Comparison of integrin alphaVbeta3 expression and glucose metabolism in primary and metastatic lesions in cancer patients: a PET study using 18F-galacto-RGD and 18F-FDG.

The expression of alpha(v)beta(3) and glucose metabolism are upregulated in many malignant lesions, and both are known to correlate with an aggressive phenotype. We evaluated whether assessment of alpha(v)beta(3) expression and of glucose metabolism with PET using (18)F-galacto-RGD and (18)F-FDG provides complementary information in cancer patients. METHODS: Eighteen patients with primary or metastatic cancer (non-small cell lung cancer [NSCLC], n = 10; renal cell carcinoma, n = 2; rectal cancer, n = 2; others, n = 4) were examined with PET using (18)F-galacto-RGD and (18)F-FDG. Standardized uptake values (SUVs) were derived by volume-of-interest analysis. (18)F-Galacto-RGD and (18)F-FDG PET results were compared using linear regression analysis for all lesions (n = 59; NSCLC, n = 39) and for primaries (n = 14) and metastases to bone (n = 11), liver (n = 10), and other organs (n = 24) separately. RESULTS: The sensitivity of (18)F-galacto-RGD PET compared with clinical staging was 76%. SUVs for (18)F-FDG ranged from 1.3 to 23.2 (mean +/- SD, 7.6 +/- 4.9) and were significantly higher than SUVs for (18)F-galacto-RGD (range, 0.3-6.8; mean +/- SD, 2.7 +/- 1.5; P < 0.001). There was no significant correlation between the SUVs for (18)F-FDG and (18)F-galacto-RGD for all lesions (r = 0.157; P = 0.235) or for primaries, osseous or soft-tissue metastases separately (P > 0.05). For the subgroup of lesions in NSCLC, there was a weak correlation between (18)F-FDG and (18)F-galacto-RGD uptake (r = 0.353; P = 0.028). CONCLUSION: Tracer uptake of (18)F-galacto-RGD and (18)F-FDG does not correlate closely in malignant lesions. Whereas (18)F-FDG PET is more sensitive for tumor staging, (18)F-galacto-RGD PET warrants further evaluation for planning and response evaluation of targeted molecular therapies with antiangiogenic or alpha(v)beta(3)-targeted drugs.     

PET-based human dosimetry of 18F-galacto-RGD, a new radiotracer for imaging alpha v beta3 expression.

(18)F-Galacto-RGD is a new tracer for PET imaging of alpha v beta3, a receptor involved in a variety of pathologic processes including angiogenesis and metastasis. Our aim was to study the dosimetry of (18)F-galacto-RGD in humans. METHODS: Eighteen patients with various tumors (musculoskeletal tumors [n = 10], melanoma [n = 5], breast cancer [n = 2], or head and neck cancer [n = 1]) were examined. After injection of 133-200 MBq of (18)F-galacto-RGD, 3 consecutive emission scans from the thorax to the pelvis were acquired at 6.7 +/- 2.9, 35.6 +/- 7.6, and 70.4 +/- 12.2 min after injection. Blood samples (n = 4) for metabolite analysis were taken 10, 30, and 120 min after injection. The OLINDA 1.0 program was used to estimate the absorbed radiation dose. RESULTS: Reversed-phase high-performance liquid chromatography of serum revealed that more than 95% of tracer was intact up to 120 min after injection. (18)F-Galacto-RGD showed rapid clearance from the blood pool and primarily renal excretion. Background activity in lung and muscle tissue was low (percentage injected dose per liter at 71 min after injection, 0.56 +/- 0.15 and 0.69 +/- 0.25, respectively). The calculated effective dose was 18.7 +/- 2.4 microSv/MBq, and the highest absorbed radiation dose was in the bladder wall (0.22 +/- 0.03 mGy/MBq). CONCLUSION: (18)F-Galacto-RGD demonstrates high metabolic stability, a favorable biodistribution, and a low radiation dose. Consequently, this tracer can safely be used for noninvasive imaging of molecular processes involving the alpha v beta3 integrin and for the planning and monitoring of therapeutic approaches targeting alpha v beta3.     

Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer 18F-galacto-RGD in cancer patients.

(18)F-Galacto-RGD has been developed for PET of alpha(v)beta(3) integrin expression, a receptor involved in, for example, angiogenesis and metastasis. Our aim was to study the kinetics and biodistribution of (18)F-Galacto-RGD in cancer patients. METHODS: Nineteen patients with metastases of malignant melanoma (n = 7), sarcomas (n = 10), or osseous metastases (n = 2) were examined. After injection of 133-200 MBq (18)F-Galacto-RGD, 3 consecutive emission scans from the pelvis to the thorax or dynamic emission scans of the tumor over 60 min, followed by 1 static emission scan of the body, were acquired. Time-activity curves and standardized uptake values (SUVs) were derived by image region-of-interest analysis with image-based arterial input functions. Compartmental modeling was used to derive the distribution volume for muscle tissue and tumors. RESULTS: (18)F-Galacto-RGD showed rapid blood clearance and primarily renal excretion. SUVs in tumors ranged from 1.2 to 9.0. Tumor-to-blood and tumor-to-muscle ratios increased over time, with peak ratios of 3.1 +/- 2.0 and 7.7 +/- 4.3, respectively, at 72 min. The tumor kinetics were consistent with a 2-tissue compartment model with reversible specific binding. Distribution volume values were, on average, 4 times higher for tumor tissue (1.5 +/- 0.8) than those for muscle tissue (0.4 +/- 0.1). The data suggest that there was only minimal free and bound (specific or nonspecific) tracer in muscle tissue. CONCLUSION: (18)F-Galacto-RGD demonstrates a highly favorable biodistribution in humans with specific receptor binding. Most important, this study shows that (18)F-Galacto-RGD allows visualization of alpha(v)beta(3) expression in tumors with high contrast. Consequently, this tracer offers a new strategy for noninvasive monitoring of molecular processes and may supply helpful information for planning and controlling of therapeutic approaches targeting the alpha(v)beta(3) integrin.     

Imaging of delayed-type hypersensitivity reaction by PET and 18F-galacto-RGD.

Radiolabeled cyclic peptides containing the amino acid sequence arginine-glycine-aspartate (RGD peptides) have successfully been used to image the expression of the alpha(v)beta(3) integrin in malignant tumors. However, the alpha(v)beta(3) integrin also plays an important role in angiogenesis induced by chronic inflammatory processes. Therefore, the aim of this study was to evaluate whether radiolabeled RGD peptides may also be used to assess alpha(v)beta(3) expression in inflammatory diseases. We studied a hapten-induced delayed-type hypersensitivity reaction (DTHR) as a model for inflammatory processes, since DTHRs are involved in many human autoimmune disorders. METHODS: The abdominal skin of mice was sensitized by application of 2,4,6-trinitrochlorobenzene (TNCB). One week later, a DTHR was elicited by challenging the right ear with TNCB. Application of TNCB was then repeated every 48 h to induce chronic skin inflammation. Small-animal PET and autoradiography with the alpha(v)beta(3) ligands (18)F-galacto-RGD and (125)I-gluco-RGD were performed at various times after TNCB application. The time course of tracer uptake by the treated ears was compared with histologic skin changes. RESULTS: The first challenge with TNCB caused, within 12 h, an acute inflammatory response with dense dermal infiltrates of polymorphonuclear leukocytes and lymphocytes. However, autoradiography revealed no significant increase in (125)I-gluco-RGD uptake at that time (mean uptake ratio for treated ear to untreated ear, 1.02 +/- 0.1 [SD]). Further challenges with TNCB resulted in chronic skin inflammation with markedly increased small-vessel density in the ear tissue. This was paralleled by a continuous increase in uptake of (125)I-gluco-RGD. After 13 challenges, the uptake ratio had increased to 2.30 +/- 0.27 (P < 0.005 compared with baseline). Enhanced uptake of radiolabeled RGD peptides in chronic inflammation was also demonstrated noninvasively by PET with (18)F-galacto-RGD. Pretreatment of the mice with nonradiolabeled cyclic peptide c(RGDfV) almost completely blocked uptake of (18)F-galacto-RGD by the challenged ear, thus confirming the specificity of tracer uptake. CONCLUSION: Radiolabeled RGD peptides allow a noninvasive assessment of alpha(v)beta(3) expression in inflammatory processes. PET with (18)F-galacto-RGD might become a powerful tool to distinguish between the acute and chronic phases of T cell-mediated immune responses and may represent a new biomarker for disease activity in autoimmune disorders.     

Potential of dual-time-point imaging to improve breast cancer diagnosis with (18)F-FDG PET.

The purpose of this study was to assess the utility of dual-time-point imaging for identifying malignant lesions in the breast by (18)F-FDG PET. METHODS: Fifty-four breast cancer patients with 57 breast lesions underwent 2 sequential PET scans (dual-time-point imaging). The average percent change in standardized uptake values (SUVs) between time point 1 and time point 2 was calculated. All PET study results were correlated with follow-up surgical pathology results. RESULTS: Of the 57 breast lesions, 39 were invasive carcinoma and 18 were postbiopsy inflammation. Among the invasive carcinoma lesions, 33 (85%) showed an increase and 6 (15%) showed either no change or a decrease in SUVs over time. The percent change in SUVs from time point 1 to time point 2 (mean +/- SD) was +12.6% +/- 11.4% (P = 0.003). Of the 18 inflammatory lesions, 3 (17%) showed an increase and 15 (83%) showed either no change or a decrease in SUVs. The percent change in SUVs from time point 1 to time point 2 (mean +/- SD) was -10.2% +/- 16.5% (P = 0.03). Of the 57 normal contralateral breasts, 2 (3.5%) showed an increase and 55 (96.5%) showed either no change or a decrease in SUVs. The percent change in SUVs from time point 1 to time point 2 (mean +/- SD) was -15.8% +/- 17% (P = 0.005). CONCLUSION: There is increasing uptake of (18)F-FDG over time in breast malignancies, whereas the uptake of (18)F-FDG in inflammatory lesions and normal breast tissues decreases over time. A percent change of +3.75 or more in SUVs over time is highly sensitive and specific in differentiating inflammatory lesions from malignant lesions.     

Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients.

The integrin alpha v beta3 receptor is upregulated on tumor cells and endothelium and plays important roles in angiogenesis and metastasis. Arg-Gly-Asp (RGD) peptide ligands have high affinity for these integrins and can be radiolabeled for PET imaging of angiogenesis or tumor development. We have assessed the safety, stability, and tumor distribution kinetics of a novel radiolabeled RGD-based integrin peptide-polymer conjugate, 18F-AH111585, and its feasibility to detect tumors in metastatic breast cancer patients using PET. METHODS: The biodistribution of 18F-AH111585 was assessed in 18 tumor lesions from 7 patients with metastatic breast cancer by PET, and the PET data were compared with CT results. The metabolic stability of 18F-AH111585 was assessed by chromatography of plasma samples. Regions of interest (ROIs) defined over tumor and normal tissues of the PET images were used to determine the kinetics of radioligand binding in tissues. RESULTS: The radiopharmaceutical and PET procedures were well tolerated in all patients. All 18 tumors detected by CT were visible on the 18F-AH111585 PET images, either as distinct increases in uptake compared with the surrounding normal tissue or, in the case of liver metastases, as regions of deficit uptake because of the high background activity in normal liver tissue. 18F-AH111585 was either homogeneously distributed in the tumors or appeared within the tumor rim, consistent with the pattern of viable peripheral tumor and central necrosis often seen in association with angiogenesis. Increased uptake compared with background (P = 0.002) was demonstrated in metastases in lung, pleura, bone, lymph node, and primary tumor. CONCLUSION: 18F-AH111585 designed to bind the alpha v beta3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.     

Correlation of Glut-1 glucose transporter expression with

Positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose (FDG) may show negative results for bronchioloalveolar lung carcinoma. We investigated the correlation of Glut-1 glucose transporter expression with [18F]FDG uptake in non-small cell lung cancer. Thirty-two patients with 34 non-small cell lung cancers (7 bronchioloalveolar carcinomas, 23 non-bronchioloalveolar adenocarcinomas, 3 squamous cell carcinomas, and 1 adenosquamous cell carcinoma) were studied. Final diagnoses were established by histology (via thoracotomy) in all patients. [18F]FDG PET was performed 40 min after i.v. injection of 185 MBq [18F]FDG. For semi-quantitative analysis of [18F]FDG uptake, standardized uptake values (SUVs) were calculated. Glut-1 expression was studied in terms of the immunohistochemistry of paraffin sections using anti-Glut-1 antibody to determine the intensity (0-3) of Glut-1 immunoreactivity and percentage of the Glut-1-positive area. Of seven bronchioloalveolar carcinomas, six (85.7%) were negative for the expression of Glut-1, while only one (4.3%) of 23 non-bronchioloalveolar adenocarcinomas was negative (P < 0.0001). The percentages of Glut-1-positive area, as well as the SUVs, were significantly lower in bronchioloalveolar carcinomas (n = 7) (2.86% +/- 7.56% and 1.25 +/- 0.75, respectively) than in non-bronchioloalveolar adenocarcinomas (n = 23) (54.83% +/- 25.64%, P < 0.0001, and 3.94 +/- 1.93, P = 0.001, respectively). The degree of cell differentiation correlated with the percentage of Glut-1-positive area and SUVs in adenocarcinoma of the lung. Correlations between SUVs and the intensity of Glut-1 immunoreactivity were also significant (intensities 0 and 1, n = 11, SUV 1.47 +/- 0.63; intensities 2 and 3, n=23, SUV 4.78 +/- 2.13; P < 0.0001). The percentage of Glut-1-positive area correlated significantly with SUVs (n = 34, r = 0.658, P < 0.01). Overexpression of Glut-1 correlated with high [18F]FDG uptake. These findings suggest that Glut-1 expression is related to [18F]FDG uptake in non-small cell lung cancer. Glut-1 expression, as well as [18F]FDG uptake, correlated with the degree of cell differentiation in adenocarcinomas, and both Glut-1 expression and [18F]FDG uptake were significantly lower in bronchioloalveolar carcinomas than in non-bronchioloalveolar carcinomas.     

Comparison of [18F]fluorodeoxyglucose uptake with glucose transporter-1 expression and proliferation rate in human glioma and non-small-cell lung cancer

To clarify the biological significance of [18F]fluorodeoxyglucose (18F-FDG) accumulation in patients with cancer, we assessed the relationships between 18F-FDG uptake and glucose transporter-1 (GLUT-1) expression and proliferation rate in human glioma and lung cancer. We obtained FDG PET images and measured standardized uptake values (SUVs) of primary tumours in 13 patients with brain glioma and 25 patients with non-small-cell lung cancer. After surgery, portions of respected tumours were obtained, and the proliferation rate was measured as proliferation index (per cent of (S+G2+M)/(G0+G1+S+G2+M)) using DNA flow cytometry. The expression of GLUT-1 in a tumour was evaluated by using immunostaining. We classified GLUT-1 expression as grade 0 (no positive cell), grade 1 (< 10% cells positive), grade 2 (11-50% cells positive) and grade 3 (51-100% cells positive). Based on the expression of GLUT-1, cases with grades 0, 1, 2 and 3 showed SUVs of 6.1 +/- 2.8, 5.0 +/- 3.2, 8.3 +/- 3.3 and 10.4 +/- 6.6, respectively (P < 0.05). Non-small-cell lung cancer showed higher FDG uptake (SUV, 8.5 +/- 5.1) and higher GLUT-1 expression (grade, 2.0 +/- 1.0) than did brain glioma (SUV, 4.7 +/- 2.5; grade, 0.8 +/- 0.8). Based on the total number of cases, SUVs did not relate to proliferation index (r = 0.19). In non-small-cell lung cancer, SUVs did not correlate with proliferation index, whereas in glioma, SUVs were strongly related to proliferation index (r = 0.79, P < 0.01). In conclusion, FDG uptake generally correlated with GLUT-1 expression in non-small-cell lung cancer and glioma. In the case of glioma, FDG uptake also indicated increased cellular proliferation, which was not demonstrated in non-small-cell lung cancer.     

microPET of tumor integrin alphavbeta3 expression using 18F-labeled PEGylated tetrameric RGD peptide (18F-FPRGD4).

In vivo imaging of alpha(v)beta(3) expression has important diagnostic and therapeutic applications. Multimeric cyclic RGD peptides are capable of improving the integrin alpha(v)beta(3)-binding affinity due to the polyvalency effect. Here we report an example of (18)F-labeled tetrameric RGD peptide for PET of alpha(v)beta(3) expression in both xenograft and spontaneous tumor models. METHODS: The tetrameric RGD peptide E{E[c(RGDyK)](2)}(2) was derived with amino-3,6,9-trioxaundecanoic acid (mini-PEG; PEG is poly(ethylene glycol)) linker through the glutamate alpha-amino group. NH(2)-mini-PEG-E{E[c(RGDyK)](2)}(2) (PRGD4) was labeled with (18)F via the N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) prosthetic group. The receptor-binding characteristics of the tetrameric RGD peptide tracer (18)F-FPRGD4 were evaluated in vitro by a cell-binding assay and in vivo by quantitative microPET imaging studies. RESULTS: The decay-corrected radiochemical yield for (18)F-FPRGD4 was about 15%, with a total reaction time of 180 min starting from (18)F-F(-). The PEGylation had minimal effect on integrin-binding affinity of the RGD peptide. (18)F-FPRGD4 has significantly higher tumor uptake compared with monomeric and dimeric RGD peptide tracer analogs. The receptor specificity of (18)F-FPRGD4 in vivo was confirmed by effective blocking of the uptake in both tumors and normal organs or tissues with excess c(RGDyK). CONCLUSION: The tetrameric RGD peptide tracer (18)F-FPRGD4 possessing high integrin-binding affinity and favorable biokinetics is a promising tracer for PET of integrin alpha(v)beta(3) expression in cancer and other angiogenesis related diseases.     

Early prediction of response to chemotherapy in metastatic breast cancer using sequential 18F-FDG PET.

Chemotherapy is currently the treatment of choice for patients with high-risk metastatic breast cancer. Clinical response is determined after several cycles of chemotherapy by changes in tumor size as assessed by conventional imaging procedures including CT, MRI, plain film radiography, or ultrasound. The aim of this study was to evaluate the use of sequential 18F-FDG PET to predict response after the first and second cycles of standardized chemotherapy for metastatic breast cancer. METHODS: Eleven patients with 26 metastatic lesions underwent 31 (18)F-FDG PET examinations (240-400 MBq of 18F-FDG; 10-min 2-dimensional emission and transmission scans). Clinical response, as assessed by conventional imaging after completion of chemotherapy, served as the reference. 18F-FDG PET images after the first and second cycles of chemotherapy were analyzed semiquantitatively for each metastatic lesion using standardized uptake values (SUVs) normalized to patients' blood glucose levels. In addition, whole-body 18F-FDG PET images were viewed for overall changes in the 18F-FDG uptake pattern of metastatic lesions within individual patients and compared with conventional imaging results after the third and sixth cycles of chemotherapy. RESULTS: After completion of chemotherapy, 17 metastatic lesions responded, as assessed by conventional imaging procedures. In those lesions, SUV decreased to 72% +/- 21% after the first cycle and 54% +/- 16% after the second cycle, when compared with the baseline PET scan. In contrast, 18F-FDG uptake in lesions not responding to chemotherapy (n = 9) declined only to 94% +/- 19% after the first cycle and 79% +/- 9% after the second cycle. The differences between responding and nonresponding lesions were statistically significant after the first (P = 0.02) and second (P = 0.003) cycles. Visual analysis of 18F-FDG PET images correctly predicted the response in all patients as early as after the first cycle of chemotherapy. As assessed by 18F-FDG PET, the overall survival in nonresponders (n = 5) was 8.8 mo, compared with 19.2 mo in responders (n = 6). CONCLUSION: In patients with metastatic breast cancer, sequential 18F-FDG PET allowed prediction of response to treatment after the first cycle of chemotherapy. The use of 18F-FDG PET as a surrogate endpoint for monitoring therapy response offers improved patient care by individualizing treatment and avoiding ineffective chemotherapy.     

Relationship between 18F-FDG uptake and breast density in women with normal breast tissue.

Breast density affects the mammographic detectability of breast cancer. The study aimed to evaluate the impact of breast density on the (18)F-FDG uptake of normal breast tissue. METHODS: The study population consisted of 45 women (median age, 54 y; age range, 42-77 y). All underwent whole-body (18)F-FDG PET for various indications other than breast cancer, and all underwent mammography within a mean of 6.6 +/- 4.9 mo of PET. On the basis of mammographic findings, breasts were categorized as extremely dense, heterogeneously dense, primarily fatty, or entirely fatty. Regions of interest were drawn on every PET image in which breast tissue was visualized. Average and peak standardized uptake values (SUVs) were calculated for the left and right breasts. RESULTS: Mammography showed that 20 of the 45 women had heterogeneously dense breasts, 1 had extremely dense breasts, 20 had primarily fatty breasts, and 4 had entirely fatty breasts. In dense breasts, the average SUV was 0.39 +/- 0.05 (right breast) and 0.36 +/- 0.07 (left breast) and the peak SUV was 0.93 +/- 0.16 and 0.89 +/- 0.18, respectively. The average and peak SUVs were significantly lower for primarily fatty breasts than for dense breasts (P < 0.01). Peak and average SUVs of entirely fatty breasts also differed significantly from peak and average SUVs of dense and primarily fatty breasts (P < 0.01). The impact of hormonal status on SUV was significant but less than the impact of breast density. No significant relationship between average SUV or peak SUV and age or serum glucose level was observed. CONCLUSION: Breast density and hormonal status affect the uptake of (18)F-FDG. Dense breasts exhibit, on average, significantly higher (18)F-FDG uptake than do nondense breasts. However, the highest peak SUV observed in dense breasts was 1.39, which is well below the SUV of 2.5 commonly used as a cutoff between benign and malignant tissue. Therefore, breast density is unlikely to affect the ability of (18)F-FDG PET to discriminate between benign and malignant breast lesions.     

Dual time point 18F-FDG PET imaging detects breast cancer with high sensitivity and correlates well with histologic subtypes.

This prospective study was designed to assess the utility of the dual time point imaging technique by (18)F-FDG PET in detecting primary breast cancer and to determine whether there is a relationship between (18)F-FDG uptake and its change over time and the histopathologic subtypes. METHODS: One hundred fifty-two patients with newly diagnosed breast cancer underwent 2 sequential PET scans (dual time point imaging) for preoperative staging. The maximum standardized uptake value (SUVmax) of (18)F-FDG was measured from both time points. The percent change in SUVmax (Delta%SUVmax) between time points 1 (SUVmax1) and 2 (SUVmax2) was calculated. Patients were divided into 2 groups according to histopathology as invasive and noninvasive. Invasive tumors were also divided into 2 groups (>10 mm and 4-10 mm). The tumor-to-contralateral normal breast (background) ratios of SUVmax at both time points for groups were measured and the Delta%SUVmax values were calculated. RESULTS: The mean +/- SD of the SUVmax1, the SUVmax2, and the Delta%SUVmax were 3.9 +/- 3.7, 4.3 +/- 4.0, and 8.3% +/- 11.5% for invasive; 2.0 +/- 0.6, 2.1 +/- 0.6, and 3.4% +/- 13.0% for noninvasive; and were 1.2 +/- 0.3, 1.1 +/- 0.2, and -10.0% +/- 10.8% for the contralateral normal breast groups, respectively. In the comparison of SUVmax1, Delta%SUVmax, and the tumor-to-background ratios among groups, all results were significant (P < 0.001). Visual assessment revealed that the sensitivity of dual time point imaging was 90.1% for invasive cancer >10 mm, 82.7% for invasive breast cancers 4-10 mm, and 76.9% for noninvasive breast cancers. CONCLUSION: Dual time point imaging is a simple and noninvasive method that may improve the sensitivity and accuracy of (18)F-FDG PET in assessing patients with primary breast cancer. The changes that are noted in SUVs in dual time point imaging vary depending on the histopathologic type of primary breast cancer.     

FDG PET measurement of the proliferative potential of non-small cell lung cancer.

The goals of this study were to correlate FDG uptake with cell proliferation and cellular density in non-small cell lung cancer. METHODS: Thirty-one patients with 32 non-small cell lung cancers were examined with FDG PET. For semiquantitative analysis, standardized uptake values (SUVs) were calculated. All patients underwent thoracotomy within 4 wk after the FDG PET study. Cell proliferation was immunohistochemically assessed as the relative number of cells expressing the proliferating cell nuclear antigen ([PCNA] labeling index). Cellular density was also evaluated using light microscopy. RESULTS: SUVs correlated significantly with PCNA labeling index (r = 0.740; P < 0.0001) but only weakly with cellular density (r = 0.392; P = 0.0266). High FDG uptake correlated with high PCNA expression. The PCNA labeling index and SUVs were significantly lower in bronchioloalveolar carcinomas (n = 8) (12.3 +/- 9.45% and 1.45 +/- 0.76, respectively) than in nonbronchioloalveolar carcinomas (n = 19) (33.5 +/- 21.8%, P = 0.015, and 3.75 +/- 1.93, P = 0.003, respectively). However, no significant differences in cellular density were seen between bronchioloalveolar carcinomas and nonbronchioloalveolar carcinomas. CONCLUSION: FDG uptake is related to cell proliferation rather than to the cellular density of non-small cell lung cancer.     

The Potential of F-18-FDG PET in Breast Cancer. Detection of Primary Lesions, Axillary Lymph Node Metastases, or Distant Metastases

This retrospective study was done to evaluate the utility of 2-[F-18]fluoro-2-deoxy-D-glucose positron emission tomography (F-18-FDG PET) in identifying primary and recurrent breast cancer and lymph node metastases. One hundred whole-body PET scans of 87 patients were reviewed. PET results obtained with F-18-FDG and an ECAT/EXACT-921 or an ECAT-931 (Siemens/CTI) were based on visual interpretation, or standardized uptake values (SUVs), related to histology and also compared to computerized tomography (CT) and mammography results. The sensitivity for PET in detecting primary (N = 35 studies) and recurrent breast cancer (N = 65 studies) was 96% and 85% with a specificity of 91% and 73%. The sensitivity for lymph node metastases at the time of initial diagnosis was 100% with a specificity of 100%. Quantitative SUV information did not improve the accuracy of F-18-FDG PET in identifying primary breast cancers. The results suggest that whole-body PET is useful in detecting recurrence or metastases, may be useful in detecting lymph node metastases prior to initial axillary lymph node dissection, but is less sensitive in excluding axillary lymph nodes metastases later in the course of the disease.     

Differential diagnosis of thymic tumors using a combination of 11C-methionine PET and FDG PET.

We assessed the usefulness of PET studies in making a differential diagnosis of thymic tumors by using 11C-methionine (MET) and 18F-fluorodeoxyglucose (FDG). METHODS: We examined 31 patients with thymic tumors, including 14 patients with thymic cancer, 9 with invasive thymoma, 5 with noninvasive thymoma and 3 with thymic cysts. The histological diagnosis was confirmed by either surgery or biopsy. MET PET and FDG PET were performed in 28 and 29 patients, respectively. Both the MET and FDG uptakes were evaluated by the standardized uptake value (SUV). RESULTS: MET uptake was not substantially different among thymic cancer (4.8 +/- 1.4), invasive thymoma (4.3 +/-1.1) and noninvasive thymoma (4.5 +/- 1.2), bat MET uptake in thymic cysts (0.9 +/- 0.1) was lower than that in the other three tumors (P < 0.01). The FDG uptake in thymic cancer (7.2 +/- 2.9) was higher than that in invasive thymoma (3.8 -/+ 1.3), noninvasive thymoma (3.0 +/- 1.0) and thymic cysts (0.9) (P < 0.01). MET uptake in thymic tumors correlated with the FDG uptake (r = 0.65), whereas MET uptake in thymic cancer was lower than FDG uptake (FDG/MET ratio = 1.52 +/- 0.52) but was higher than FDG uptake in both invasive and noninvasive thymoma (FDG/ MET ratio = 0.86 +/- 0.33). To differentiate thymic cancer from thymoma, a receiver operating characteristic (ROC) analysis was performed. The area under the curve of FDG PET was 0.90, whereas the FDG/MET ratio was 0.87. CONCLUSION: The MET PET, FDG PET and the FDG/MET ratios were unable to differentiate benign thymic tumors from malignant ones, although FDG PET was considered to be useful in the differential diagnosis between thymic cancer and thymoma. Although the difference in the uptake ratio between FDG and MET suggests a different origin of the tumors, the FDG/MET ratio is not considered to be useful as a complementary method for the differential diagnosis of thymic tumors.     

Positron emission tomography with 11C-acetate and 18F-FDG in prostate cancer patients

Visualisation of primary prostate cancer, its relapse and its metastases is a clinically relevant problem despite the availability of state-of-the-art methods such as CT, MRI, transrectal ultrasound and fluorine-18 fluorodeoxyglucose positron emission tomography ((18)F-FDG PET). The aim of this study was to evaluate the efficacy of carbon-11 acetate and (18)F-FDG PET in the detection of prostate cancer and its metastases. Twenty-five patients were investigated during the follow-up of primary prostate cancer, suspected relapse or metastatic disease using (11)C-acetate PET; 15 of these patients were additionally investigated using (18)F-FDG PET. Fourteen patients were receiving anti-androgen treatment at the time of the investigation. Lesions were detected in 20/24 (83%) patients using (11)C-acetate PET and in 10/15 (75%) patients using (18)F-FDG PET. Based on the results of both PET scans, one patient was diagnosed with recurrent lung cancer. Median (18)F-FDG uptake exceeded that of (11)C-acetate in distant metastases (SUV =3.2 vs 2.3). However, in local recurrence and in regional lymph node metastases, (11)C-acetate uptake (median SUVs =2.9 and 3.8, respectively) was higher than that of (18)F-FDG (median SUVs =1.0 and 1.1, respectively). A positive correlation was observed between serum PSA level and both (11)C-acetate uptake and (18)F-FDG uptake. (11)C-acetate seems more useful than (18)F-FDG in the detection of local recurrences and regional lymph node metastases. (18)F-FDG, however, appears to be more accurate in visualising distant metastases. There may be a role for combined (11)C-acetate/(18)F-FDG PET in the follow-up of patients with prostate cancer and persisting or increasing PSA.     

Usefulness of standardized uptake values for distinguishing adrenal glands with pheochromocytoma from normal adrenal glands by use of 6-18F-fluorodopamine PET.

6-(18)F-Fluorodopamine ((18)F-FDA) PET is a highly sensitive tool for the localization of pheochromocytoma (PHEO). The aim of this study was to establish cutoff values for pathologic and physiologic adrenal gland tracer uptake. METHODS: (18)F-FDA PET with CT coregistration was performed in 14 patients (10 men and 4 women; age [mean +/- SD], 42.9 +/- 13.3 y) with unilateral adrenal gland PHEO and in 13 control subjects (5 men and 8 women; age, 51.7 +/- 12.5 y) without PHEO. Standardized uptake values (SUVs) were compared between adrenal glands with PHEO and normal left adrenal glands in control subjects. RESULTS: (18)F-FDA accumulation was observed in all adrenal glands with PHEO and in 6 of 13 control adrenal glands (P = 0.02). The SUV was higher in adrenal glands with PHEO (mean +/- SD, 16.1 +/- 6.1) than in (18)F-FDA-positive control adrenal glands (7.7 +/- 1.4) (P = 0.005). SUV cutoffs for distinguishing between adrenal glands with PHEO and normal adrenal glands were 7.3 (100% sensitivity) and 10.1 (100% specificity). CONCLUSION: The SUVs of adrenal foci on (18)F-FDA PET facilitate the distinction between adrenal glands with PHEO and normal adrenal glands.     

Glycosylated RGD-containing peptides: tracer for tumor targeting and angiogenesis imaging with improved biokinetics.

The alpha(v)beta3 integrin plays an important role in metastasis and tumor-induced angiogenesis. Targeting with radiolabeled ligands of the alpha(v)beta3 integrin may provide information about the receptor status and enable specific therapeutic planning. Previous studies from our group resulted in tracers that showed alpha(v)beta3-selective tumor uptake. However, these first-generation compounds predominantly revealed hepatobiliary excretion with high radioactivity found in the liver. In this report, the synthesis and biological evaluation of the first glycosylated RGD-containing peptide (RGD-peptide) for the noninvasive imaging of alpha(v)beta3 expression are described. METHODS: Peptides were assembled on a solid support using fluorenylmethoxycarbonyl-coupling protocols. The precursor cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP1 was synthesized by coupling 3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-beta-D-glycero-D-gulo-heptonic acid (SAA(Bn3)) with cyclo(-Arg(Mtr)-Gly-Asp(OtBu)-D-Tyr(tBu)-Lys-) and subsequent removal of the protection groups. Iodine labeling was performed by the Iodo-Gen method (radiochemical yield > 50%). The in vitro binding assays were performed using purified immobilized alpha(IIb)beta3, alpha(v)beta5, and alpha(v)beta3 integrins. For in vivo experiments, nude mice bearing xenotransplanted melanomas and mice with osteosarcomas were used. RESULTS: The glycosylated peptide 3-iodo-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Lys(SAA)-) GP2 showed high affinity and selectivity for alpha(v)beta3 in vitro (50% inhibitory concentration = 40 nmol/L). Pretreatment studies indicate specific binding of [125I]GP2 on alpha(v)beta3-expressing tumors in vivo. Comparison of the pharmacokinetics of [125I]GP2 and [125I]-3-iodo-Tyr4-cyclo(-Arg-Gly-Asp-D-Tyr-Val-) [125I]P2 revealed for [125I]GP2 an increased activity concentration in the blood (e.g., 3.59 +/- 0.35 percentage injected dose [%ID]/g vs. 1.72 +/- 0.44 %ID/g at 10 min postinjection) and a significantly reduced uptake in the liver (e.g., 2.59 +/- 0.24 %ID/g vs. 21.96 +/- 2.78 %ID/g at 10 min postinjection). Furthermore, a clearly increased activity accumulation in the tumor was found (e.g., 3.05 +/- 0.31 %ID/g vs. 0.92 +/- 0.16 %ID/g at 240 min postinjection), which remained almost constant between 60 and 240 min postinjection. This resulted in good tumor-to-organ ratios for the glycosylated tracer (e.g., 240-min postinjection osteosarcoma model: tumor-to-blood = 16; tumor-to-muscle = 7; tumor-to-liver = 2.5), which were confirmed by the first gamma-camera images of osteosarcoma-bearing mice at 240 min postinjection. CONCLUSION: This study demonstrates that the introduction of a sugar moiety improves the pharmakokinetic behavior of a hydrophobic peptide-based tracer. Additionally, this alpha(v)beta3-selective glycosylated radioiodinated second-generation tracer GP2 shows high tumor uptake and good tumor-to-organ ratios that allow noninvasive visualization of alpha(v)beta3-expressing tumors and monitoring therapy with alpha(v)beta3 antagonists. Finally, the favorable biokinetics make the glycosylated RGD-peptide a promising lead structure for tracers to quantify the alpha(v)beta3 expression using PET.     

Dual time point 18F-FDG PET imaging for differentiating malignant from inflammatory processes.

The aim of this study was to investigate the difference in the rates of FDG uptake between malignant and inflammatory cells and processes. METHODS: In vitro studies: (18)F-FDG uptake by different tumor cell lines (human mesothelioma [REN]; rat mesothelioma [II45]; mice melanoma [B18F10]; mice mesothelioma [AB12]; human myeloma [GM1500]; and human ovarian cancer [SKOV3]) and peripheral blood mononuclear cells isolated from 8 healthy human volunteers was measured 20 and 60 min after FDG was added into growth medium. Animal studies: II45 cells were implanted into the left flank of rats (n = 5) and a focal inflammatory reaction (mechanical irritation) was generated in the right flank. PET images at 45 and 90 min after injection of FDG were obtained and standardized uptake values (SUVs) were determined. Patient studies: Seventy-six patients who had dual time FDG PET scans were retrospectively analyzed. All results were expressed as the percentage change in SUV of the later time image from that of the earlier time (mean +/- SD). RESULTS: In vitro studies: Except for the SKOV3 cell line, which had only minimally increased FDG uptake (+10% +/- 26%; P > 0.3), all other tumor cell lines tested showed significantly increased FDG uptake over time (GM1500, +59% +/- 19%; B18F10, +81% +/- 15%; AB12, 93% +/- 21%; II45, +161% +/- 21%; REN, +198% +/- 48%; P < 0.01 for all). By contrast, FDG uptake in mononuclear cells was decreased in 7 of 8 donors. Animal studies: SUVs of tumors from 90-min images were significantly higher than those from 45-min images (+18% +/- 8%; P < 0.01), whereas the SUVs of inflammatory lesions decreased over time (-17% +/- 13% of the early images; P < 0.05). Clinical studies: The SUVs of delayed images from the known malignant lesions compared with those of earlier scans increased over time (+19.18% +/- 9.58%; n = 31; P < 0.001; 95% confidence interval, 15.8%-22.6%). By contrast, the SUVs of benign lung nodules decreased slightly over time (-6.3% +/- 8.1%; n = 12; P < 0.05; 95% confidence interval, -10.9% to -1.7%). The SUV of inflammatory lesions caused by radiation therapy (+1.16% +/- 7.23%; n = 8; P > 0.05; 95% confidence interval, -3.9%-6.2%) and the lesions of painful lower limb prostheses (+4.03% +/- 11.32%; n = 25; P > 0.05; 95% confidence interval, -0.4%-8.5%) remained stable over time. CONCLUSION: These preliminary data show that dual time imaging appears to be useful in distinguishing malignant from benign lesions. Further research is necessary to confirm these results.     

Dual-function probe for PET and near-infrared fluorescence imaging of tumor vasculature.

To date, the in vivo imaging of quantum dots (QDs) has been mostly qualitative or semiquantitative. The development of a dual-function PET/near-infrared fluorescence (NIRF) probe can allow for accurate assessment of the pharmacokinetics and tumor-targeting efficacy of QDs. METHODS: A QD with an amine-functionalized surface was modified with RGD peptides and 1,4,7,10-tetraazacyclodocecane-N,N',N',N'-tetraacetic acid (DOTA) chelators for integrin alpha(v)beta(3)-targeted PET/NIRF imaging. A cell-binding assay and fluorescence cell staining were performed with U87MG human glioblastoma cells (integrin alpha(v)beta(3)-positive). PET/NIRF imaging, tissue homogenate fluorescence measurement, and immunofluorescence staining were performed with U87MG tumor-bearing mice to quantify the probe uptake in the tumor and major organs. RESULTS: There are about 90 RGD peptides per QD particle, and DOTA-QD-RGD exhibited integrin alpha(v)beta(3)-specific binding in cell cultures. The U87MG tumor uptake of (64)Cu-labeled DOTA-QD was less than 1 percentage injected dose per gram (%ID/g), significantly lower than that of (64)Cu-labeled DOTA-QD-RGD (2.2 +/- 0.3 [mean +/- SD] and 4.0 +/- 1.0 %ID/g at 5 and 18 h after injection, respectively; n = 3). Taking into account all measurements, the liver-, spleen-, and kidney-to-muscle ratios for (64)Cu-labeled DOTA-QD-RGD were about 100:1, 40:1, and 1:1, respectively. On the basis of the PET results, the U87MG tumor-to-muscle ratios for DOTA-QD-RGD and DOTA-QD were about 4:1 and 1:1, respectively. Excellent linear correlation was obtained between the results measured by in vivo PET imaging and those measured by ex vivo NIRF imaging and tissue homogenate fluorescence (r(2) = 0.93). Histologic examination revealed that DOTA-QD-RGD targets primarily the tumor vasculature through an RGD-integrin alpha(v)beta(3) interaction, with little extravasation. CONCLUSION: We quantitatively evaluated the tumor-targeting efficacy of a dual-function QD-based probe with PET and NIRF imaging. This dual-function probe has significantly reduced potential toxicity and overcomes the tissue penetration limitation of optical imaging, allowing for quantitative targeted imaging in deep tissue.