Improved beta-amyloid PET reproducibility using two-phase acquisition and grey matter delineation.

PURPOSE: We investigated whether the reproducibility of standard visual reporting (STD method) in flutemetamol (FMM) PET can be improved using a newly introduced method that uses grey matter edges derived from the perfusion phase (GM-EDGE method). METHODS: Two-phase FMM PET was performed in 121 patients with mild cognitive impairment. Five nuclear medicine physicians blindly and independently evaluated all late-phase scans, initially employing the STD method and later the GM-EDGE method. A five-point scale was used to express the degree of amyloid positivity, and a binary classification (positive/negative) was used in combination with subjective confidence (five-point scale). Multirater Fleiss' kappa, intraclass correlation coefficient (ICC) and inter-rater reliability (Cohen's kappa) were determined for the STD and GM-EDGE methods. RESULTS: The weighted Cohen's kappa values for the five-point measure of amyloid positivity ranged from 0.63 to 0.73 (median 0.70) for the STD method and from 0.76 to 0.89 (median 0.80) for the GM-EDGE method (ICC 0.84, 95% CI 0.79-0.88, for the STD method; 0.91, 95% CI 0.89-0.94, for the GM-EDGE method). The nonweighted Cohen's kappa value for the binary classification ranged from 0.73 to 0.93 (median 0.82) for the STD method and 0.90 to 0.97 (median 0.93) for the GM-EDGE method (Fleiss' kappa 0.82, 95% CI 0.77-0.88, for the STD method; 0.93, 95% CI 0.87-0.99, for the GM-EDGE method). The GM-EDGE method resulted in significantly greater subjective confidence in the readings of four physicians (p < 0.010). The binary classification was concordant among all five physicians in 80.8% of the scans using the STD method and in 91.6% of the scans using the GM-EDGE method (p = 0.016). CONCLUSION: The newly introduced GM-EDGE method was associated with significantly higher inter-rater agreement among physicians and higher subjective confidence in the reading. The method is easy to implement in clinical practice, especially when the perfusion phase is utilized clinically.

An easy way to increase confidence in beta-amyloid PET evaluation.

BACKGROUND: In patients with brain atrophy, it is not easy to distinguish pathologic uptake of flutemetamol (FMM) in the gray matter from nonspecific, physiologic uptake in the white matter. In this paper we suggest an easy image processing method. MATERIAL AND METHODS: The proof-of-concept study involved three patients with mild cognitive impairment and different graphical findings at FMM-PET. Two-phase FMM-PET was acquired; the early phase represented the perfusion of gray matter, while the late phase depicted the white matter and beta-amyloid load in the gray matter. The border of the gray matter was easily extracted from the early-phase images using thresholding and the isocontour "Edges" color table. The late phase was registered with the edge images of the early phase and displayed using alpha-blending. RESULTS: Early- and late-phase image fusion displayed with appropriate color tables is presented in three different cases to illustrate the added value of the suggested approach. CONCLUSIONS: Composite late-phase images with enhanced gray matter borders strongly facilitate assessment of beta-amyloid presence in the gray matter. This is especially helpful in patients with brain atrophy.

FDG-PET/CT lymph node staging after neoadjuvant chemotherapy in patients with adenocarcinoma of the esophageal-gastric junction.

OBJECTIVES: The aim of the analysis was to assess the accuracy of various FDG-PET/CT parameters in staging lymph nodes after neoadjuvant chemotherapy. METHODS: In this prospective study, 74 patients with adenocarcinoma of the esophageal-gastric junction were examined by FDG-PET/CT in the course of their neoadjuvant chemotherapy given before surgical treatment. Data from the final FDG-PET/CT examinations were compared with the histology from the surgical specimens (gold standard). The accuracy was calculated for four FDG-PET/CT parameters: (1) hypermetabolic nodes, (2) large nodes, (3) large-and-medium large nodes, and (4) hypermetabolic or large nodes. RESULTS: In 74 patients, a total of 1540 lymph nodes were obtained by surgery, and these were grouped into 287 regions according to topographic origin. Five hundred and two nodes were imaged by FDG-PET/CT and were grouped into these same regions for comparison. In the analysis, (1) hypermetabolic nodes, (2) large nodes, (3) large-and-medium large nodes, and (4) hypermetabolic or large nodes identified metastases in particular regions with sensitivities of 11.6%, 2.9%, 21.7%, and 13.0%, respectively; specificity was 98.6%, 94.5%, 74.8%, and 93.6%, respectively. The best accuracy of 77.7% reached the parameter of hypermetabolic nodes. Accuracy decreased to 62.0% when also smaller nodes (medium-large) were taken for the parameter of metastases. CONCLUSIONS: FDG-PET/CT proved low sensitivity and high specificity. Low sensitivity was based on low detection rate (32.6%) when compared nodes imaged by FDG-PET/CT to nodes found by surgery, and in inability to detect micrometastases. Sensitivity increased when also medium-large LNs were taken for positive, but specificity and accuracy decreased.

[18F]FDG-PET scan in patients with fasting hyperglycemia.

BACKGROUND: It is generally accepted that a non-fasting state reduces [18F]FDG-PET quality, but the significance of higher levels of fasting blood glucose has aroused some doubts over time. The aim of this work was to provide further evidence to clarify this issue and its impact on the handling of hyperglycemic patients in daily routine. METHODS: Muscle and liver standardized uptake values (SUV) and their ratio, tumor SUV and the frequency of positive PET findings were retrospectively analyzed in 116 hyperglycemic (HG) patients (>11 mmol/L), in 116 patients with slightly elevated glycemia (SEG) (5.6-7.0 mmol/L) and in 116 normoglycemic (NG) patients (4.7 mmol/L). RESULTS: No significant difference was found in the muscle to liver ratio, in muscle SUV and in the frequency of positive PET findings among HG, SEG and NG patients. HG patients exhibited ~10% higher liver SUV in comparison to SEG and NG patients; a positive correlation (r=0.2849) was found between liver SUV and blood glucose levels. Significantly higher tumor SUV was present in SEG patients. CONCLUSIONS: We did not confirm that hyperglycemia in a fasting state negatively influences the diagnostic quality of [18F]FDG-PET. The positive correlation between liver SUV and blood glucose levels is clinically negligible and might be explained by increased fasting hepatic gluconeogenesis in diabetics. Our data encourage the performance of [18F]FDG-PET investigations under fasting conditions, regardless of the mild to medium elevation of fasting blood glucose level.

Assessment of left ventricular diastolic function by radionuclide ventriculography in patients with chronic heart failure and reduced ejection fraction.

STUDY OBJECTIVE: To compare parameters of diastolic function as assessed by radionuclide ventriculography (RNVG) and Doppler echocardiography (ECHO) in the patients with chronic heart failure and reduced ejection fraction (HF REF). PATIENTS AND METHODS: RNVG and ECHO were performed on the same day in 40 patients with systolic chronic HF, NYHA II and III, with LV EF < 50 % and sinus rhythm, followed at tertiary HF clinic. Diastolic function was assessed by RNVG using parameters: PFR (peak filling rate [% SV/sec]), TFR - time to peak filling rate (ms), and by ECHO using pulse Doppler parameters: the peak Doppler velocities of early (E) and late diastolic flow (A), the E/A ratio, the calculated mean of the early (E´) diastolic velocity of septal and lateral mitral annulus measured by tissue Doppler imaging, and the E/E´ ratio. RESULTS: The mean PFR was 421.7 (median 371.0) % SV/sec and TPF was 198.7 ms (median 169.5), the mean E/A ratio was 1.21 (median 0.85) and the E/E´ ratio was 9.0 (median 8.40). TPF correlated significantly (inverse correlation) with the E/A ratio (r = -0.34, p = 0.030), and not significantly with E´ (r = -0.27, p = 0.082), the PFR/age ratio correlated with the E/E´ ratio (r = -0.31, p = 0.05). CONCLUSION: Significant correlations of parame-ters of diastolic function as assessed by radionuclide and Doppler studies were identified in the HF REF patients.

FLT-PET in previously untreated patients with low-grade glioma can predict their overall survival.

BACKGROUND: Low-grade gliomas (LGG) of the brain have an uncertain prognosis, as many of them show continuous growth or upgrade over the course of time. We retrospectively investigated the role of positron emission tomography with 3'-deoxy-3'-[18F]fluorothymidine (FLT-PET) in the prediction of overall survival and event free survival in patients with untreated LGG. No such information is yet available in the literature. MATERIAL AND METHODS: Forty-one patients with previously untreated LGG underwent 55 FLT-PET investigations during their follow-up because of subjective complaints, objective worsening of clinical conditions, equivocal findings or progression on magnetic resonance imaging. The time interval before referral for neurosurgical or radiation treatment was considered to be event free survival, the interval until death as overall survival, respectively. Standardized uptake values (SUV) were measured, and a 3-point scale of subjective assessment was also applied. ROC analysis was used to define cut-off values. The log rank test was used for comparison of Kaplan-Meier survival curves. RESULTS: Eight patients (a total of 9 FLT-PET studies performed) died during follow-up. Progression leading to referral to therapy was recorded in 24 patients (a total of 33 FLT-PET studies). With a cut-off value of SUV(mean) = 0.236, a median overall survival of 1.007 days was observed in the test positive subgroup while median overall survival for the test negative subgroup was not achieved (p = 0.0002), hazard ratio = 17.6. Subjective assessment resulted in hazard ratio 11.5 (p = 0.0001). Only marginal significance (p=0.0562) was achieved in prediction of event free survival. CONCLUSIONS: Increased FLT uptake in previously untreated patients with LGG is a strong predictor of overall survival. On the other hand, prediction of event free survival was not successful in our cohort, probably because of high prevalence of patients who needed treatment due to symptoms caused by a space-occupying lesion without respect to the proliferative activity of the tumour.

Monte Carlo simulation of PET images for injection dose optimization.

When a patient is examined by positron emission tomography (PET), radiotracer dose amount (activity) has to be determined. However, the rules for activity correction according to patients' weight used nowadays do not correspond with practical experience. Very high image quality is achieved for slim patients, whereas noisy images are produced for obese patients. There is opportunity to modify the correction rule with the aim to equalize image quality within the broad spectrum of patients and to diminish radiation risk to slim patients, with special importance for children. We have built a model of a particular PET scanner and approximated human trunk, which is our region of interest, by a cylindrical model with segments of liver, outer adipose tissue, and the rest. We have performed Monte Carlo simulations of PET imaging using the GATE simulation package. Under reasonably simplifying assumptions and for special parameters, we have developed curves that recommend amount of injected activity based on body parameters to give PET images of constant quality, the quality being expressed in terms of noise equivalent counts. The dependence qualitatively differs from the rules used in clinical practice nowadays, and the results indicate potential for improvement.

The analysis of factors affecting the threshold on repeated 18F-FDG-PET/CT investigations measured by the PERCIST protocol in patients with esophageal carcinoma.

BACKGROUND: When applying the PET Response Criteria in Solid Tumors protocol, a threshold value based on standardized uptake value corrected to lean body mass (SUL) in liver parenchyma, or in the blood pool, is used: to metabolically specify a measurable lesion; to calculate metabolic tumor volume (mTV) and its product total lesion glycolysis (TLG); and as a limit for response measurement. The problem with using changes in glucose metabolism as a marker for response to therapy is its reproducibility on test-retest examinations. Therefore, before the evaluation of tumor treatment response, we verified our diagnostic protocol for homogeneity using the PET Response Criteria in Solid Tumors quality parameters. In addition, we analyzed the effect of the time span between examinations on the average value of SUL (SUL MEAN) in liver parenchyma at three different points: first at baseline (BL), after the first course of chemotherapy (ChT1), and finally after finishing therapy (ChT3). We also analyzed the influence of SUL MEAN variation on mTV and TLG. METHODS: Eighty-four patients with esophageal cancer were prospectively examined at BL using 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG)-PET/CT; 53 of 84 patients were examined after ChT1, 47 of 84 after ChT3, and 41 of 84 underwent all three examinations. Coefficient of variance (CV) and relative differences (RDw) were assessed for test-retest liver SUL values. The influence of liver SUL MEAN to mTV and TLG was modeled on BL examinations by artificial changes in liver SUL MEAN by ± 20%. RESULTS: No significant differences were found in test-retest liver SUL MEAN values. Comparing BL with ChT1, BL with ChT3, and ChT1 with ChT3, the CV of the liver SUL MEAN was 10.4, 10.7, and 10.3%; nevertheless, in 34.0, 38.3, and 36.6% of these examinations, respectively, the liver average SUL MEAN values exceeded the limit for inclusion in the study; that is, the difference was less than ± 0.3 U and ± 20%. The corresponding CV of blood background was 14.9, 16.5, and 17.2%. The artificial decrease of -20% in the liver SUL MEAN resulted in an increase of +43.6% in mTV and of +20.4% in TLG, whereas an increase of +20% in the liver SUL MEAN resulted in a decrease of -20.6% in mTV and -11.9% in TLG. CONCLUSION: SUL MEAN values in reference tissues (liver parenchyma or descending aorta) measured before chemotherapy did not differ significantly from those measured during chemotherapy. The CV of liver SUL MEAN was comparable to that seen in published data, but some patients had to be excluded from the study because of the individual variability of their mean liver SUL MEAN, which consequently hinders the clinical usage of mTV and TLG. Even in the standardized protocol, all potential sources of variability should be minimized.

Use of PET and PET/CT for radiation therapy planning: IAEA expert report 2006-2007.

Positron Emission Tomography (PET) is a significant advance in cancer imaging with great potential for optimizing radiation therapy (RT) treatment planning and thereby improving outcomes for patients. The use of PET and PET/CT in RT planning was reviewed by an international panel. The International Atomic Energy Agency (IAEA) organized two synchronized and overlapping consultants' meetings with experts from different regions of the world in Vienna in July 2006. Nine experts and three IAEA staff evaluated the available data on the use of PET in RT planning, and considered practical methods for integrating it into routine practice. For RT planning, (18)F fluorodeoxyglucose (FDG) was the most valuable pharmaceutical. Numerous studies supported the routine use of FDG-PET for RT target volume determination in non-small cell lung cancer (NSCLC). There was also evidence for utility of PET in head and neck cancers, lymphoma and in esophageal cancers, with promising preliminary data in many other cancers. The best available approach employs integrated PET/CT images, acquired on a dual scanner in the radiotherapy treatment position after administration of tracer according to a standardized protocol, with careful optimization of images within the RT planning system and carefully considered rules for contouring tumor volumes. PET scans that are not recent or were acquired without proper patient positioning should be repeated for RT planning. PET will play an increasing valuable role in RT planning for a wide range of cancers. When requesting PET scans, physicians should be aware of their potential role in RT planning.

Prognostic and diagnostic accuracy of [18F]FDG-PET/CT in 190 patients with carcinoma of unknown primary.

PURPOSE: The aim of the study was to determine the accuracy of [(18)F]fluorodeoxyglucose (FDG) PET/CT in the search for the primary and the presence of a malignancy. The prognostic value of FDG-PET/CT information was tested. METHODS: A total of 190 patients were retrospectively analysed: 82 with histologically proven metastases (HPM) and 108 with clinical suspicion of the presence of a malignancy (CSM). The sensitivity and specificity were determined. Overall survival was calculated to evaluate the prognostic value of the FDG-PET/CT findings. RESULTS: In the search for the primary, the sensitivity and specificity were 62.0% and 81.9%, respectively. In the search for the presence of a malignancy, the sensitivity and specificity were 93.6% and 85.7%, respectively. Between the HPM and CSM groups, no significant difference in sensitivity and specificity was found either in the search for the primary or in the search for the presence of a malignancy. No significant difference in the sensitivity and specificity was found between 78 patients who were investigated by contrast-enhanced FDG-PET/CT and the remaining patients. A significantly shorter overall survival was found among patients with positive FDG-PET/CT findings compared with patients with negative findings (p = 0.00001); no significant difference in survival was found between the HPM and the CSM group (p = 0.770). CONCLUSION: FDG-PET/CT imaging is very helpful in the search for the presence of a malignancy in patients with carcinoma of unknown primary syndrome. FDG-PET/CT is less accurate in identifying exactly the site of a primary. Discovery of a hypermetabolic lesion was associated with the worst survival rate.

18FDG PET in hallucinating and non-hallucinating patients.

OBJECTIVE: The aim of the study was to detect whether the abnormal regional brain activity correlates with auditory verbal hallucination-proneness (AVH) in a group of patients with schizophrenia and schizophrenia-related psychoses. METHODS: 15 patients with prominent AVH (score for hallucination intensity--item 3 in the PANSS > or =4) and 15 control patients without AVH (item 3 PANSS score < or =2) underwent 18FDG positron emission tomography at rest. RESULTS: SPM group analysis revealed an increased uptake of 18FDG in the right middle frontal gyrus (BA46) in subjects with high verbal hallucination score compared to non-hallucinating patients (p<0.001, uncorrected). Activation in BA46 positively correlated with the intensity of hallucinations (Spearman r=0.57; p<0.001). CONCLUSIONS: The observed functional recruitment of the right prefrontal cortex in subjects with high hallucination score may reflect impairment in the integration of intended actions and sensory feedback resulting in misattribution of internal events to an external source. This mechanism may form the cognitive basis for AVH.

The role of FDG-PET/CT in the detection of recurrent colorectal cancer.

PURPOSE: The conventional diagnostic techniques used to assess recurrence of colorectal cancer (CRCR) often yield unspecific findings. Integrated FDG-PET/CT seems to offer promise for the differential diagnosis of benign and malignant lesions. The aim of this study was to compare the value of FDG-PET and PET/CT in the detection of CRCR subsequent to colonic resection or rectal amputation. METHODS: The population for this retrospective study comprised 84 patients with suspected CRCR. The sensitivity, specificity and accuracy of PET and PET/CT were calculated for (a) intra-abdominal extrahepatic recurrences, (b) extra-abdominal and/or hepatic recurrences and (c) all recurrences, and tumour marker levels were analysed. RESULTS: The sensitivity, specificity and overall accuracy of PET in detecting intra-abdominal extrahepatic CRCR were 82%, 88% and 86%, respectively, compared with 88%, 94% and 92%, respectively, for PET/CT. The corresponding figures for detection of extra-abdominal and/or hepatic CRCR were 74%, 88% and 85% for PET and 95%, 100% and 99% for PET/CT. Considering the entire population, the sensitivity, specificity and overall accuracy of PET were 80%, 69% and 75%, respectively, compared with 89%, 92% and 90%, respectively, for PET/CT. FDG-PET/CT examination correctly detected 40 out of a total of 45 patients with CRCR. Two of five patients with falsely negative FDG-PET/CT findings had local microscopic recurrences and one had miliary liver metastases. Of 39 patients without CRCR, three showed false positive FDG-PET/CT results. Two of these cases were due to increased accumulation in inflammatory foci in the bowel wall, while one was due to haemorrhaging into the adrenal gland. CONCLUSION: FDG-PET/CT appears to be a very promising method for distinguishing a viable tumour from fibrous changes, thereby avoiding unnecessary laparotomy.

Comparison of 18F-FDG-PET and standard procedures for the pretreatment staging of children and adolescents with Hodgkin's disease.

PURPOSE: The aim of this study was to perform a prospective, blinded comparison of( 18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and conventional staging methods (CSMs) for initial staging of children and adolescents with Hodgkin's disease (HD). METHODS: Over a period of 4 years, 55 children and adolescents with HD (mean age 15.5 years, range 3.9-18.9 years) were prospectively recruited into the study. They underwent 61 FDG-PET studies using a dedicated whole-body PET scanner as a part of their initial staging work-up. PET findings were correlated with the results of CSMs, including computed tomography (CT), ultrasound, bone scanning and bone marrow examination. Discordant findings were resolved by magnetic resonance imaging or clinical follow-up (range 2-47 months). RESULTS: PET correctly changed the staging in 15% of patients (seven upstagings, two downstagings). Only two out of 61 patients (3%) were not accurately staged by PET; in these children, PET missed small lymphoma nodules detected on lung CT. The sensitivity of PET and CSMs for pretreatment staging was 96.5% and 87.5%, respectively; specificity was 100% and 60%, and accuracy, 96.7% and 85.2%, respectively. Upon combination of FDG-PET and lung CT, the diagnostic accuracy reached 100% in our series. CONCLUSION: Our study showed that whole-body FDG-PET is an efficient and useful method for the initial staging of children with HD. FDG-PET in combination with lung CT should be recommended as a screening method prior to other conventional imaging modalities to plan a rational staging protocol. Large multicentre prospective studies are necessary to verify this conclusion.

Langerhans cell histiocytosis with central nervous system involvement: follow-up by FDG-PET during treatment with cladribine.

The prognosis of patients with Langerhans cell histiocytosis (LCH) involving the central nervous system (CNS) is generally poor, despite reports of clinical responses to chemotherapy, surgery, and radiation. We report on a patient with a 20-year history of relapsing multisystem LCH who developed progressive neuropsychiatric symptoms, including diplopia, ataxia, and mental deterioration. There was a regression of lesions in the brain stem and cerebellum following chemotherapy with cladribine (2-CdA) as evidenced by positron emission tomography (PET) scans. In conclusion, our experience is encouraging for the use of cladribine in CNS LCH. PET may be a useful modality for the monitoring of CNS disease activity in LCH and provides additional information in comparison with NMR imaging.

The change of regional brain metabolism (18FDG PET) in panic disorder during the treatment with cognitive behavioral therapy or antidepressants.

BACKGROUND: The goal of our study was to identify brain structures in patients with panic disorder (PD) that show changes in 18FDG PET during the treatment with cognitive behavioral therapy (CBT) or antidepressants. METHOD: Twelve patients suffering from panic disorder were studied with [18F]-2-fluoro-deoxyglucose positron emission tomography (18FDG PET) scanning during resting state (condition of random episodic silent thinking, REST). After PET examination patients were randomly assigned to either cognitive behavioral treatment group (6 patients) or antidepressants treatment group (6 patients). After a 3 month period 18FDG PET examination was repeated in both groups. Psychopathology was assessed using the rating scales HAMA, CGI and Panic Disorder Severity Scale (PDSS). Data were analysed using software for statistical parametric mapping (SPM99). RESULTS: The scores of psychopathology rating scales (CGI, HAMA, PDSS) decreased in both groups. Changes of 18FDG uptake in the pharmacotherapy group: decreases were found in the a priori hypothesized regions in the right hemisphere, in the superior, middle, medial and inferior frontal gyrus, superior and middle temporal gyrus, and increases were detected in the a priori hypothesized regions, mainly in the left hemisphere in medial and middle frontal gyrus, superior, middle and transverse temporal gyrus. Changes of 18FDG uptake in the CBT group: decreases were found in the a priori hypothesized regions of the right hemisphere in the inferior temporal gyrus, superior and inferior frontal gyrus, and increases were detected in the a priori hypothesized region, mostly in the left hemisphere: inferior frontal gyrus, middle temporal gyrus and insula. We did not detect changes in 18FDG uptake in the limbic region (hippocampus, parahippocampal gyrus and amygdala). CONCLUSIONS: Changes in brain metabolism (18FDG uptake) after the treatment either with CBT or with antidepressants were similar in number of brain areas, with prominent right-left difference. This is in concordance with the asymmetry of brain activity noted in patients with PD according to previous PET (and SPECT) studies.