FDG uptake, a surrogate of tumour hypoxia?

INTRODUCTION: Tumour hyperglycolysis is driven by activation of hypoxia-inducible factor-1 (HIF-1) through tumour hypoxia. Accordingly, the degree of 2-fluro-2-deoxy-D: -glucose (FDG) uptake by tumours might indirectly reflect the level of hypoxia, obviating the need for more specific radiopharmaceuticals for hypoxia imaging. DISCUSSION: In this paper, available data on the relationship between hypoxia and FDG uptake by tumour tissue in vitro and in vivo are reviewed. In pre-clinical in vitro studies, acute hypoxia was consistently shown to increase FDG uptake by normal and tumour cells within a couple of hours after onset with mobilisation or modification of glucose transporters optimising glucose uptake, followed by a delayed response with increased rates of transcription of GLUT mRNA. In pre-clinical imaging studies on chronic hypoxia that compared FDG uptake by tumours grown in rat or mice to uptake by FMISO, the pattern of normoxic and hypoxic regions within the human tumour xenografts, as imaged by FMISO, largely correlated with glucose metabolism although minor locoregional differences could not be excluded. In the clinical setting, data are limited and discordant. CONCLUSION: Further evaluation of FDG uptake by various tumour types in relation to intrinsic and bioreductive markers of hypoxia and response to radiotherapy or hypoxia-dependent drugs is needed to fully assess its application as a marker of hypoxia in the clinical setting.

Gastrin-releasing peptide receptor imaging in human breast carcinoma versus immunohistochemistry.

UNLABELLED: This study reports on the uptake of (99m)Tc-RP527 by human breast carcinoma and its relationship to gastrin-releasing peptide receptor (GRP-R) expression as measured by immunohistochemistry (IHC). METHODS: Nine patients referred because of a clinical diagnosis suggestive of breast carcinoma and 5 patients with tamoxifen-resistant bone-mestastasized breast carcinoma underwent (99m)Tc-RP527 scintigraphy. The findings were compared with routine staging examinations in all patients and with routine histology and IHC GRP-R staining in the first 9 patients. All 9 patients with suspected breast lesions were tumor positive. RESULTS: The uptake of (99m)Tc-RP527 was evident in the primary tumor in 8 of 9 patients and in involved lymph nodes and part of the distant metastasis limited to the bone when present. (99m)Tc-RP527 uptake was not found in any of the tamoxifen-resistant patients. CONCLUSION: Uptake by primary breast carcinoma was significantly correlated with the presence of GRP-Rs as assessed by means of IHC.

(123)I-Interleukin-2 uptake in squamous cell carcinoma of the head and neck carcinoma.

INTRODUCTION: Information obtained on the IL-2 receptor status of tumour infiltrating lymphocytes in patients suffering from squamous cell carcinoma of the head and neck (SSCHN) before and after IL-2 treatment may lead to a better understanding of the immunological changes and related kinetics induced at the tumour level and ultimately to a strategy that allows selection of those patients that will benefit from IL-2 therapy. This study set out to assess the relationship between (123)I-IL2 single-photon emission computed tomography (SPECT) findings and the presence of IL-2 receptors (CD25 staining) on tumour-infiltrating lymphocytes as well as on SCCHN tumour cells in patients suffering from SCCHN. MATERIALS AND METHODS: Seventeen consecutive patients (12 men; mean age, 57 years) highly suspected to suffer from SSCHN were prospectively included in the study. All patients underwent planar and whole body (123)I-IL2 scintigraphy and underwent surgery or had a biopsy taken within 1 week from imaging. Surgical resected primary lesions as well as biopsy material from primary tumours were histologically analysed with respect to the presence and intensity of CD25 expression on tumour infiltrating lymphocytes and tumour cells (HSCORE). Tumor-to-background (T/N) ratios of the primary tumour derived from planar and tomographic (123)I-IL2 scintigraphy were related to the results derived from histology. RESULTS: All patients suffered from SSCHN. T/N ratios derived from SPECT images were significantly correlated with CD25 lymphocyte HSCOREs (r = 0.66; p = 0.03), but not with CD25 tumour cell HSCOREs. CONCLUSIONS: (123)I-IL-2 SPECT imaging allows for non-invasive imaging of the relative amount of IL-2 receptors present on tumour infiltrating lymphocytes in SCCHN.

Comparison among tomographic radionuclide ventriculography algorithms for computing left and right ventricular normal limits.

BACKGROUND: Various algorithms have been developed to compute right ventricular (RV) and left ventricular (LV) end-diastolic volumes, end-systolic volumes, and ejection fractions (EF) from tomographic radionuclide ventriculography (TRV). The aims of this investigation were to establish sex-specific normal limits, to determine whether different algorithms produce the same normal values, and to compare TRV normal limits vs for magnetic resonance imaging values in the literature. METHODS: Fifty-one healthy volunteers (29 men, 22 women) were studied prospectively. All subjects had normal electrocardiograms and echocardiographic examinations, and underwent both planar radionuclide ventriculography and TRV. Four algorithms were used to process TRV data. RESULTS: Normal limits for most functional parameters differed significantly from one algorithm to another. Volumes were greater in men, but no statistically significant differences were found between men and women for LV EF or RV EF values for any method. Normal LV and RV EF and volumes were largely consistent with the literature for cardiac magnetic resonance imaging. CONCLUSIONS: Ventricular measurements differ significantly among TRV algorithms. Therefore, it is important to apply sex-specific normal limits that are specific to a given TRV algorithm in interpreting LV and RV EF and volume measurements for each patient.

Agreement between four available algorithms to evaluate global systolic left and right ventricular function from tomographic radionuclide ventriculography and comparison with planar imaging.

BACKGROUND AND AIM: Left and right ventricular ejection fractions (LVEF and RVEF) and end-diastolic and end-systolic volumes (LVEDV, RVEDV, LVESV and RVESV) can be calculated from tomographic radionuclide ventriculography (TRV). The aim of this study was to validate and compare these parameters obtained using four different TRV software programs (QBS, QUBE, 4D-MSPECT and BP-SPECT). METHODS: LVEF obtained from planar radionuclide ventriculography (PRV) was compared with LVEF obtained from TRV using the four different software programs in 166 patients. Furthermore, ventricular volumes obtained using TRV (QBS, QUBE and 4D-MSPECT) were compared with those obtained using BP-SPECT, the latter being the only method with the validation of ventricular volumes in the literature. RESULTS: The correlation of LVEF between PRV and TRV was good for all methods: 0.81 for QBS, 0.79 for QUBE, 0.71 for 4D-MSPECT and 0.79 for BP-SPECT. The mean differences+/-standard deviation (SD) were 3.16+/-9.88, 10.72+/-10.92, 3.43+/-11.79 and 2.91+/-10.39, respectively. The correlation of RVEF between BP-SPECT and QUBE and QBS was poor: 0.33 and 0.38, respectively. LV volumes calculated using QBS, QUBE and 4D-MSPECT correlated well with those obtained using BP-SPECT (0.98, 0.90 and 0.98, respectively), with mean differences+/-SD of 7.31+/-42.94, -22.09+/-36.07 and -40.55+/-39.36, respectively. RV volumes showed poorer correlation between QBS and BP-SPECT and between QUBE and BP-SPECT (0.82 and 0.57, respectively). CONCLUSION: LVEF calculated using TRV correlates well with that calculated using PRV, but is not interchangeable with the value obtained using PRV. Volume calculations (for left and right ventricle) and RVEF require further validation before they can be used in clinical practice.

Accuracy of 4 different algorithms for the analysis of tomographic radionuclide ventriculography using a physical, dynamic 4-chamber cardiac phantom.

UNLABELLED: Various automatic algorithms are now being developed to calculate left ventricular (LV) and right ventricular (RV) ejection fraction from tomographic radionuclide ventriculography. We tested the performance of 4 of these algorithms in estimating LV and RV volume and ejection fraction using a dynamic 4-chamber cardiac phantom. METHODS: We developed a realistic physical, dynamic 4-chamber cardiac phantom and acquired 25 tomographic radionuclide ventriculography images within a wide range of end-diastolic volumes, end-systolic volumes, and stroke volumes. We assessed the ability of 4 algorithms (QBS, QUBE, 4D-MSPECT, and BP-SPECT) to calculate LV and RV volume and ejection fraction. RESULTS: For the left ventricle, the correlations between reference and estimated volumes (0.93, 0.93, 0.96, and 0.93 for QBS, QUBE, 4D-MSPECT, and BP-SPECT, respectively; all with P < 0.001) and ejection fractions (0.90, 0.93, 0.88, and 0.92, respectively; all with P < 0.001) were good, although all algorithms underestimated the volumes (mean difference [+/-2 SDs] from Bland-Altman analysis: -39.83 +/- 43.12 mL, -33.39 +/- 38.12 mL, -33.29 +/- 40.70 mL, and -16.61 +/- 39.64 mL, respectively). The underestimation by QBS, QUBE, and 4D-MSPECT was greater for higher volumes. QBS, QUBE, and BP-SPECT could also be tested for the right ventricle. Correlations were good for the volumes (0.93, 0.95, and 0.97 for QBS, QUBE, and BP-SPECT, respectively; all with P < 0.001). In terms of absolute volume estimation, the mean differences (+/-2 SDs) from Bland-Altman analysis were -41.28 +/- 43.66 mL, 11.13 +/- 49.26 mL, and -13.11 +/- 28.20 mL, respectively. Calculation of RV ejection fraction correlated well with true values (0.84, 0.92, and 0.94, respectively; all with P < 0.001), although an overestimation was seen for higher ejection fractions. CONCLUSION: Calculation of LV and RV ejection fraction based on tomographic radionuclide ventriculography was accurate for all tested algorithms. All algorithms underestimated LV volume; estimation of RV volume seemed more difficult, with different results for each algorithm. The more irregular shape and inclusion of a relatively hypokinetic RV outflow tract in the right ventricle seemed to cause the greater difficulty with delineation of the right ventricle, compared with the left ventricle.

Biodistribution and dosimetry of (99m)Tc-depreotide (P829) in patients suffering from breast carcinoma.

OBJECTIVE: This paper reports on the biodistribution and dosimetry of (99m)Tc-depreotide in patients. METHODS: Whole body planar images were acquired 30 minutes, 1, 2, 4, 9, and 24 hours after intravenous injection of 555-740MBq (99m)Tc-depreotide in 5 breast cancer patients. Urine was collected up to 24 hours after injection, allowing for a calculation of renal clearance and an interpretation of whole body clearance. Time activity curves were generated for the thyroid, lungs, liver, spleen, kidneys, colon, thoracic vertebrae/sternum, and whole body by fitting the organ-specific geometric mean counts, obtained from regions of interest (ROIs). The Medical Internal Radiation Dose (MIRD) formulation was applied to calculate the absorbed radiation dose for various organs. RESULTS: The whole body images show most of the activity distributed in the liver, spleen, and kidneys. Nearly all excretion of activity occurred by the renal system, and hepatobiliary excretion was negligible. Elimination of administered activity occurred predominantly through physical decay. The mean cumulative measured urinary excretion at 24 hours postinjection was 14.0% (standard deviation; 11.8%) of the administered activity. The highest absorbed dose was received by the kidneys, thyroid, and spleen. The average effective dose was estimated to be 1.15E-02mSv/MBq (standard deviation; 1.41E-03mSv/MBq). CONCLUSION: The biodistribution of (99m)Tc-depreotide demonstrated low lung and myocardial uptake allowing early imaging of the supradiaphragmatic region and this with a dosimetry favorable for clinical whole body and single photon emission computed tomography (SPECT) imaging.

Nuclear medicine imaging to predict response to radiotherapy: a review.

PURPOSE: To review available literature on positron emission tomography (PET) and single photon emission computerized tomography (SPECT) for the measurement of tumor metabolism, hypoxia, growth factor receptor expression, and apoptosis as predictors of response to radiotherapy. METHODS AND MATERIALS: Medical literature databases (Pubmed, Medline) were screened for available literature and critically analyzed as to their scientific relevance. RESULTS: Studies on 18F-fluorodeoxyglucose PET as a predictor of response to radiotherapy in head-and-neck carcinoma are promising but need confirmation in larger series. 18F-fluorothymine is stable in human plasma, and preliminary clinical data obtained with this marker of tumor cell proliferation are promising. For imaging tumor hypoxia, novel, more widely available radiopharmaceuticals with faster pharmacokinetics are mandatory. Imaging of ongoing apoptosis and growth factor expression is at a very early stage, but results obtained in other domains with radiolabeled peptides appear promising. Finally, for most of the tracers discussed, validation against a gold standard is needed. CONCLUSION: Optimization of the pharmacokinetics of relevant radiopharmaceuticals as well as validation against gold-standard tests in large patient series are mandatory if PET and SPECT are to be implemented in routine clinical practice for the purpose of predicting response to radiotherapy.

Tumour angiogenesis pathways: related clinical issues and implications for nuclear medicine imaging.

Tumour angiogenesis is essential for growth, invasion and metastasis. Retrospective studies suggest that it is an independent prognostic factor that merits prospective validation. Furthermore, as tumour blood vessels show many differences from normal vessels and are not genetically unstable, they form a key area for therapy development. However, as anti-angiogenic therapy is primarily cytostatic and not cytotoxic, novel tailor-made specific end-points for treatment monitoring are required. In this regard, suitable molecular parameters for imaging tumour angiogenesis by means of nuclear medicine are being explored. Here we review current knowledge on the multiple pathways controlling tumour angiogenesis and try to assess which are the most clinically relevant for nuclear medicine imaging. Parameters that may influence the imaging potential of radiopharmaceuticals for angiogenesis imaging such as molecular weight and structure, their targeted location within the tumour and their usefulness in terms of specificity and constancy of the targeted molecular pathway are discussed.

Peptide receptor imaging: advances in the diagnosis of pulmonary diseases.

Radiolabeled cell-surface peptide receptor-binding molecules are emerging as an important class of radiopharmaceuticals. Their binding to specific cell membrane receptors allows for noninvasive assessment of regional receptor proteomics in vivo. Information thus obtained can be used for diagnostic purposes and for predicting and monitoring response to treatment. This paradigm also applies to pulmonary diseases. In this review, available radiopharmaceuticals of great potential or already in clinical use for imaging of lung cancer, lung inflammation and infection and pulmonary embolism are discussed. In lung cancer, somatostatin receptor imaging by means of technetium-99m (99mTc)-octreotide scintigraphy has proven useful for characterizing malignancy in solitary pulmonary nodules. Additionally, several radiopharmaceuticals targeting tyrosine-kinase, e.g. 99mTc labeled epidermal growth factor and indium-111 (111In)-diethylene triamine penta-acetic acid-trastuzumab, or G-protein coupled receptors, e.g. 99mTc-bombesin, iodine-123-vasoactive intestinal peptide and 111In-tetraazacyclododecane tetra-acetic acid (DOTA)-cholecystokinine-B, are being explored for their diagnostic as well as treatment monitoring potential. With the purpose of better evaluating the source of pulmonary embolism, as well as to differentiate acute from chronic deep venous thrombosis, several radiolabeled peptides targeting the glycoprotein IIb/IIIa fibrinogen receptor found on activated platelets have been developed. Out of these, 99mTc-P280 is now approved by the US Food and Drug Administration for scintigraphic imaging of suspected acute venous thrombosis in the lower extremities of patients. In the field of lung inflammation and infection, non-specific 111In and 99mTc-human polyclonal immunoglobulins have been successfully used to identify the presence and extent of Pneumocystis carinii, cytomegalovirus, Mycobaterium avium and fungal infections in patients with HIV infection. The clinical role of other radiopharmaceuticals such as 99mTc-J001X, a nonpyrogenic acylated polygalactoside isolated from Klebsiella pneumoniae and binding with high affinity to CD11b and CD14 lipopolysaccharide receptors expressed on monocytes/macrophages, and 111In-octreotide, binding to up-regulated somatostatin receptors on activated lymphocytes needs to be further defined.