Noise-Induced Variability of Immuno-PET with Zirconium-89-Labeled Antibodies: an Analysis Based on Count-Reduced Clinical Images

Purpose

Positron emission tomography (PET) with Zirconium-89 (Zr-89)-labeled antibodies can be used for in vivo quantification of antibody uptake. Knowledge about measurement variability is required to ensure correct interpretation. However, no clinical studies have been reported on measurement variability of Zr-89 immuno-PET. As variability due to low signal-to-noise is part of the total measurement variability, the aim of this study was to assess noise-induced variability of Zr-89 -immuno-PET using count-reduced clinical images.

Procedures

Data were acquired from three previously reported clinical studies with [⁸⁹Zr]antiCD20 (74 MBq, n?=?7), [⁸⁹Zr]antiEGFR (37 MBq, n?=?7), and [⁸⁹Zr]antiCD44 (37 MBq, n?=?13), with imaging obtained 1 to 6 days post injection (D0–D6). Volumes of interest (VOIs) were manually delineated for liver, spleen, kidney, lung, brain, and tumor. For blood pool and bone marrow, fixed-size VOIs were used. Original PET list mode data were split and reconstructed, resulting in two count-reduced images at 50 % of the original injected dose (e.g., 37 MBq_74inj).Repeatability coefficients (RC) were obtained from Bland-Altman analysis on standardized uptake values (SUV) derived from VOIs applied to these images.

Results

The RC for the combined manually delineated organs for [⁸⁹Zr] antiCD20 (37 MBq_74inj) increased from D0 to D6 and was less than 6 % at all time points. Blood pool and bone marrow had higher RC, up to 43 % for 37 MBq_74inj at D6. For tumor, the RC was up to 42 % for [⁸⁹Zr]antiCD20 (37 MBq_74inj). For [⁸⁹Zr]antiCD20, (18 MBq_74inj), [⁸⁹Zr]antiEGFR (18 MBq_37inj), and [⁸⁹Zr]antiCD44 (18 MBq_37inj), measurement variability was independent of the investigated antibody.

Conclusions

Based on this study, noise-induced variability results in a RC for Zr-89-immuno-PET (37 MBq) around 6 % for manually delineated organs combined, increasing up to 43 % at D6 for blood pool and bone marrow, assuming similar biodistribution of antibodies. The signal-to-noise ratio leads to tumor RC up to 42 %.

     

Practice, efficacy, and costs of thyroid nodule evaluation: a retrospective study in a Dutch university hospital.

Fine-needle aspiration (FNA) of thyroid nodules has markedly reduced the role of thyroid scintigraphy. This is often limited to nondiagnostic or follicular (tumor) FNA classifications. In this study, we evaluated the efficacy and cost of such a strategy in a university center. From 1992-1998, 995 aspirations were done in 667 patients with palpable nodules. FNA was classified as malignant, suspicious, follicular, benign or inadequate. The Gold standard was surgery or extended follow-up, including physical examination, FNA, and/or ultrasound (US) with a time interval of half a year. Cost analysis was limited to operated patients. The first FNA yielded inadequate results in 28%, decreasing to 6% after 4 aspirations (n = 42). The other final classifications were: 76%, benign; 14%, follicular; 2%, suspicious; 1%, malignant (n = 7). Scintigraphy ((99m)Tc) suggested a hyperfunctioning autonomous nodule (adenoma) in 12% and 3% of the inadequate and follicular subset, respectively. Surgery for diagnostic reasons (n = 105) yielded 24 malignancies (23%): in 47% of suspicious, 12% of the follicular, and in all with malignant FNA. Postoperative morbidity occurred in 14 (5 laryngeal nerve paralyses) with benign histology. Major cost drivers were surgery and hospitalization: mean costs per patient amounting to Euro 3.311 in case of benign histology. We conclude that current work-up is still unable to prevent unnecessary surgery for benign thyroid nodules. Thyroid scintigraphy proved most productive in the inadequate FNA category. Improvement of the diagnostic process using immunohistochemistry and/or imaging is needed from the patient's and society's perspective.     

Hexokinase III, cyclin A and galectin-3 are overexpressed in malignant follicular thyroid nodules

Background Distinguishing malignant thyroid nodules in patients with follicular cytology by fine‐needle aspiration (FNA) remains problematic. The large majority of thyroid nodules (> 85%) are overtreated. Therefore, a clear need exists to develop more accurate initial diagnostic tests for follicular thyroid nodules. Galectin‐3 is the most recent promising marker to aid discrimination between benign and malignant thyroid lesions; however, this biomarker can be absent in follicular malignancies. Aims This study was undertaken to determine whether additional biomarkers can help to discriminate between benign and malignant thyroid nodules. Methods Surgical specimens of 36 patients with benign (n = 12) and malignant (n = 24) thyroid nodules showing follicular cytology were assessed by immunohistochemistry for the expression of galectin‐3 and novel biomarkers. Results Expression of hexokinase III (HK III) (P = 0·000) cyclin A (P = 0·002) and galectin‐3 (P = 0·003) differed significantly between benign and malignant thyroid nodules. HK III had a sensitivity of 79% [95% confidence interval (CI) 60–91] and a specificity of 100% (95% CI 76–100) in predicting malignancy. Galectin‐3 had a sensitivity of 79% (95% CI 56–91) and a specificity of 75% (95% CI 47–91) in predicting malignancy. Combining HK III, cyclin A and galectin‐3 in a parallel test increased the sensitivity to 96% (95% CI 80–99) while the specificity remained at a high level of 75% (95% CI 47–91). Leave‐one‐out cross‐validation demonstrated a stable predictive validity of a model based on HK III, cyclin A and galectin‐3. Conclusions In this study, we have demonstrated that in addition to galectin‐3, HK III and cyclin A profiles could be important biomarkers in predicting malignancy in follicular thyroid nodules. The use of these biomarkers may allow an accurate preoperative diagnosis of thyroid cancer, which can be cost saving and may avoid serious morbidity such as vocal cord paralysis. The value of the suggested biomarkers warrants further evaluation in a large prospective study on cytological samples of follicular thyroid nodules.     

Median frequency--a new parameter for predicting defibrillation success rate

STUDY HYPOTHESIS: Current American Heart Association guidelines recommend immediate defibrillation of ventricular fibrillation. When this is unsuccessful, there are no guidelines to help determine the optimum time at which to defibrillate after the administration of an alpha-adrenergic agonist. Previous studies have shown that the median frequency of the ventricular fibrillation ECG signal correlates with myocardial perfusion during CPR. We hypothesized that median frequency could predict the success of defibrillation and thus accurately determine the most appropriate time at which to defibrillate during ventricular fibrillation. STUDY POPULATION: Twenty-two mixed-breed swine weighing more than 15 kg were studied. METHODS: Ventricular fibrillation was induced electrically, and the ventricular fibrillation ECG signal was analyzed using fast Fourier analysis. After ten minutes of ventricular fibrillation, mechanical CPR was begun. After three minutes of CPR, the animals received one of three alpha-adrenergic agonists and CPR was continued. Defibrillation was attempted three and one-half minutes after drug administration. The average median frequency 20 seconds before defibrillation was calculated. Sensitivity and specificity of median frequency with respect to defibrillation success were determined. RESULTS: A median frequency of 9.14 Hz had a sensitivity of 100% and a specificity of 92.31% in predicting the results of defibrillation in this model. CONCLUSION: The median frequency may serve as a valuable parameter to guide defibrillation therapy during ventricular fibrillation.     

Real-Time Polymerase Chain Reaction for Detection of Schistosoma DNA in Small-Volume Urine Samples Reflects Focal Distribution of Urogenital Schistosomiasis in Primary School Girls in KwaZulu Natal,South Africa

Schistosoma haematobium eggs and Schistosoma DNA levels were measured in urine samples from 708 girls recruited from 18 randomly sampled primary schools in South Africa. Microscopic analysis of two 10-mL urine subsamples collected on three consecutive days confirmed high day-to-day variation; 103 (14.5%) girls had positive results at all six examinations, and at least one positive sample was seen in 225 (31.8%) girls. Schistosoma-specific DNA, which was measured in a 200-μL urine subsample by using real-time polymerase chain reaction, was detected in 180 (25.4%) cases, and levels of DNA corresponded significantly with average urine egg excretion. In concordance with microscopic results, polymerase chain reaction results were significantly associated with history of gynecologic symptoms and confirmed highly focal distribution of urogenital schistosomiasis. Parasite-specific DNA detection has a sensitivity comparable to single urine microscopy and could be used as a standardized high-throughput procedure to assess distribution of urogenital schistosomiasis in relatively large study populations by using small sample volumes.     

Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome

Alterations in intestinal microbiota are associated with obesity and insulin resistance. We studied the effects of infusing intestinal microbiota from lean donors to male recipients with metabolic syndrome on the recipients' microbiota composition and glucose metabolism. Subjects were assigned randomly to groups that were given small intestinal infusions of allogenic or autologous microbiota. Six weeks after infusion of microbiota from lean donors, insulin sensitivity of recipients increased (median rate of glucose disappearance changed from 26.2 to 45.3 μmol/kg/min; P < .05) along with levels of butyrate-producing intestinal microbiota. Intestinal microbiota might be developed as therapeutic agents to increase insulin sensitivity in humans; www.trialregister.nl; registered at the Dutch Trial Register (NTR1776).     

The effect of ABCG1 deficiency on atherosclerotic lesion development in LDL receptor knockout mice depends on the stage of atherogenesis

ObjectiveAs ABCG1 plays a role in cholesterol efflux, macrophage ABCG1 expression has been suggested to protect against atherosclerosis. However, we and others observed varying effects of ABCG1 deficiency on atherosclerotic lesion size. The objective of this study was to define the effect of ABCG1 deficiency during atherosclerotic lesion progression in LDL receptor knockout (LDLr^?/?) mice.Methods and resultsABCG1^?/?/LDLr^?/? and ABCG1^+/+/LDLr^?/? littermates were fed a Western-type diet for 10 and 12 weeks in order to study the effect of ABCG1 deficiency in the exponential phase of atherosclerotic lesion formation. At 10 weeks of diet feeding, a significant 1.5-fold increase in early atherosclerotic lesion size (130 ± 12 × 10³ μm²) was observed in ABCG1^?/?/LDLr^?/? mice compared to ABCG1^+/+/LDLr^?/? mice (88 ± 11 × 10³ μm²; p < 0.05). Interestingly, in more advanced lesions, induced by 12 weeks of WTD feeding, ABCG1^?/?/LDLr^?/? mice showed a significant 1.7-fold decrease in atherosclerotic lesion size (160 ± 20 × 10³ μm² vs 273 ± 19 × 10³ μm² in control mice; p < 0.01), indicating that in the ABCG1^?/?/LDLr^?/? mice progression of lesion formation is retarded as compared to ABCG1^+/+/LDLr^?/? mice. In addition, correlation analysis performed on 7 independent published studies and the current study confirmed that ABCG1 is atheroprotective in early lesions, while the development of advanced lesions is stimulated.ConclusionsIt appears that the effect of ABCG1 deficiency on lesion development in LDLr^?/? mice depends on the stage of atherogenesis, whereby the absence of ABCG1 leads to increased lesions at sizes < 167 × 10³ μm² while in more advanced stages of atherosclerosis enhanced apoptosis and/or compensatory mechanisms lead to retarded lesion progression.