Assessment of operability by means of CTPA and perfusion SPECT in patients with chronic thromboembolic pulmonary hypertension.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) can potentially be cured by pulmonary thrombendarterectomy (PEA), the criteria for differentiation between operable and non-operable patients are not standardized. PURPOSE: To retrospectively evaluate the value of rigidly registered computed tomography pulmonary angiography (CTPA) and single photon emission CT (SPECT) in differentiating for PEA. MATERIAL AND METHODS: Forty-nine patients with CTEPH (21 men; age, 58 ± 13 years) were evaluated by an interdisciplinary expert board using all available diagnostic information and their consensus statement as gold standard. For SPECT a lobe based perfusion score was visually assessed using the score of 0 (lack of perfusion) to 1 (normal perfusion) calculating percentage of vascular obstruction (PVO). By CTPA, vascular obstruction index (OI) of central, peripheral, and global PA-bed were determined. The accuracy of the alignment between CTPA and SPECT was determined by fusion score (FS) ranging from 1 (no alignment) to 5 (exact alignment). Angiography provided PA pressure (PAP), pulmonary vascular resistance (PVR), and PA wedge pressure (PAWP). Receiver operating characteristics (ROC) analysis was performed. RESULTS: Twenty-nine patients were considered surgically amenable, and 20 patients were inoperable. Mean PAP, PVR, and PAWP were 48 ± 11 mmHg, 868 ± 461 dynes*sec*cm(-5), and 11 ± 5 mmHg, without differences between surgical and non-surgical patients (P > 0.5). In all patients accurate registration was reached (FS = 4.1 ± 0.7; range, 2-5). PVO and central OI separated PEA-amenable patients (P ≤ 0.001) resulting in the area under the curve of 0.828 (cutoff for PVO: 37.8% with a sensitivity of 82% and specificity of 79%) and 0.755 (cutoff for central OI: 29% with a sensitivity and specificity of 86.2% and 79%) for operability. CONCLUSION: An accurate interpretation of rigidly registered CTPA and perfusion SPECT may contribute to stratification of operability in patients with CTEPH.

PET-based delineation of tumour volumes in lung cancer: comparison with pathological findings.

PURPOSE: The objective of the study was to validate an adaptive, contrast-oriented thresholding algorithm (COA) for tumour delineation in (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for non-small cell lung cancer (NSCLC) in comparison with pathological findings. The impact of tumour localization, tumour size and uptake heterogeneity on PET delineation results was also investigated. METHODS: PET tumour delineation by COA was compared with both CT delineation and pathological findings in 15 patients to investigate its validity. Correlations between anatomical volume, metabolic volume and the pathology reference as well as between the corresponding maximal diameters were determined. Differences between PET delineations and pathological results were investigated with respect to tumour localization and uptake heterogeneity. RESULTS: The delineated volumes and maximal diameters measured on PET and CT images significantly correlated with the pathology reference (both r > 0.95, p < 0.0001). Both PET and CT contours resulted in overestimation of the pathological volume (PET 32.5 ± 26.5%, CT 46.6 ± 27.4%). CT volumes were larger than those delineated on PET images (CT 60.6 ± 86.3 ml, PET 48.3 ± 61.7 ml). Maximal tumour diameters were similar for PET and CT (51.4 ± 19.8 mm for CT versus 53.4 ± 19.1 mm for PET), slightly overestimating the pathological reference (mean difference CT 4.3 ± 3.2 mm, PET 6.2 ± 5.1 mm). PET volumes of lung tumours located in the lower lobe were significantly different from those determined from pathology (p = 0.037), whereas no significant differences were observed for tumours located in the upper lobe (p = 0.066). Only minor correlation was found between pathological tumour size and PET heterogeneity (r = -0.24). CONCLUSION: PET tumour delineation by COA showed a good correlation with pathological findings. Tumour localization had an influence on PET delineation results. The impact of tracer uptake heterogeneity on PET delineation should be considered carefully and individually in each patient. Altogether, PET tumour delineation by COA for NSCLC patients is feasible and reliable with the potential for routine clinical application.

Impact of rigid and nonrigid registration on the determination of 18F-FDG PET-based tumour volume and standardized uptake value in patients with lung cancer.

PURPOSE: Assessment of the metabolically active tumour tissue by FDG PET is evolving for use in the diagnosis of non-small-cell lung cancer (NSCLC), in the planning of radiotherapy, and in follow-up and response evaluation. For exact evaluation accurate registration of PET and CT data is required. The registration process is usually based on rigid algorithms; however, nonrigid algorithms are increasingly being used. The influence of the registration method on FDG PET-based standardized uptake value (SUVmax) and metabolic tumour volume (MTV) definition has not yet been evaluated. We compared intra- and interindividual differences in SUV and MTV between rigid- and nonrigid-registered PET and CT acquired during different breathing manoeuvres. METHODS: The study group comprised 28 radiotherapy candidates with histologically proven NSCLC who underwent FDG PET acquisition and three CT acquisitions (expiration - EXP, inspiration - INS, mid-breath-hold - MID). All scans were registered with both a rigid (R) and a nonrigid (NR) procedure resulting in six fused datasets: R-INS, R-EXP, R-MID, NR-INS, NR-EXP and NR-MID. For the delineation of MTVs a contrast-oriented contouring algorithm developed in-house was used. To accelerate the delineation a semiautomatic software prototype was utilized. RESULTS: Tumour mean SUVmax did not differ for R and NR registration (R 17.5 ± 7, NR 17.4 ± 7; p=0.2). The mean MTV was higher by 3 ± 12 ml (p=0.02) in the NR group than in the R group, as was the mean tumour diameter (by 0.1 ± 0.2 cm; p<0.01). With respect to the three different breathing manoeuvres, there were no differences in MTV in the R group (p > 0.7). In intraindividual comparison there were no significant differences in MTVs concerning the registration pairs R-EXP (68 ± 88 ml) vs. NR-EXP (69 ± 85 ml) und R-MID (68 ± 86 ml) vs. NR-MID (69 ± 83 ml) (both p > 0.4). However, the MTVs were larger after NR registration during inspiration (R-INS 68 ± 82 vs. NR-INS 78 ± 93 ml; p=0.02). CONCLUSION: The use of nonrigid algorithms may lead to a change in MTV, whose extent is influenced by the breathing manoeuvre on CT. Nonrigid registration methods cannot be recommended for the definition of MTV if the CT scan is performed during inspiration. The choice of registration algorithm has no significant impact on SUVmax.

FP-CIT SPECT does not predict the progression of motor symptoms in Parkinson's disease.

BACKGROUND/AIMS: FP-CIT (fluoropropyl-2ß-carbomethoxy-3ß-4-iodophenyl-nortroptane) SPECT is a well-established nuclear medicine method to support the clinical diagnosis of Parkinson's disease (PD). In this study, we examined the prognostic value of FP-CIT SPECT concerning the PD motor symptoms. METHODS: All 38 PD patients (age 57 ± 7 years, Hoehn & Yahr stage 1.6 ± 0.8, mean ± SD) underwent a baseline visit and a follow-up visit 3-7 years (5.2 ± 1.3 years) after the baseline visit. Cerebral [(123)I]FP-CIT SPECT was performed only once at the baseline visit. At both visits the motor symptoms bradykinesia, rigidity, resting tremor, postural tremor and axial symptoms were quantified by means of the UPDRS motor scale. RESULTS: There was no significant correlation between the initial striatal FP-CIT uptake and the annual progress of any motor symptom (= difference [(motor symptom at follow-up visit) - (motor symptom at baseline visit)]/time (in years) between assessments). CONCLUSION: The initial striatal FP-CIT SPECT does not predict the velocity of progress of PD motor symptoms within an interval of 3-7 years.

Risk stratification of solitary pulmonary nodules by means of PET using (18)F-fluorodeoxyglucose and SUV quantification.

PURPOSE: (18)F-fluorodeoxyglucose (FDG) PET is the most accurate imaging modality in characterizing a solitary pulmonary nodule (SPN). Besides visual image interpretation, semiquantitative analysis using standardized uptake values (SUV) is performed to improve diagnostic accuracy. Mostly, an SUV threshold of 2.5 is applied to differentiate between benign and malignant lesions. In this study we analysed the use different SUV thresholds to predict the post-test probability of malignancy for the individual patient considering his pre-test probability. Furthermore, we investigated the prognostic value of SUV in SPN for survival. METHODS: This retrospective study included 140 consecutive patients who underwent FDG PET for evaluation of SPN. Visual interpretation was performed by two readers. For semiquantitative analysis, maximum SUV (SUV(max)) was measured in all SPN. A final diagnosis was obtained by pathological examination or follow-up of more than 2 years. In a nomogram, positive and negative predictive values (PPV and NPV) were plotted against the hypothetical SUV threshold to determine the optimum SUV threshold. Survival was analysed using the Kaplan-Meier method and log-rank test. RESULTS: The prevalence of malignancy was 57%. The FDG uptake in malignant SPNs was higher than in benign SPNs (SUV 9.7 +/- 5.5 vs 2.6 +/- 2.5, p < 0.01). More than 90% of SPNs with an SUV below 2.0 were benign (sensitivity, specificity, NPV of 96, 55 and 92%). The highest diagnostic accuracy was achieved with an SUV of 4.0 (sensitivity, specificity and accuracy of 85%). Visual interpretation achieved corresponding values of 94, 70 and 84%, respectively. In lung cancer higher FDG uptake (SUV(max) >or= 9.5) was associated with shorter survival (median survival 20 months) and low FDG uptake with longer survival (>75 months). CONCLUSION: FDG PET allows assessment of the individual risk for malignancy in SPNs by considering tumoural SUV and pre-test probability. Higher FDG uptake in lung cancer as measured by SUV analysis is a prognostic factor. In patients with low FDG uptake in an SPN and increased risk during surgery omission of diagnostic thoracotomy may be warranted.

Prospective study of p-[123I]iodo-L-phenylalanine and SPECT for the evaluation of newly diagnosed cerebral lesions: specific confirmation of glioma.

PURPOSE: The differentiation between gliomas, metastases and gliotic or inflammatory lesions by imaging techniques remains a challenge. Gliomas frequently exhibit increased uptake of radiolabelled amino acids and are thus amenable to PET or SPECT imaging. Recently, p-[123I]iodo-L-phenylalanine (IPA) was validated for the visualization of glioma by SPECT and received orphan drug status. Here we investigated its diagnostic performance for differentiating indeterminate brain lesions. METHODS: This prospective open study included 67 patients with newly diagnosed brain lesions suspicious for glioma (34 without and 33 with contrast enhancement in the MRI scan). Patients received 250 MBq IPA intravenously after overnight fasting. SPECT images at 30 min and 3 h post-injection were iteratively reconstructed and visually interpreted after image fusion with an MRI brain scan (fluid-attenuated inversion recovery sequence or T1-weighted contrast-enhanced image). Findings were correlated with results of stereotactic or open biopsies or serial imaging. RESULTS: Twenty-seven low-grade (2 WHO I, 25 WHO II) and 24 high-grade gliomas (1 WHO III, 23 WHO IV), 3 metastases originating from lung cancer as well as 13 non-neoplastic lesions were proven. All non-neoplastic lesions and all metastases were negative with IPA SPECT. Forty gliomas were true-positive (TP) and 11 false-negative (FN) findings (8 WHO II, 1 WHO III, 2 WHO IV) occurred. There were no false-positive (FP) findings. For the differentiation of primary brain tumours and non-neoplastic lesions, sensitivity and specificity were 78 and 100%. In 34 lesions without contrast enhancement in MRI, IPA SPECT resulted in 17 TP, 8 true-negative, 9 FN and no FP findings (sensitivity 65%, specificity 100%). CONCLUSION: In patients with suspected glioma, IPA SPECT shows a high specificity, but especially in low-grade gliomas FN findings may occur. Due to the high positive predictive value a positive finding allows a suspected glioma to be confirmed.

A contrast-oriented algorithm for FDG-PET-based delineation of tumour volumes for the radiotherapy of lung cancer: derivation from phantom measurements and validation in patient data.

PURPOSE: An easily applicable algorithm for the FDG-PET-based delineation of tumour volumes for the radiotherapy of lung cancer was developed by phantom measurements and validated in patient data. METHODS: PET scans were performed (ECAT-ART tomograph) on two cylindrical phantoms (phan1, phan2) containing glass spheres of different volumes (7.4-258 ml) which were filled with identical FDG concentrations. Gradually increasing the activity of the fillable background, signal-to-background ratios from 33:1 to 2.5:1 were realised. The mean standardised uptake value (SUV) of the region-of-interest (ROI) surrounded by a 70% isocontour (mSUV(70)) was used to represent the FDG accumulation of each sphere (or tumour). Image contrast was defined as C=(mSUV(70)-BG)/BG where BG is the mean background - SUV. For the spheres of phan1, the threshold SUVs (TS) best matching the known sphere volumes were determined. A regression function representing the relationship between TS/(mSUV(70) - BG) and C was calculated and used for delineation of the spheres in phan2 and the gross tumour volumes (GTVs) of eight primary lung tumours. These GTVs were compared to those defined using CT. RESULTS: The relationship between TS/(mSUV(70) - BG) and C is best described by an inverse regression function which can be converted to the linear relationship TS=a x mSUV(70)+b x BG. Using this algorithm, the volumes delineated in phan2 differed by only -0.4 to +0.7 mm in radius from the true ones, whilst the PET-GTVs differed by only -0.7 to +1.2 mm compared with the values determined by CT. CONCLUSION: By the contrast-oriented algorithm presented in this study, a PET-based delineation of GTVs for primary tumours of lung cancer patients is feasible.

Intra-individual comparison of p-[123I]-iodo-L-phenylalanine and L-3-[123I]-iodo-alpha-methyl-tyrosine for SPECT imaging of gliomas.

OBJECTIVES: Radioactive amino-acids accumulate in gliomas even with an intact blood-brain-barrier. L-3-[(123)I]-iodo-alpha-methyl-tyrosine (IMT) is well established for SPECT imaging of gliomas. Recently, we introduced p-[(123)I]-iodo-L-phenylalanine (IPA) for the characterisation of brain lesions. This study compares both tracers in glioma patients. METHODS: Eleven patients with gliomas (1 WHO grade 1, 5 grade 2, 1 grade 3, 2 grade 4 gliomas, 1 unconfirmed upgrading and 1 post-therapeutic non-neoplastic lesion) underwent SPECT imaging with IPA (early and delayed acquisitions at 30 min and 3 h) and IMT (early only). Maximum tumour-to-brain ratios (TBR) were calculated using region-of-interest analysis to assess uptake of IMT and IPA. Imaging results were compared to histopathological findings. RESULTS: Early TBRs of IMT and IPA were strongly correlated (r = 0.828, p = 0.002). TBRs were higher for IMT than IPA (1.95+/-0.50 versus 1.79+/-0.42; p < 0.05), but independent from tumour cell density (p > 0.1). Visual interpretation by different observers was more concordant for IMT-SPECT than IPA-SPECT (kappa 1.0 versus 0.774). No differences in early TBRs were observed between low-grade and high-grade gliomas for IMT (1.97+/-0.53 versus 2.21+/-0.44, p > 0.5) or IPA (1.70+/-0.23 versus 2.21+/-0.56, p = 0.167) with a trend to higher TBRs in low-grade tumours for IMT (p = 0.093). In contrast to the known wash-out of IMT, we observed persistent accumulation of IPA in gliomas. CONCLUSIONS: IPA shows lower TBRs than IMT, especially in low-grade tumours, so IMT should be preferred for the delineation of low-grade gliomas by SPECT imaging. Due to its prolonged retention, however, IPA remains promising for therapeutic use in gliomas after labelling with I-131.

18F-FDG PET for mediastinal staging of lung cancer: which SUV threshold makes sense?

UNLABELLED: (18)F-FDG PET is the most accurate noninvasive modality for staging mediastinal lymph nodes in lung cancer. Besides using visual image interpretation, some institutions use standardized uptake value (SUV) measurements in lymph nodes. Mostly, an SUV of 2.5 is used as the cutoff, but this choice was never deduced from respective studies. Receiver operating characteristic (ROC) analyses demonstrated that SUV thresholds of more than 4 resulted in the highest accuracy. But these high cutoffs imply high false-negative rates (FNRs). The aim of our evaluation was to determine an optimal SUV threshold and to compare its diagnostic performance with the results of visual interpretation. METHODS: This retrospective study included 95 patients with suspected lung cancer who underwent mediastinoscopy/mediastinal lymphadenectomy after (18)F-FDG PET (90-150 min after 250 MBq of (18)F-FDG). Maximum SUV was measured in 371 lymph node regions biopsied afterward and visually interpreted using a 6-level score (- - - through + + +). Diagnostic performance was assessed by ROC analysis. FNR and false-positive rate (FPR), the sum of both error rates (FNR + FPR), and diagnostic accuracy were plotted against a hypothetical SUV threshold to determine the optimum SUV threshold. RESULTS: SUVs in metastatic lymph nodes were higher (mean +/- SD, 7.1 +/- 4.5; range, 1.4-26.9; n = 70) than in tumor-free lymph node stations (2.4 +/- 1.7; range, 0.6-14.9; n = 301; P < 0.01). Inflammatory lymph nodes exhibited slightly increased SUVs (2.7 +/- 2.0; range, 0.8-14.9; n = 146). The plot of error rates featured a minimum of the sum FNR + FPR for an SUV of 2.5. With increasing SUV threshold, the FPR decreased most prominently up to that value whereas a continuous rise of FNR was noticed. Highest diagnostic accuracy was achieved with an SUV of 4.5. The areas under the ROC curves demonstrated that visual interpretation tends to be more accurate than SUV quantification (visual, 0.930 +/- 0.022; SUV, 0.899 +/- 0.025; P = 0.241). Using an SUV of 2.5 as the threshold, the resulting sensitivity, specificity, and negative predictive value were 89%, 84%, and 96%, respectively. CONCLUSION: For mediastinal staging, the choice of an SUV of 2.5 as the threshold is justified because FNR + FPR is minimized. The resulting high negative predictive value of 96% allows the omission of mediastinoscopy in patients with negative mediastinal findings on (18)F-FDG PET images. For the experienced observer, visual analysis should be relied on primarily, with calculation of the SUV used, at most, as a secondary aid. For the less experienced observer, the SUV may be of greater value.

Validation of 8-[123I]iodo-L-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid as an imaging agent for prostate cancer in experimental models of human prostate cancer.

INTRODUCTION: Very few tracers are currently available for the detection and staging of prostate cancer with positron emission tomography and single-photon emission computed tomography. This study evaluates the potential of 8-[123I]iodo-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid [ITIC(OH)] as an imaging agent for prostate cancer in experimental models of human prostate cancer. METHODS: ITIC(OH) was prepared by the IODO-GEN method, with 82+/-7% radiochemical yield and >99% radiochemical purity after high-performance liquid chromatography. Thereafter, ITIC(OH) was examined in CD-1 nu/nu mice engrafted with human PC-3 and DU-145 prostate cancer in the flank or orthotopically in the prostate. Bioevaluation involved examination of the in vivo stability and uptake characteristics of ITIC(OH) into tumors and different organs by dynamic in vivo analysis and gamma counting of organs of interest after dissection. RESULTS: ITIC(OH) showed good in vivo stability for biological investigations and was primary cleared through urine. In vivo, ITIC(OH) accumulated highly and specifically in tumors, reaching 13.6+/-2.1% to 16.2+/-2.5% injected dose per gram (ID/g) in heterotopic tumors compared with 14.8+/-2.6% and 17.6+/-3.4% ID/g in orthotopic tumor engrafts at 60 and 240 min postinjection, respectively. In contrast, radioactivity uptake in the blood, spleen, liver and gastrointestinal tract was moderate and decreased with time, resulting in marked tumor-to-background and excellent visualization of tumors. CONCLUSION: These results suggest that ITIC(OH) is a promising candidate as radiotracer for detecting prostate cancer and warrants further studies in patients to ascertain its potential as an imaging agent for clinical use.

Transcranial sonography and [123I]FP-CIT SPECT disclose complementary aspects of Parkinson's disease.

Hyperechogenic signal of substantia nigra (SN) in transcranial sonography (TCS) and reduced striatal uptake in FP-CIT SPECT are common findings in idiopathic Parkinson's disease (PD). But so far it is unknown whether the extent of SN hyperechogenicity represents a correlate for the degeneration of presynaptic dopaminergic neurons in PD. We performed TCS and 123I-labelled N-(3-fluoropropyl)-2ss-carbomethoxy-3ss-(4-iodophenyl)nortropane ([123I]FP-CIT) SPECT in 53 patients with PD. Striatal FP-CIT uptake was quantified by measuring the striatal/posterior lobe binding of [123I]FP-CIT. SN echogenicity was quantified by planimetric measurement of the maximum extension of hyperechogenic signals. We found no correlation between striatal FP-CIT uptake and echogenicity of the SN, neither contralateral to the clinically more affected body side (r = +0.08, P = 0.57; Pearson's correlation) nor ipsilateral (r = +0.01; P = 0.92). Our data show that the extent of SN hyperechogenicity does not correlate with the degeneration of presynaptic dopaminergic nerve terminals. Obviously SN hyperechogenicity and degeneration of presynaptic dopaminergic nerve terminals exist independently from each other and may be based on different pathomechanisms.

Preparation and tumor affinity testing of the radioiodinated tetrahydroisoquinoline derivative [123I]TIC(OH) for targeting prostate cancer.

This work describes the synthesis and tumor affinity testing of 8-[123I]iodo-l-1,2,3,4-tetrahydro-7-hydroxyisoquinoline-3-carboxylic acid [ITIC(OH)], a cyclic non-naturally occurring amino acid as an imaging probe for prostate cancer. Parameters for labelling were optimized with regard to the amount of precursor, the temperature and time. Thereafter, ITIC(OH) was evaluated in terms of its uptake in primary human PC-3 and DU-145 prostate cancer cells, followed by analysis of the underlying mechanisms of the radioactivity accumulation in tumor cells. No-carrier-added ITIC(OH) was obtained in 80+/-15% radiochemical yield and >98% radiochemical purity by a one-step radioiodination, using IODO-GEN as oxidant. The total synthesis time was less than 30 min, and compatible with a clinical routine production. ITIC(OH) accumulated intensively in primary human prostate cancer cells. The radioactivity incorporation in tumor following a 10-min incubation at 37 degrees C/pH 7.4 varied from 35% to 58% of the total loaded activity per 10(6) tumor cells (355-540 cpm/1000 cells). Inhibition experiments revealed that ITIC(OH) was taken up into tumor by an active transport different from the common amino acid carrier systems, including the sodium-dependent system A and B+,0, and the sodium-independent L- and ASC-type transporter. In contrast, the cellular incorporation was dependent on the membrane potential and correlated with the activity of the mitochondria. In conclusion, the specific and high-level accumulation of ITIC(OH) in human prostate carcinoma cells, indicates that the new radiopharmaceutical is a good candidate for further in vivo investigations to ascertain its potential as an imaging probe for prostate cancer by SPET.

Effects of catheter-based renal denervation on cardiac sympathetic activity and innervation in patients with resistant hypertension.

OBJECTIVES: To investigate, whether renal denervation (RDN) has a direct effect on cardiac sympathetic activity and innervation density. BACKGROUND: RDN demonstrated its efficacy not only in reducing blood pressure (BP) in certain patients, but also in decreasing cardiac hypertrophy and arrhythmias. These pleiotropic effects occur partly independent from the observed BP reduction. METHODS: Eleven patients with resistant hypertension (mean office systolic BP 180 ± 18 mmHg, mean antihypertensive medications 6.0 ± 1.5) underwent I-123-mIBG scintigraphy to exclude pheochromocytoma. We measured cardiac sympathetic innervation and activity before and 9 months after RDN. Cardiac sympathetic innervation was assessed by heart to mediastinum ratio (H/M) and sympathetic activity by wash out ratio (WOR). Effects on office BP, 24 h ambulatory BP monitoring, were documented. RESULTS: Office systolic BP and mean ambulatory systolic BP were significantly reduced from 180 to 141 mmHg (p = 0.006) and from 149 to 129 mmHg (p = 0.014), respectively. Cardiac innervation remained unchanged before and after RDN (H/M 2.5 ± 0.5 versus 2.6 ± 0.4, p = 0.285). Cardiac sympathetic activity was significantly reduced by 67 % (WOR decreased from 24.1 ± 12.7 to 7.9 ± 25.3 %, p = 0.047). Both, responders and non-responders experienced a reduction of cardiac sympathetic activity. CONCLUSION: RDN significantly reduced cardiac sympathetic activity thereby demonstrating a direct effect on the heart. These changes occurred independently from BP effects and provide a pathophysiological basis for studies, investigating the potential effect of RDN on arrhythmias and heart failure.

Clinical value of iodine-123-alpha-methyl-L-tyrosine single-photon emission tomography in the differential diagnosis of recurrent brain tumor in patients pretreated for glioma at follow-up.

PURPOSE: To assess the clinical potential of iodine-123-alpha-methyl-L-tyrosine (IMT) and single-photon emission tomography (SPET) in the differential diagnosis of recurrences in patients pretreated for gliomas at follow-up. PATIENTS AND METHODS: Seventy-eight patients were examined after primary therapy over 36 months. Histopathologic diagnoses of all patients was known at first treatment; magnetic resonance and/or computed tomography examination was performed in addition to IMT-SPET. Cerebral SPET images were acquired 20 minutes after intravenous application of 190 +/- 10 MBq of IMT. SPET images were classified as positive or negative for recurrent tumor visually and by calculating the ratios between tracer accumulation in the lesion and the unaffected contralateral regions of reference using region of interest. Final diagnoses were based on prospective clinicopathologic findings obtained independently of IMT-SPET. RESULTS: IMT-SPET detected all high-grade recurrent gliomas (grade 4; sensitivity, 100%). A difference could be demonstrated in grade 2 and 3 recurrences (sensitivity, 84% and 92%, respectively). Moreover, benign posttherapeutic lesions (postoperative scars, radiation necrosis) were correctly diagnosed as negative for tumor recurrence. In general, IMT uptake in grade 2 (1.45 +/- 0.24) was significantly lower than that in grades 3 (1.70 +/- 0.41) and 4 (1.88 +/- 0.32). However, it was difficult to evaluate tumor grade only from the IMT accumulation in individual cases. CONCLUSION: IMT-SPET seems highly useful for detecting and delineating recurrent gliomas and differentiating between benign posttherapeutic lesions and malignant tumor tissue. It may be a valuable clinical tool to diagnose recurrences in patients pretreated for gliomas at follow-up. However, it showed limitations in determining histologic tumor grade.

Comparison of different methods for delineation of 18F-FDG PET-positive tissue for target volume definition in radiotherapy of patients with non-Small cell lung cancer.

UNLABELLED: PET with (18)F-FDG ((18)F-FDG PET) is increasingly used in the definition of target volumes for radiotherapy, especially in patients with non-small cell lung cancer (NSCLC). In this context, the delineation of tumor contours is crucial and is currently done by different methods. This investigation compared the gross tumor volumes (GTVs) resulting from 4 methods used for this purpose in a set of clinical cases. METHODS: Data on the primary tumors of 25 patients with NSCLC were analyzed. They had (18)F-FDG PET during initial tumor staging. Thereafter, additional PET of the thorax in treatment position was done, followed by planning CT. CT and PET images were coregistered, and the data were then transferred to the treatment planning system (PS). Sets of 4 GTVs were generated for each case by 4 methods: visually (GTV(vis)), applying a threshold of 40% of the maximum standardized uptake value (SUV(max); GTV(40)), and using an isocontour of SUV = 2.5 around the tumor (GTV(2.5)). By phantom measurements we determined an algorithm, which rendered the best fit comparing PET with CT volumes using tumor and background intensities at the PS. Using this method as the fourth approach, GTV(bg) was defined. A subset of the tumors was clearly delimitable by CT. Here, a GTV(CT) was determined. RESULTS: We found substantial differences between the 4 methods of up to 41% of the GTV(vis). The differences correlated with SUV(max), tumor homogeneity, and lesion size. The volumes increased significantly from GTV(40) (mean 53.6 mL) < GTV(bg) (94.7 mL) < GTV(vis) (157.7 mL) and GTV(2.5) (164.6 mL). In inhomogeneous lesions, GTV(40) led to visually inadequate tumor coverage in 3 of 8 patients, whereas GTV(bg) led to intermediate, more satisfactory volumes. In contrast to all other GTVs, GTV(40) did not correlate with the GTV(CT). CONCLUSION: The different techniques of tumor contour definition by (18)F-FDG PET in radiotherapy planning lead to substantially different volumes, especially in patients with inhomogeneous tumors. Here, the GTV(40) does not appear to be suitable for target volume delineation. More complex methods, such as system-specific contrast-oriented algorithms for contour definition, should be further evaluated with special respect to patient data.

Radioiodinated phenylalanine derivatives to image pancreatic cancer: a comparative study with [18F]fluoro-2-deoxy-D-glucose in human pancreatic carcinoma xenografts and in inflammation models.

This work validated an in vivo model of human pancreatic cancer for preclinical studies and evaluated p-amino-3-[123I]iodo-L-phenylalanine (AIPA) and p-[123I]iodo-L-phenylalanine (IPA) as potential imaging agents for pancreatic cancer. The primary human pancreatic adenocarcinoma PaCa44 and PanC1 cells (1.5-2.5x10(6)) were inoculated either subcutaneously into the flank or orthotopically into the pancreas of severe combined immunodeficient (SCID) mice. Tumor formation was recorded by palpation and monitored by magnetic resonance imaging (MRI). After intravenous injection, tumor affinity and organ distribution of AIPA and IPA were compared with those of [18F]fluoro-2-deoxy-D-glucose (FDG) in tumor-bearing SCID mice and in concanavalin A (ConA)-induced inflammation models. All SCID mice developed a pancreatic tumor 2-4 weeks after cell implantation. All subcutaneously transplanted tumors were detected by MRI and confirmed histologically, whereas 90% and 68% of the histopathologically confirmed orthotopic PaCa44 and PanC1 tumors were accurately demonstrated by MRI. Tumor formation and spread after orthotopic implantation showed invasion into adjacent organs and metastases in different sites of the abdomen. In contrast, no organ invasion or metastases were demonstrated by subcutaneous implantation. In vivo, AIPA and IPA displayed high affinity for pancreatic tumors. Radioactivity uptake into a tumor at 60 and 240 min amounted to 7.2+/-2.1% and 10.7+/-2.5% I.D./g for AIPA and 13.3+/-3.5% and 15.2+/-3.8% I.D./g for IPA in heterotopic tumors as compared with 11.8+/-3.2% and 15.2+/-2.4% I.D./g for AIPA and 16.7+/-3.5% and 22.5+/-4.3% I.D./g for IPA in orthotopically implanted tumors. In comparison, the FDG uptake was 10.8+/-2.9% and 2.5+/-0.6% I.D./g into heterotopic tumors and 12.5+/-3.8% and 3.5+/-1.2% I.D./g into the orthotopic ones at 60 and 240 min postinjection. The FDG uptake markedly increased (>400%) in the area of inflammation, whereas accumulation of AIPA and IPA in inflammation remained moderate and comparable with that determined in muscle. In summary, the orthotopic implantation model, more than the heterotopic one, reflects more closely the clinical course of the disease, thus representing the appropriate in vivo model for preclinical studies. The specific and high-level targeting of AIPA and IPA to human pancreatic tumor xenografts, with marked tumor-to-background ratios, indicate that AIPA and IPA are interesting candidates as radiotracers for noninvasive imaging of pancreatic cancer. IPA has the advantage of relatively low renal uptake and thus presents as the most promising candidate.

Cellular uptake of vitamin B12 in patients with chronic renal failure.

BACKGROUND/AIMS: Elevated concentration of plasma homocysteine (tHcy) is common in renal patients, however, the reason behind the resistance to vitamin B(12) and folate therapy are poorly understood. METHODS: We investigated vitamin B12 uptake by mononuclear cells (MC) from predialysis patients (n = 19) as compared to healthy controls (n = 15). Serum levels of tHcy, methylmalonic acid and cystathionine, holotranscobalamin (holoTC), total vitamin B12 and folate were also measured. RESULTS: The uptake of vitamin B12 by MC from renal patients was lower than that by MC from controls (9.3 vs. 12.5 pg/3 x 10(6) cells; p = 0.001). Nonetheless, the receptor-binding capacity was comparable between patients and controls (6.1 vs. 6.5 pg/3 x 10(6) cells; p = 0.627). Average reduction of vitamin B12 uptake in patients as compared to the controls was 18.1%. CONCLUSIONS: Our results show that vitamin B12 uptake is impaired in MC from renal patients, with no evidence that the surface receptor is down-regulated. High serum concentrations of holoTC are common in renal patients and might be related to a generalized resistance to this vitamin. Serum concentrations of vitamin B12 within the reference range are not likely to ensure vitamin delivery into the cells. Supraphysiological doses of vitamin B12 may be necessary to deliver a sufficient amount of the vitamins to the cells via mechanisms largely independent of holoTC receptor.

Mapping of the cardiac sympathetic nervous system by single photon emission tomography with technetium-99m-labelled fluorobenzylpiperidine derivative (99mTc-FBPBAT): result of a feasibility study in a porcine model and an initial dosimetric estimation in humans.

BACKGROUND: Positron emission tomography (PET) and single photon emission tomography (SPET) offer the most promising tools for the in-vivo assessment of the cardiac autonomic nervous system in humans. However, the clinical application of PET and SPET on a routine basis is severely limited by the lack of widely available selective radiotracers. Technetium-99m-labelled 4-fluorobenzyl-4-(2-mercapto-2-methyl-4-aza-pentyl)-4-(2-mercapto-2-methyl-propylamino)-piperidine (99mTc-FBPBAT) is a recently developed radiotracer which exhibited marked adrenergic affinity in previous investigations in vascular smooth muscle cells and cardiac myocytes, and in rats. In this study, we have verified these findings in a porcine model, and evaluated the potential of SPET with 99mTc-FBPBAT to assess the adrenergic nervous system of the heart. METHODS: Using a SPET camera, scintigraphic evaluations were carried out in pigs following intravenous injection of 99mTc-FBPBAT. The specificity of the cardiac uptake was determined by pharmacological intervention, using alpha- and beta-adrenoceptor antagonists and adrenergic re-uptake blocker. Whole-body kinetic and radiation absorbed doses were estimated from whole-body scintigraphies in two healthy volunteers. RESULTS: 99mTc-FBPBAT-SPET demonstrated a homogeneous distribution of radioactivity in myocardium of pigs and in humans. The cardiac uptake was specifically suppressed by previous treatment of the animals with metoprolol and prazosin, and was displaceable by norepinephrine. In contrast, the inhibition of radioactivity uptake into the heart was less pronounced after pretreatment with desipramine. The peak radioactivity in blood was determined after 1.5-2 min, followed by a plateau of nearly constant radioactivity from 25-30 min onwards. Within 6 h, more than 35% of the injected activity was excreted in the urine. The effective dose according to International Commission on Radiological Protection Publication 60 (ICRP 60) was 0.0064 mSv.MBq-1 for adults. CONCLUSION: In view of these findings, we conclude that the myocardial uptake of 99mTc-FBPBAT reflects the sympathetic adrenergic nervous system of the heart. The effective dose estimated indicates that the clinical use of 99mTc-FBPBAT results in an acceptable radiation dose in humans. Despite the relatively high radioactivity uptake into the lung and liver, 99mTc-FBPBAT appears to be the first promising Tc-based radiotracer for scintigraphic assessment of the cardiac adrenergic system. This result encourages further development of Tc-based agents for routine SPET studies in humans.

2-Deoxy-2-[18F]fluoro-D-glucose positron emission tomography in target volume definition for radiotherapy of patients with non-small-cell lung cancer.

PURPOSE: To discuss the potential contribution of 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) in radiotherapy planning for non-small-cell lung cancer (NSCLC) considering new concepts on target volume definition. PROCEDURES: Recent investigations on the topic are reviewed with regard to current concepts of target volume definition for NSCLC. RESULTS: As intrathoracic recurrence is the leading cause of death after primary radiotherapy of NSCLC, there is a need for improving local control by escalating treatment intensity to gross disease. The value of elective nodal irradiation (ENI), resembling prophylactic irradiation of macroscopically unaffected parts of the mediastinum, is being considered. CONCLUSION: As FDG-PET has been shown to enhance the diagnostic accuracy of computed tomography (CT), and to have a potentially high impact on the identification of malignant tissue, it should be implicated in prospective clinical trials on dose escalation and three-dimensional conformal radiotherapy, especially in those including a reduction of target volumes.

Value of F-18-fluorodeoxyglucose positron emission tomography after induction therapy of locally advanced bronchogenic carcinoma.

OBJECTIVES: Induction therapy is an important treatment option in locally advanced non-small cell lung cancer. F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) has an important role in initial staging. The aim of this study was to assess the value of FDG-PET in restaging after induction therapy and in analyzing tumor viability, nodal status, distant metastases, and prognosis. METHODS: Forty-seven patients with locally advanced non-small cell lung cancer accepted for resection after induction therapy underwent FDG-PET. Images were interpreted visually for mediastinal nodal status and metastatic spread. The FDG accumulation in the tumor site was measured by using the maximum standardized uptake value. RESULTS: Unexpected metastases were detected by means of FDG-PET in 9 patients. Surgical intervention was not performed in 8 patients with confirmed metastases. The rate of unexpected findings increased from complete radiologic remission (0%) over partial remission (9%) to no change (67%). The standardized uptake value was higher in tumors with (n = 26) than in those without (n = 11) histologic proof of viability (6.4 +/- 5.3 vs 2.9 +/- 1.6, P = .006). All patients with standardized uptake values of greater than 5.8 had viable tumors. Sensitivity, specificity, and negative predictive value were 81%, 64%, and 58% for tumor viability and 50%, 88%, and 85% for persistent mediastinal disease. Median survival after resection was greater than 56 months for patients with tumor standardized uptake values of less than 4 and 19 months for patients with standardized uptake values of 4 or greater ( P < .001). CONCLUSION: FDG-PET helps in the selection of patients for resection after induction therapy. It can be used to detect unexpected distant metastases, especially after poor response to induction therapy. Its high negative predictive value in mediastinal restaging allows for omission of repeat mediastinoscopy. Tumor standardized uptake value after induction is a prognostic factor.