F-FDG PET/CT, the best interpretation criterion for osteomyelitis was a maximal standardized uptake value (SUVmax) greater than 2.0 at 1 and 2 h and increasing with time. A SUVmax greater than 2.0 after 1 and 2 h but stable or decreasing with time was suggestive of a soft-tissue infection. An SUVmax less than 2.0 excluded an infection. 18F-FDG PET at 10 min was not useful. Using these criteria, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for osteomyelitis were 43%, 67%, 60%, 50%, and 54%, respectively. Combining visual assessment of PET at 1 h and CT was best for differentiating between osteomyelitis and soft-tissue infection, with a diagnostic accuracy of 62%. Conclusion: 18F-FDG PET/CT, even with sequential imaging, has a low diagnostic accuracy for osteomyelitis and cannot replace WBC scintigraphy in patients with diabetic foot.