Mike Sathekge

Dual time-point FDG PET-CT for differentiating benign from malignant solitary pulmonary nodules in a TB endemic area

OBJECTIVE Fluorodeoxyglucose (FDG)-positron emission tomography (PET) is an accurate non-invasive imaging test for differentiating benign from malignant solitary pulmonary nodules (SPNs). We aimed to assess its diagnostic accuracy for differentiating benign from malignant SPNs in a tuberculosis (TB)-endemic area. METHODS Thirty patients, 22 men and 8 women, mean age 60 years, underwent dual time point FDG-PET/computed tomography (CT) imaging, followed by histological examination of the SPN. Maximum standard uptake values (SUVmax) with the greatest uptake in the lesion were calculated for two time points (SUV1 and SUV2), and the percentage change over time per lesion was calculated (%DSUV). Routine histological findings served as the gold standard. RESULTS Histological examination showed that 14 lesions were malignant and 16 benign, 12 of which were TB. SUVmax for benign and malignant lesions were 11.02 (standard deviation (SD) 6.6) v. 10.86 (SD 8.9); however, when tuberculomas were excluded from the analysis, a significant difference in mean SUV1max values between benign and malignant lesions was observed (p=0.0059). Using an SUVmax cut-off value of 2.5, a sensitivity of 85.7% and a specificity of 25% was obtained. Omitting the TB patients from analysis resulted in a sensitivity of 85.7% and a specificity of 100%. Mean %DSUV of benign lesions did not differ significantly from mean %DSUV of malignant lesions (17.1% (SD 16.3%) v. 19.4% (SD 23.7%)). Using a cut-off of %DSUV>10% as indicative of malignancy, a sensitivity of 85.7% and a specificity of 50% was obtained. Omitting the TB patients from the analysis yielded a sensitivity of 85.7% and a specificity of 75%. CONCLUSION Our findings suggest that FDG-PET cannot distinguish malignancy from tuberculoma and therefore cannot reliably be used to reduce futile biopsy/thoracotomy.

Use of 18F-FDG PET to Predict Response to First-Line Tuberculostatics in HIV-Associated Tuberculosis

This prospective pilot study examined the relationship between the severity and extent of tuberculosis as assessed by 18F-FDG PET at the time of diagnosis and response to treatment or treatment failure at 4 mo. Methods: Twenty-four consecutive HIV patients with newly diagnosed tuberculosis were prospectively included in the study after providing written informed consent. Seventeen patients had pulmonary tuberculosis, and 7 patients had extrapulmonary tuberculosis. All patients underwent whole-body 18F-FDG PET; none were receiving tuberculostatics at the time of the PET investigation. After undergoing 18F-FDG PET, the patients were given tuberculosis treatment (the classic triad: isoniazid, rifampicin, and ethambutol) and reevaluated for treatment response: monthly assessment of sputum, smears, and cultures in patients who proved positive at the time of diagnosis, and clinical and radiologic (when relevant) assessment 4 mo after treatment instigation in all patients. Quantitative 18F-FDG PET results (averaged 18F-FDG maximum standardized uptake value [SUVmax] derived from early and delayed imaging), percentage change in SUVmax, and number of involved lymph node bastions were related to treatment response or failure. Results: Age, sex, viral load, CD4 status, duration of HIV treatment, SUVmax of lung and splenic lesions (early and delayed), and percentage change in SUVmax of lymph nodes were not significantly different between responders and nonresponders (P ≥ 0.3). In contrast, SUVmax of involved lymph node bastions (both early and delayed) and number of involved lymph node bastions were significantly higher in nonresponders than in responders (respective P values were 0.03, 0.04, and 0.002). Using a cutoff of 5 or more involved lymph node bastions, responders could be separated from nonresponders with a sensitivity, specificity, and positive and negative predictive value of, respectively, 88%, 81%, 70%, and 93%. Using a cutoff of 8.15 for early SUVmax of lymph node bastions and of 10 for late SUVmax of lymph node bastions, a comparable sensitivity of 88% came at the cost of a lower specificity: 73% and 67%, respectively. Conclusion: In this pilot study, a cutoff of 5 or more involved lymph node bastions allowed for separation of tuberculostatic responsive and nonresponsive tuberculosis-infected HIV patients with a sensitivity of 88%, a specificity of 81%, and a negative predictive value of 93%. These findings warrant confirmation by additional studies on larger cohorts of patients.

Combined 18F-Fluoride and 18F-FDG PET/CT Scanning for Evaluation of Malignancy: Results of an International Multicenter Trial

18F-FDG PET/CT is used in a variety of cancers, but because of variable rates of glucose metabolism, not all cancers are reliably identified. 18F− PET/CT allows for the acquisition of highly sensitive and specific images of the skeleton. We prospectively evaluated combined 18F−/18F-FDG as a single PET/CT examination for evaluation of cancer patients and compared it with separate 18F− PET/CT and 18F-FDG PET/CT scans. Methods: One hundred fifteen participants with cancer were prospectively enrolled in an international multicenter trial evaluating 18F− PET/CT, 18F-FDG PET/CT, and combined 18F−/18F-FDG PET/CT. The 3 PET/CT scans were performed sequentially within 4 wk of one another for each patient. Results: 18F−/18F-FDG PET/CT allowed for accurate interpretation of radiotracer uptake outside the skeleton, with findings similar to those of 18F-FDG PET/CT. In 19 participants, skeletal disease was more extensive on 18F− PET/CT and 18F−/18F-FDG PET/CT than on 18F-FDG PET/CT. In another 29 participants, 18F− PET/CT and 18F−/18F-FDG PET/CT showed osseous metastases where 18F-FDG PET/CT was negative. The extent of skeletal lesions was similar in 18 participants on all 3 scans. Conclusion: This trial demonstrated that combined 18F−/18F-FDG PET/CT shows promising results when compared with separate 18F− PET/CT and 18F-FDG PET/CT for evaluation of cancer patients. This result opens the possibility for improved patient care and reduction in health-care costs, as will be further evaluated in future trials.

Preclinical Evaluation of 68Ga-Labeled 1,4,7-Triazacyclononane-1,4,7-Triacetic Acid-Ubiquicidin as a Radioligand for PET Infection Imaging

Antimicrobial peptides such as ubiquicidin (UBI) are believed to differentiate between mammalian and bacterial or fungal cells. 99mTc-UBI29-41 was previously tested for detecting infection in humans using SPECT. For the present study, the UBI fragment UBI29-41 (TGRAKRRMQYNRR) was conjugated to 1,4,7-triazacyclononane-triacetic acid (NOTA), radiolabeled with 68Ga, and investigated in a rabbit infection model. Methods: 68Ga was obtained from a 1.85-GBq 68Ge/68Ga generator. New Zealand White rabbits were anesthetized with ketamine/medetomidine before tracer administration and placed in a clinical PET/CT scanner. 68Ga-1,4,7-triazacyclononane-1,4,7-triacetic-acid-ubiquicidin29-41 (68Ga-NOTA-UBI29-41) was formulated in saline solution, and 101 ± 41 MBq were administered intravenously. The tracer distribution was studied by PET/CT imaging in animals (a) that were healthy, (b) bearing muscular Staphylococcus aureus infections and turpentine oil-induced muscular inflammations, and (c) bearing ovalbumin-induced lung inflammations. Static PET/CT imaging was performed at different time intervals up to 120 min after injection. For calculation of target-to-nontarget ratios, standardized uptake values were normalized against healthy thigh muscle, representing nontargeted tissue. Results: PET/CT images of healthy animals showed predominant distribution in the kidneys, liver, and bladder; heart and spleen showed moderate, declining uptake, only. The biologic half-life in blood was 29 min. Urinary accumulation of 68Ga-NOTA-UBI29-41 peaked at 3.8 ± 0.91 percentage injected dose per gram (%ID) at 120 min, and 88 ± 5.2 %ID was recovered in total urine. 68Ga-NOTA-UBI29-41 imaging in (b) selectively visualized the muscular infection site and was differentiated from sterile inflammatory processes. Standardized uptake value ratios for muscles (infected/inflamed) were 2.9 ± 0.93, 2.9 ± 0.50, 3.5 ± 0.86, and 3.8 ± 0.90 at 5, 30, 60, and 90 min after injection, respectively. Rabbit lungs with asthma showed insignificant uptake. Conclusion: 68Ga-NOTA-UBI29-41 was strongly localized in bacteria-infected areas and minimally detected in a sterile inflammation area in rabbit muscles. The findings propose this compound to be an excellent first-line PET/CT tracer to allow the distinguishing of infection from inflammation.

Advances in imaging of tuberculosis: the role of ¹⁸F-FDG PET and PET/CT.

Purpose of review To review the main applications, advantages and limitations of 18F-FDG PET and PET/computed tomography (CT), and some other tracers in imaging of tuberculosis (TB). Recent findings In pulmonary TB, granulomas typically demonstrate increased 18F-FDG uptake, and areas of active TB can be differentiated from old or inactive disease by dual time point imaging. However, standardized uptake value measurements are high in both TB and malignant lesions, with significant overlap that limits their usefulness. In extrapulmonary TB, 18F-FDG PET detects more tuberculous lesions than CT, is of value in assessing response to tuberculostatic treatment, and helps in diagnosing spinal infection and identifying TB-related spondylitis; however, again, differentiation of malignant versus TB lymph node involvement is problematic. 18F-FDG PET can also be considered a marker of disease status in patients with HIV and TB co-infection. Overall, evaluation of treatment response is potentially the most important clinical application of 18F-FDG PET in TB, owing to its ability to distinguish active from inactive disease. Summary 18F-FDG PET and PET/CT may assist early diagnosis and facilitate differentiation between malignancies and TB, identification of extrapulmonary TB, staging of TB, and assessment of treatment response.

Development and prospects of dedicated tracers for the molecular imaging of bacterial infections.

Bacterial infections have always been, and still are, a major global healthcare problem. For accurate treatment it is of upmost importance that the location(s), severity, type of bacteria, and therapeutic response can be accurately staged. Similar to the recent successes in oncology, tracers specific for molecular imaging of the disease may help advance patient management. Chemical design and bacterial targeting mechanisms are the basis for the specificity of such tracers. The aim of this review is to provide a comprehensive overview of the molecular imaging tracers developed for optical and nuclear identification of bacteria and bacterial infections. Hereby we envision that such tracers can be used to diagnose infections and aid their clinical management. From these compounds we have set out to identify promising targeting mechanisms and select the most promising candidates for further development.

Antimicrobial peptides: their role as infection-selective tracers for molecular imaging.

Antimicrobial peptides (AMPs) are a heterogeneous class of compounds found in a variety of organisms including humans and, so far, hundreds of these structures have been isolated and characterised. They can be described as natural microbicide, selectively cytotoxic to bacteria, whilst showing minimal cytotoxicity towards the mammalian cells of the host organism. They act by their relatively strong electrostatic attraction to the negatively charged bacterial cells and a relatively weak interaction to the eukaryote host cells. The ability of these peptides to accumulate at sites of infection combined with the minimal hosts cytotoxicity motivated for this review to highlight the role and the usefulness of AMPs for PET with emphasis on their mechanism of action and the different interactions with the bacterial cell. These details are key information for their selective properties. We also describe the strategy, design, and utilization of these peptides as potential radiopharmaceuticals as their combination with nuclear medicine modalities such as SPECT or PET would allow noninvasive whole-body examination for detection of occult infection causing, for example, fever of unknown origin.

68 Ga-PSMA imaging of metastatic breast cancer

Ga-labelled prostate-specific membrane antigen (PSMA) is rapidly emerging as a significant step forward in the diagnosis of recurrent prostate cancer, based on the fact that PSMA is a type II transmembrane protein with high expression in prostate carcinoma cells [1, 2]. Recently it has been demonstrated to accumulate in metastatic clear-cell renal cell carcinoma [3] and interestingly several studies have provided evidence that PSMA is also expressed in the tumour-associated vasculature of primary breast cancers and distant metastases [4, 5]. We report the case of a 33-year-old woman with metastatic breast carcinoma who underwent Ga-PSMA and F-FDG PET/CT imaging for restaging and evaluation of the most appropriate therapeutic option. Images demonstrated intense and extensive skeletal uptake in the axial and appendicular skeleton with liver metastases. Concordance of Ga-PSMA and F-FDG lesions suggests that Ga-PSMA may provide helpful prognostic information. Furthermore, Ga-PSMA-avid metastatic sites may in future aid in selecting tumours with high PSMA expression for PSMA-directed therapy.

Positron emission tomography in patients suffering from HIV-1 infection

This paper reviews currently available PET studies performed either to improve our understanding of the pathogenesis of HIV-1 infection or to assess the value of PET imaging in the clinical decision making of patients infected with HIV-1 presenting with AIDS-related opportunistic infections and malignancies. FDG PET has shown that HIV-1 infection progresses by distinct anatomical steps, with involvement of the upper torso preceding involvement of the lower part of the torso, and that the degree of FDG uptake relates to viral load. The former finding suggests that lymphoid tissues are engaged in a predictable sequence and that diffusible mediators of activation might be important targets for vaccine or therapeutic intervention strategies. In lipodystrophic HIV-infected patients, limited available data support the hypothesis that stavudine-related lipodystrophy is associated with increased glucose uptake by adipose tissue as a result of the metabolic stress of adipose tissue in response to highly active antiretroviral treatment (HAART). Finally, in early AIDS-related dementia complex (ADC), striatal hypermetabolism is observed, whereas progressive ADC is characterized by a decrease in subcortical and cortical metabolism. In the clinical setting, PET has been shown to allow the differentiation of AIDS-related opportunistic infections and malignancies, and to allow monitoring of side effects of HAART. However, in patients suffering from HIV infection and presenting with extracerebral lymphoma or other human malignancies, knowledge of viraemia is essential when interpreting FDG PET imaging.

Prevalence and pattern of brown adipose tissue distribution of 18F-FDG in patients undergoing PET-CT in a subtropical climatic zone.

BackgroundThe uptake of 18F-FDG in brown adipose tissue (BAT) may have important implications in understanding the pathophysiology of BAT and obesity. Because of the thermal implications of BAT uptake of 18F-FDG, this study aimed to contribute to existing knowledge by assessing patients scanned in a subtropical environment with particular reference to ethnicity. Patients and methodsA retrospective study was carried out to determine the prevalence and pattern of BAT uptake in patients undergoing 18F-FDG PET-CT imaging in a PET facility located in a subtropical climatic zone. Standardized uptake values were obtained for regions of BAT uptake of 18F-FDG, and the distribution pattern was assessed according to anatomical region, sex, age, BMI and ethnicity. ResultsFollowing a reveiw of a total of 386 scans, 38 patients showed BAT uptake of 18F-FDG (9.85%), with the mass and activity of BAT being greater in women than in men (11.95 and 6.88%, respectively). BAT uptake of 18F-FDG in the neck/supraclavicular, axillary and mediastinal regions was greater in adults whose BMI was less than 18 kg/m2. However, perirenal BAT activity was shown to be greater in obese individuals. The frequency of BAT uptake of 18F-FDG was 55% in winter as against 45% during summer (P<0.012). There was no statistical difference in BAT uptake between black and white patients. ConclusionThis study shows the pattern and prevalence of BAT in patients in a subtropical environment. Although the average seasonal temperatures are higher in a subtropical climate, a seasonal variation in BAT expression was observed, although there were no differences with respect to patient ethnicity.