Splenic fluorodeoxyglucose uptake increased by granulocyte colony-stimulating factor therapy: PET imaging results.

Using PET, we investigated the change in 18F-fluorordeoxyglucose (FDG) uptake in the spleen after granulocyte colony-stimulating factor (G-CSF) treatment. METHODS: Forty-two FDG PET scans in 12 patients with locally advanced breast cancer who received G-CSF treatment were studied (12 baseline, 10 during G-CSF, 20 after G-CSF treatment). The PET images obtained at 50-60 and 60-70 min after intravenous FDG (370 MBq) injection were assessed visually and were compared with those before G-CSF treatment. For a semiquantitative index of FDG uptake, we determined the standardized uptake value calculated on the basis of predicted lean body mass (SUL) on these images, and we calculated the SUL ratios normalized to their baseline SUL values. RESULTS: During G-CSF treatment (n = 10), 9 scans (90%) showed increased splenic FDG uptake (3 slightly, 6 substantially). After G-CSF treatment (n = 20), 13 (65%) showed no change, 7 (35%) showed slightly increased uptake, but no case showed substantially increased FDG uptake in the spleen (P = 0.0003). Out of 30 PET scans obtained during and after G-CSF treatment, 16 (53%) showed increased FDG uptake in the spleen (10 slightly, 6 substantially), whereas 26 (87%) showed increased bone marrow FDG uptake (14 slightly, 12 substantially). The FDG uptake in other normal organs (liver, blood and lung) showed no change during or after G-CSF treatment. Similar to the change in the bone marrow, the SULs in the spleen significantly increased during G-CSF treatment (baseline, 1.50+/-0.31, versus during G-CSF, 2.69+/-0.84; P = 0.0004), then decreased after discontinuation of G-CSF (1.65+/-0.23). There was a significant correlation between the SUL ratios in the spleen and those in the bone marrow (r = 0.778, P < 0.0001), whereas there were no correlations between those in other organs and those in the bone marrow. CONCLUSION: Substantially increased FDG uptake was observed in the spleen during and after G-CSF treatment, although this change was less frequent and not as marked as the change observed in the bone marrow. The recognition and understanding of this phenomenon will be increasingly important when interpreting FDG PET images in cancer patients to avoid confusing this normal phenomenon with pathological splenic (tumor) involvement.     

Imaging gastric cancer with PET and the radiotracers 18F-FLT and 18F-FDG: a comparative analysis.

In this pilot study, we evaluated 3'-deoxy-3'-(18)F-fluorothymidine (FLT) PET for the detection of gastric cancer and compared the diagnostic accuracy with that of (18)F-FDG PET. METHODS: Forty-five patients (31 male and 14 female) with histologically proven locally advanced gastric cancer underwent attenuation-corrected whole-body (18)F-FLT PET and (18)F-FDG PET/CT (low-dose CT). (18)F-FLT emission images were acquired on a full-ring PET scanner 45 min after the injection of 270-340 MBq of (18)F-FLT. (18)F-FDG PET/CT was performed 60 min after the injection of 300-370 MBq of (18)F-FDG. Mean standardized uptake values for (18)F-FLT and (18)F-FDG were calculated using circular ROIs (diameter, 1.5 cm) in the primary tumor manifestation site, in a reference segment of the liver, and in the bone marrow and were compared on a lesion-by-lesion basis. RESULTS: According to the Lauren classification, 15 tumors (33%) were of the intestinal subtype and 30 (67%) of the nonintestinal subtype. (18)F-FLT PET images showed high contrast for the primary tumor and proliferating bone marrow. In all patients (45/45), focal (18)F-FLT uptake could be detected in the primary tumor. In contrast, 14 primary tumors were negative for (18)F-FDG uptake, with lesional (18)F-FDG uptake lower than or similar to background activity. The mean standardized uptake value for (18)F-FLT in malignant primaries was 6.0 +/- 2.5 (range, 2.4-12.7). In the subgroup of (18)F-FDG-positive patients, the mean value for (18)F-FDG was 8.4 +/- 4.1 (range, 3.8/19.0), versus 6.8 +/- 2.6 for (18)F-FLT (Wilcoxon test: P = 0.03). Comparison of mean (18)F-FLT and (18)F-FDG uptake in tumors with signet ring cells revealed no statistically significant difference between the tracers (6.2 +/- 2.1 for (18)F-FLT vs. 6.4 +/- 2.8 for (18)F-FDG; Wilcoxon test: P = 0.94). CONCLUSION: The results of this study indicate that imaging gastric cancer with the proliferation marker (18)F-FLT is feasible. (18)F-FLT PET was more sensitive than (18)F-FDG PET, especially in tumors frequently presenting without or with low (18)F-FDG uptake, and may improve early evaluation of response to neoadjuvant treatment.     

淋巴瘤骨髓浸润的18F-FDG PET显像研究

目的 用^18F-脱氧葡萄糖（FDG）PET显像研究淋巴瘤细胞骨髓浸润。方法 恶性淋巴癌患者30例，其中非霍奇金淋巴瘤（NHL）20例、霍奇金病（HD）10例，进行全身^18F-FDG PET显像。局灶性边缘清楚的淋巴结相应区域^18F-FDG浓聚视为恶性淋巴结显影。利用灰度色标，视觉分析骨髓及肝脏内^18F-FDG浓聚情况。骨髓的^18F-FDG分布不均，摄取高于肝脏，判断为骨髓^18F-FDG摄取异常；骨髓的^18F-FDG分布均匀，摄取低于或等于肝脏，判断为骨髓^18F-FDG摄取正常。所有患者均行髂棘的骨髓活组织检查。结果 30例中18例有淋巴结摄取^18F-FDG；12例淋巴结摄取^18F-FDG阴性患者中，8例NHL，4例HD。有26例患者的骨髓^18F-FDG摄取情况与骨髓组织学检查结果一致，其中骨髓有淋巴细胞浸润7例，无淋巴细胞浸润19例。有3例骨髓组织学检查阴性的患者，^18F-FDG PET示骨髓^18F-FDG摄取异常、骨髓有淋巴细胞浸润；1例NHL患者，骨髓组织学检查阳性但^18F-FDG PET示骨髓^18F-FDG摄取正常。结论 ^18F-DG PET全身显像能正确评价骨髓淋巴细胞浸润情况，减少对淋巴瘤分期所进行的骨髓组织学检查。     

Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model.

Increased glucose metabolism of inflammatory tissues is the main source of false-positive (18)F-FDG PET findings in oncology. It has been suggested that radiolabeled nucleosides might be more tumor specific. METHODS: To test this hypothesis, we compared the biodistribution of 3'-deoxy-3'-(18)F-fluorothymidine (FLT) and (18)F-FDG in Wistar rats that bore tumors (C6 rat glioma in the right shoulder) and also had sterile inflammation in the left calf muscle (induced by injection of 0.1 mL of turpentine). Twenty-four hours after turpentine injection, the rats received an intravenous bolus (30 MBq) of either (18)F-FLT (n = 5) or (18)F-FDG (n = 5). Pretreatment of the animals with thymidine phosphorylase (>1,000 U/kg, intravenously) before injection of (18)F-FLT proved to be necessary to reduce the serum levels of endogenous thymidine and achieve satisfactory tumor uptake of radioactivity. RESULTS: Tumor-to-muscle ratios of (18)F-FDG at 2 h after injection (13.2 +/- 3.0) were higher than those of (18)F-FLT (3.8 +/- 1.3). (18)F-FDG showed high physiologic uptake in brain and heart, whereas (18)F-FLT was avidly taken up by bone marrow. (18)F-FDG accumulated in the inflamed muscle, with 4.8 +/- 1.2 times higher uptake in the affected thigh than in the contralateral healthy thigh, in contrast to (18)F-FLT, for which this ratio was not significantly different from unity (1.3 +/- 0.4). CONCLUSION: In (18)F-FDG PET images, both tumor and inflammation were visible, but (18)F-FLT PET showed only the tumor. Thus, the hypothesis that (18)F-FLT has a higher tumor specificity was confirmed in our animal model.     

Whole-body tumor imaging using PET and 2-18F-fluoro-L-tyrosine: preliminary evaluation and comparison with 18F-FDG.

18F-FDG PET imaging is now established as a valuable tool for evaluating cancer patients. However, a limitation of (18)F-FDG is its absence of specificity for tumor. Both protein synthesis and amino acid transport are enhanced in most tumor cells, but their metabolism is less affected in inflammation. We therefore decided to evaluate the ability of PET with 2-(18)F-fluoro-L-tyrosine ((18)F-TYR) to visualize cancer lesions in patients compared with (18)F-FDG PET. METHODS: (18)F-FDG PET and (18)F-TYR PET were performed on 23 patients with histologically proven malignancies (11 non-small cell lung cancers (NSCLCs), 10 lymphomas, and 2 head and neck carcinomas). Fully corrected, whole-body PET studies were obtained on separate days. (18)F-FDG studies were performed after routine clinical fashion. (18)F-TYR studies were started 36 +/- 6 min after tracer injection and a second scan centered over a reference lesion was acquired after completion of the whole-body survey-on average, 87 min after injection. Standardized uptake values (SUVs) were calculated for all abnormal foci and for various normal structures. Results were compared with pathologic or correlative studies. RESULTS: (18)F-FDG PET correctly identified 54 malignant lesions, among which 36 were also visualized with (18)F-TYR (67%). (18)F-TYR did not detect any additional lesion. Tumor SUVs (SUV(bw), 5.2 vs. 2.5), tumor-to-muscle (7.4 vs. 2.7), and tumor-to-mediastinum activity ratios (3 vs. 1.4) were higher with (18)F-FDG than with (18)F-TYR. Two of 11 NSCLCs and 4 of 10 lymphomas were understaged with (18)F-TYR compared with (18)F-FDG. Although the NSCLC lesions missed by (18)F-TYR PET were small, several large lymphoma lesions did not accumulate the tracer. In 4 patients, (18)F-TYR-positive lesions coexisted with (18)F-TYR-negative lesions. There was a high physiologic (18)F-TYR uptake by the pancreas (average SUV(bw), 10.3) and the liver (average SUV(bw), 6.3). Muscle and bone marrow uptakes were also higher with (18)F-TYR than with (18)F-FDG: average SUV(bw), 1 versus 0.7 and 2.6 versus 1.8, respectively. There was no change over time in the (18)F-TYR uptake by the tumors or the normal structures. CONCLUSION: (18)F-TYR PET is not superior to (18)F-FDG PET for staging patients with NSCLC and lymphomas.     

Use of insulin to improve [18 F]fluorodeoxyglucose labelling and retention for in vivo positron emission tomography imaging of monocyte trafficking

While 18F-FDG labelling of monocytes would allow in vivo trafficking with positron emission tomography (PET), present methods suffer from poor retention of radioactivity. We investigated the feasibility of utilizing insulin for improved [18F]fluorodeoxyglucose (18F-FDG) labelling. Separated human monocytes and lymphocytes were labelled with 18F-FDG with or without 3 h insulin pre-incubation. Insulin had no effect on lymphocyte labelling (21.4+/-0.8% vs 20.8+/-1.1% efficiency, P=NS). However, for monocytes, insulin pre-incubation led to a 169+/-9% increase in labelling efficiency (19.3+/-4.1 vs 32.5+/-1.8, P<0.05), without significant effects on cell activation or viability. Moreover, while only 57.7+/-4.8% and 40.4+/-5.6% of the 18F-FDG was retained at 1 and 3 h for controls, the retention rate increased to 91.6+/-2.1% (P=0.01) and 86.5+/-1.9% (P<0.01) after insulin pre-incubation. Improved 18F-FDG retention was accompanied by a 70.3+/-7.4% decrease in glucose-6-phosphatase activity (P=0.02). PET imaging of rats showing hepatic ischaemia-reperfusion injury demonstrated higher liver uptake for monocytes labelled after insulin treatment. Thus, insulin improves monocytic 18F-FDG uptake and retention, and may provide a feasible labelling method for PET imaging.     

Dual time point 18F-FDG PET for the evaluation of pulmonary nodules.

18F-FDG PET has reached widespread application in the assessment of pulmonary nodules. This study compares the diagnostic accuracy of standard 18F-FDG PET scanning with those of dual time point 18F-FDG PET scanning. METHODS: Thirty-six patients (21 women, 15 men; mean age, 67 y; range, 36-88 y) with 38 known or suspected malignant pulmonary nodules underwent PET of the thorax at 2 time points: scan 1 at 70 min (range, 56-110 min) and scan 2 at 123 min (range, 100-163 min) after the intravenous injection of 2.5 MBq 18F-FDG per kilogram of body weight. All scanning was performed on a dedicated C-PET scanner. The mean interval between the scans was 56 min (range, 49-64 min). Regions of interest were overlaid onto each fully corrected image in the areas of the radiographically known lung densities. The standardized uptake values (SUVs) were calculated for both time points. RESULTS: Surgical pathology and follow-up revealed 19 patients with 20 malignant tumors, whereas 16 patients had benign lesions. The tumor SUVs (mean +/- SD) were 3.66 +/- 1.95 (scan 1) and 4.43 +/- 2.43 (scan 2) (20.5% +/- 8.1% increase; P < 0.01). Four of 20 malignant tumors had SUVs of <2.5 on scan 1 (range, 1.12-1.69). Benign lesions had SUVs of 1.14 +/- 0.64 (scan 1) and 1.11 +/- 0.70 (scan 2) (P = not significant). Standard PET scanning (single time point) with a threshold SUV of 2.5 (at time point 1) reached a sensitivity of 80% and a specificity of 94%; dual time point scanning with a threshold value of 10% increase between scan 1 and scan 2 reached a sensitivity of 100% with a specificity of 89%. CONCLUSION: Dual time point 18F-FDG PET results in a very high sensitivity and specificity for detection of malignant lung tumors.     

Comparison of sigma-ligands and metabolic PET tracers for differentiating tumor from inflammation.

Novel radiopharmaceuticals for the detection of tumors and their metastases may be of clinical interest if they are more tumor selective than (18)F-FDG. Increased glucose metabolism of inflammatory tissues is the main source of false-positive (18)F-FDG PET findings in oncology. METHODS: We compared the biodistribution of 4 PET tracers (2 sigma-receptor ligands, (11)C-choline, and (11)C-methionine) with previously published biodistribution data of 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) and of (18)F-FDG in the same animal model. The model consisted of male Wistar rats that bore tumors (C6 rat glioma in the right shoulder) and also had sterile inflammation in the left calf muscle (induced by injection of 0.1 mL of turpentine). Twenty-four hours after turpentine injection, the rats received an intravenous bolus of PET tracer (approximately 30 MBq in the case of (18)F and 74 MBq for (11)C). RESULTS: (18)F-FDG showed the highest tumor-to-muscle ratio of all radiopharmaceuticals (13.2 +/- 3.0, mean +/- SD), followed at a large distance by the sigma-1 ligand (11)C-SA4503 (5.1 +/- 1.7), (18)F-FLT (3.8 +/- 1.3), the non-subtype-selective sigma-ligand (18)F-FE-SA5845 (3.3 +/- 1.5), (11)C-choline (3.1 +/- 0.4), and (11)C-methionine (2.8 +/- 0.3). sigma-Ligands and (18)F-FLT were relatively tumor selective ((18)F-FE-SA5845, greater than 30-fold; (11)C-SA4503 and (18)F-FLT, greater than 10-fold). The tumor selectivity of (11)C-methionine was only slightly better than that of (18)F-FDG. (11)C-Choline showed equal uptake in tumor and inflammation. All tracers were avidly taken up by proliferative tissue (small intestine, bone marrow). High physiologic uptake of some compounds was observed in brain, heart, lung, pancreas, spleen, and salivary gland. CONCLUSION: sigma-Ligands and (18)F-FLT were more tumor selective than (18)F-FDG, (11)C-choline, or (11)C-methionine in our animal model. However, these novel radiopharmaceuticals were less sensitive than were the established oncologic tracers.     

Splenic and bone marrow increased 18F-FDG uptake in a PET scan performed following treatment with G-CSF

We present the case of an 11 year-old Caucasian girl who presented chest pain of 12 weeks evolution, with no other symptoms and a negative physical examination. Lactate dehydrogenase levels were increased to 797 U/l, whereas beta-2-microglobulin (BM2) levels were normal. The thoracic CT showed a bulky mediastinal mass that occupied the pretracheal, paratracheal and right prevascular regions. The gallium scintigraphy showed high uptake in the mediastinic region; the bone scintigraphy was negative. Biopsy of the mediastinal mass revealed the presence of diffuse large B-cell non-Hodgkin's lymphoma. Treatment included 4 cycles of chemotherapy followed by 7 days of subcutaneous granulocyte colony-stimulating factor (G-CSF, Lenogastrim) at a dose of 5 mg/Kg/day. Following treatment, a CT scan was performed to evaluate response, finding a calcification of the mass without significant reduction of the overall size. Because CT was inconclusive in the assessment of response to therapy, a 18F-FDG PET scan was performed. The 18F-FDG PET scan did not show any pathological uptake in the mediastinum but revealed a splenic and bone marrow diffusely increased 18F-FDG uptake. The differential diagnosis included a secondary effect induced by G-CSF therapy as one of the main possibilities, but other possibilities such as a malignant infiltration by lymphoma could not be discarded. Therefore, a second 18F-FDG PET scan was performed 3 months later. This study showed no pathological findings, with a normal 18F-FDG uptake in the spleen and bone marrow. Thus, the benign and reactive nature of the splenic and bone marrow 18F-FDG increased uptake found in the previous study was confirmed. We consider that the stimulating effect that G-CSF therapy has on the spleen and bone marrow must be taken into account when performing a 18F-FDG PET scan, as it can be an important source of false-positive results.     

18F-FDG small-animal PET for monitoring the therapeutic effect of CT-guided radiofrequency ablation on implanted VX2 lung tumors in rabbits.

The primary goals of this study were to investigate the behavior of normal lung tissues after radiofrequency ablation (RFA) and to determine the suitability of 18F-FDG PET, using a dedicated small-animal scanner, for monitoring the early therapeutic effects of RFA on VX2 lung tumors (VX2s) in rabbits. METHODS: Fourteen Japanese white rabbits with normal lungs underwent RFA, followed by 18F-FDG PET at 1 d and at 1, 2, 4, and 8 wk. In addition, 7 rabbits with untreated VX2s underwent 18F-FDG PET, and 13 rabbits with RFA-treated VX2s underwent 18F-FDG PET at 1 d (n = 7) or 1 wk (n = 6) after the treatment. RESULTS: After RFA of normal lungs, ring-shaped accumulations of 18F-FDG, which coincided with inflammation caused by ablation, were observed. The mean early- (40-60 min after injection) and delayed (100-120 min)-phase ablated lesion-to-muscle ratios were, respectively, 2.9 +/- 1.0 and 3.3 +/- 0.8 (1 d), 4.1 +/- 0.6 and 5.2 +/- 0.9 (1 wk), 4.1 +/- 1.0 and 5.3 +/- 1.5 (2 wk), 3.1 +/- 0.5 and 3.6 +/- 1.1 (4 wk), and 1.8 +/- 0.1 and 2.3 +/- 0.1 (8 wk). At 4 and 8 wk, the uptake was less than that at 1 and 2 wk (P < 0.05). VX2s showed mean tumor-to-muscle ratios of 6.6 +/- 2.1 and 8.6 +/- 3.3 at the early and delayed phases, respectively. For ablated tumors, the respective ratios were 0.8 +/- 0.4 and 1.1 +/- 0.7 (1 d) and 1.2 +/- 0.5 and 1.5 +/- 0.7 (1 wk). These values were significantly lower than those for nonablated tumors (P < 0.001). Histopathologic examination confirmed the absence of viable tumors. 18F-FDG accumulation around ablated tumors reflected thermally damaged normal tissues and was significantly lower than that of control VX2s (P < 0.01). CONCLUSION: Our data suggest that 18F-FDG PET is promising for evaluating the therapeutic response of lung malignancies to RFA: Accumulation of 18F-FDG in surrounding normal tissues appears to be time dependent, and the data suggest that, clinically, 18F-FDG PET should be performed 4 wk or more after RFA. Delayed-phase images seem to better distinguish tumor from inflammation than do early-phase images.     

Usefulness of 11C-methionine for differentiating tumors from granulomas in experimental rat models: a comparison with 18F-FDG and 18F-FLT.

Many clinical PET studies have shown that increased (18)F-FDG uptake is not specific to malignant tumors. (18)F-FDG is also taken up in inflammatory lesions, particularly in granulomatous lesions such as sarcoidosis or active inflammatory processes after chemoradiotherapy, making it difficult to differentiate malignant tumors from benign lesions, and is the main source of false-positive (18)F-FDG PET findings in oncology. These problems may be overcome by multitracer studies using 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) or l-(11)C-methionine. However, (18)F-FLT or (11)C-methionine uptake in granulomatous lesions remains unclarified. In this study, the potentials of (18)F-FLT and (11)C-methionine in differentiating malignant tumors from granulomas were compared with (18)F-FDG using experimental rat models. METHODS: Dual-tracer tissue distribution studies using (18)F-FDG and (3)H-FLT (groups I and III) or (18)F-FDG and (14)C-methionine (groups II and IV) were performed on rats bearing both granulomas (Mycobacterium bovis bacillus Calmette-Guérin [BCG]-induced) and hepatomas (KDH-8-induced) (groups I and II) or on rats bearing both turpentine oil-induced inflammation and hepatomas (groups III and IV). One hour after the injection of a mixture of (18)F-FDG and (3)H-FLT or of (18)F-FDG and (14)C-methionine, tissues were excised to determine the radioactivities of (18)F-FDG, (3)H-FLT, and (14)C-methionine (differential uptake ratio). RESULTS: Mature epithelioid cell granuloma formation and massive lymphocyte infiltration were observed in the granuloma tissue induced by BCG, histologically similar to sarcoidosis. The granulomas showed high (18)F-FDG uptake comparable to that in the hepatomas (group I, 8.18 +/- 2.40 vs. 9.13 +/- 1.52, P = NS; group II, 8.43 +/- 1.45 vs. 8.91 +/- 2.32, P = NS). (14)C-Methionine uptake in the granuloma was significantly lower than that in the hepatoma (1.31 +/- 0.22 vs. 2.47 +/- 0.60, P < 0.01), whereas (3)H-FLT uptake in the granuloma was comparable to that in the hepatoma (1.98 +/- 0.70 vs. 2.30 +/- 0.67, P = NS). Mean uptake of (18)F-FDG, (3)H-FLT, and (14)C-methionine was markedly lower in the turpentine oil-induced inflammation than in the tumor. CONCLUSION: (14)C-Methionine uptake was significantly lower in the granuloma than in the tumor, whereas (18)F-FDG and (3)H-FLT were not able to differentiate granulomas from tumors. These results suggest that (14)C-methionine has the potential to accurately differentiate malignant tumors from benign lesions, particularly granulomatous lesions, providing a biologic basis for clinical PET studies.     

Evaluation of the early effect of local irradiation on normal rodent bone marrow metabolism using FDG: preclinical PET studies.

Our aim was to evaluate the early effect of local irradiation on normal bone marrow glucose metabolism in rodents, assessed by FDG biodistribution measured by tissue excision and gamma counting. METHODS: Sixty-one rats were divided into nine groups (n = 4-11 per group). Eight groups of rats received either local irradiation (10 Gy) or sham irradiation to the right femur on day 0. Irradiation was performed using a 60Co gamma-ray unit under anesthesia. Each group of rats was fasted overnight and then injected with 5.5-7.4 MBq FDG on day 1, 9, 18, or 30 after the local or sham irradiation. A control group of rats that received neither local nor sham irradiation was studied with FDG on day 0. 18F activity in tissue 1 h after injection was measured using a gamma counter. Smear specimens of bone marrow from bilateral femurs were examined by light microscopy. RESULTS: Tracer uptake was relatively stable in marrow from the sham-irradiated rats. By contrast, FDG uptake of the irradiated marrow on day 1 was significantly higher (mean +/- SD, 0.257 +/- 0.036 percentage injected dose [ID] per gram of tissue per kilogram of rat weight [%ID/g/kg]) than that of the sham group on day 1 (0.187 +/- 0.028 %ID/g/kg) and the control group (0.184 +/- 0.009 %ID/g/kg) (P < 0.05). Tracer uptake in the irradiated marrow on day 9 was significantly lower (0.148 +/- 0.023 %ID/g/kg) than that of the sham group on day 9 (0.193 +/- 0.021 %ID/g/kg) and the control group (P < 0.01). In contrast, the nonirradiated contralateral marrow from irradiated rats showed increased FDG uptake on day 18 (0.274 +/- 0.063 %ID/g/kg) that was significantly higher than that of the sham group on day 18 (0.208 +/- 0.030 %ID/g/kg) and the control group (0.183 +/- 0.018 %ID/g/kg) (P < 0.05). The irradiated marrow smear specimens initially revealed increased percentages of neutrophils on day 1 (45% of 500 nucleoid cells examined per slide) compared with that of the sham group (20%), followed by severely decreased overall cellularity on day 9. CONCLUSION: In this experimental system, normal marrow uptake of FDG transiently rose, then fell, and ultimately returned to baseline after external beam irradiation. Knowledge of this biphasic early irradiation effect on normal bone marrow may be important when the efficacy of radiation therapy on bone metastasis is evaluated using FDG PET after irradiation.     

Increased metabolic activity of indolent liver metastases after resection of a primary colorectal tumor.

In murine models, resection of a primary tumor leads to increased vascularization and accelerated growth of metastases that previously had remained microscopic. To study such a potentially inhibitory effect of primary tumors on the outgrowth of distant metastases in humans, we assessed the metabolic activity of liver metastases by 18F-FDG PET before and after resection of primary colorectal tumors. METHODS: Group A consisted of 8 patients with synchronous colorectal liver metastases who were scheduled for resection of their primary tumor. These patients underwent an (18)F-FDG PET scan shortly before resection and 2-3 wk after resection of the primary tumor. The patients in a control group (group B, n = 9) underwent an 18F-FDG PET scan at the time of diagnosis of the liver metastases and a second scan several weeks later, before initiating treatment. There was no surgical intervention between the two 18F-FDG PET scans in this group. RESULTS: In group A, the maximum and mean standardized uptake values of the liver metastases clearly increased after resection of the primary tumor, by 38% +/- 55% and 42% +/- 52%, respectively, as compared with the first 18F-FDG PET scan. In group B, the maximum and mean standardized uptake values of the second 18F-FDG PET scan were not significantly higher than those of the first 18F-FDG PET scan; -11% +/- 23% and 1% +/- 29%, respectively. The difference in standardized uptake value increase between the 2 groups was statistically significant (P < 0.05). CONCLUSION: Our data cannot differentiate between the immunologic sequels caused by the surgical trauma itself and those caused by removal of the primary tumor. The observation itself, however, of increased metabolic activity after surgical resection of the primary tumor may have direct clinical applications and suggests the administration of antiangiogenic therapy after surgery of the primary tumor.     

Reversal of vascular 18F-FDG uptake with plasma high-density lipoprotein elevation by atherogenic risk reduction

Vascular 18F-FDG uptake marker represents inflammation in atherosclerotic lesions, but whether inflammation can be reversed by risk-modifying interventions has not, to our knowledge, been demonstrated. In this study, we evaluated the change of vascular 18F-FDG uptake in response to lifestyle intervention on serial PET/CT scans and further assessed how the findings relate to atherogenic risk reduction. METHODS: A total of 60 healthy adults underwent 18F-FDG PET/CT scans and atherogenic risk-factor assessment at baseline and again after 17.1 +/- 8.3 mo of practicing lifestyle modification. The PET/CT images were evaluated for the presence of vascular 18F-FDG lesions, and vessel-to-blood-pool 18F-FDG ratios were measured. Indices from summed ratios of positive lesions were compared and correlated to atherogenic risk factors. RESULTS: At follow-up, significant reductions in diastolic blood pressure (P < 0.05), total cholesterol (P < 0.05), and low-density lipoprotein level (P < 0.05) and an increase in high-density lipoprotein (HDL) level (P < 0.0001) were demonstrated. On the initial PET/CT scan, 50 of 60 subjects showed 1 or more 18F-FDG-positive lesions (5.9 +/- 5.0/subject), leading to a total of 352 vascular sites. On follow-up, 18F-FDG-positive lesions were significantly reduced to 2.1 +/- 2.2 sites per subject (P < 0.0001) and a total of 124 sites (64.8% reduction). Follow-up 18F-FDG-positive rates were significantly reduced for the aorta and iliac arteries. In addition, significant reductions in the whole-body 18F-FDG index from 1.39 +/- 1.23 to 0.53 +/- 0.59 (P < 0.0001) and carotid 18F-FDG index from 0.08 +/- 0.16 to 0.03 +/- 0.06 (P = 0.01) were shown. The whole-body 18F-FDG index correlated with total cholesterol (P < 0.05) and HDL level (P < 0.05), and the magnitude of reduction in the 18F-FDG index closely correlated to the amount of increase in plasma HDL level (P = 0.005). CONCLUSION: Our study demonstrated that vascular 18F-FDG uptake is reversed in response to atherogenic risk reduction by lifestyle intervention and that the magnitude of improvement correlates to increases in plasma HDL levels. Thus, serial 18F-FDG PET/CT may be useful for monitoring improvements in the inflammatory component of atherosclerotic lesions in response to risk modification.     

Effects of anesthetic agents and fasting duration on 18F-FDG biodistribution and insulin levels in tumor-bearing mice.

Small-animal PET has opened the way for imaging (18)F-FDG uptake in murine tumor models, but the need for anesthesia raises concern over its potential influence on (18)F-FDG kinetics. We thus investigated such effects on cultured cells and on tumor-bearing mice after short- and long-term fasting. METHODS: Lewis lung carcinoma (LLC) cells and cardiomyoblasts were treated for 2 h with a 100 micromol/L concentration of xylazine, ketamine, xylazine plus ketamine (Xy/Ke), or pentobarbital and were measured for (18)F-FDG uptake. LLC tumor-bearing C57BL6 mice that had been kept fasting for either 4 or 20 h were injected with Xy/Ke, pentobarbital, or saline and were administered 1.8 MBq of (18)F-FDG 15 min later. Biodistribution studies and plasma glucose and insulin assays were performed 45 min after injection. Separate anesthetized and control mice underwent (18)F-FDG PET. RESULTS: (18)F-FDG uptake in LLC cells was unaffected by anesthetic agents, whereas xylazine and ketamine caused a small increase of uptake in cardiomyoblasts. In mice kept fasting 4 h, Xy/Ke induced a marked elevation of (18)F-FDG activity (percentage injected dose [%ID]) in blood (6.8 +/- 0.9%ID/g vs. 1.1 +/- 0.6%ID/g) and kidneys while decreasing myocardial uptake (2.3 +/- 1.3%ID/g vs. 4.7 +/- 1.8%ID/g). Target-to-blood ratios were significantly reduced. Pentobarbital caused a moderate increase in blood activity (2.5 +/- 0.8%ID/g), decreased myocardial uptake (2.8 +/- 0.5%ID/g), and reduced target-to-blood ratios. PET images of mice kept fasting 4 h were consistent with the biodistribution data. Insulin levels were lower with Xy/Ke and higher with pentobarbital. In mice kept fasting 20 h, Xy/Ke and pentobarbital increased blood (18)F-FDG activity (5.5 +/- 2.2 and 4.9 +/- 0.9%ID/g vs. 2.4 +/- 0.3%ID/g) and reduced target-to-blood ratios, but these changes were substantially attenuated, compared with those in mice kept fasting 4 h. In addition, insulin levels were low and unaffected by anesthesia. CONCLUSION: Xy/Ke anesthesia markedly elevates blood (18)F-FDG activity and reduces tumor uptake ratios through inhibition of insulin release in mice kept fasting 4 h, whereas pentobarbital induces a similar but less severe response through insulin resistance. These metabolic effects, however, are substantially attenuated after 20 h of fasting. Hence both the choice of anesthetic and the duration of fasting have important effects on (18)F-FDG kinetics and PET images of tumor-bearing mice and should be considered when such studies are performed.     

Detection by (18)F-FDG PET of unsuspected extensive bone marrow metastases in a case of basosquamous carcinoma of the cheek

Basosquamous carcinoma (BSC) is a rare type of malignancy with features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with a potential for aggressive behaviour infiltration and destruction. First reported by MacCormac in 1910 in a series of rodent ulcers, this entity does have an increased risk of recurrence and metastases as well, which distinguish it from other forms of basal cell carcinoma. The overall incidence of basosquamous carcinoma ranges from 1.2% to 2.7%. An unusual case of basosquamous carcinoma (BSC) is presented where 18- fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) scan diagnosed unsuspected extensive metastatic disease in the bone marrow, which was further proven histopathologically. The patient was a 32 years old man with history of recently diagnosed basosquamous carcinoma of left cheek involving left lower eyelid and left eyeball. Contrast enhanced computed tomography(ceCT) of the head and neck demonstrated involvement of the left cheek skin by the malignancy along with erosion of zygomatic bone and phthisis bulbi of the left eye. The serum alkaline phosphatase was elevated (255units, normal range 50-150units). The patient was referred for (18)F-FDG PET, for disease status evaluation. The scan showed intense tracer uptake in the left zygomatic region, the site of known primary disease. Intense tracer uptake was noted in the multiple lesions of bone marrow of axial as well as appendicular skeleton. The scan appearance was highly suggestive of metastatic bone marrow involvement. A bone marrow biopsy was performed to confirm the scan findings. Guided by the (18)F-FDG PET scan findings, bone marrow biopsy was performed and metastatic basosquamous carcinoma was diagnosed. We believe this is the first reported case of basosquamous carcinoma where extensive metastatic bone marrow disease was diagnosed with the aid of (18)F-FDG PET. At first diagnosis, an advanced stage of BSC is often present. Due to its metastatic potential, extensive primary surgical resection of BSC, possibly completed by radiation or photodynamic adjuvant treatment is recommended. Given the aggressive nature of basosquamous carcinoma, whole body (18)F-FDG PET is very useful in diagnosing metastatic BSC. In conclusion, this is the first reported case of the use of (18)F-FDG PET study for diagnosing metastatic bone marrow disease in a patient with basosquamous carcinoma.     

Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG.

3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) is a recently developed PET tracer to image tumor cell proliferation. We characterized (18)F-FLT PET of brain gliomas and compared (18)F-FLT with (18)F-FDG PET in side-by-side studies of the same patients. METHODS: Twenty-five patients with newly diagnosed or previously treated glioma underwent PET with (18)F-FLT and (18)F-FDG on consecutive days. Three stable patients in long-term remission were included as negative control subjects. Tracer kinetics in normal brain and tumor were measured. Uptake of (18)F-FLT and (18)F-FDG was quantified by the standardized uptake value (SUV) and the tumor-to-normal tissue (T/N) ratio. The accuracy of (18)F-FLT and (18)F-FDG PET in evaluating newly diagnosed and recurrent gliomas was compared. More than half of the patients underwent resection after the PET study and correlations between PET uptake and the Ki-67 proliferation index were examined. Patients were monitored for a mean of 15.4 mo (range, 12-20 mo). The predictive power of PET for tumor progression and survival was analyzed using Kaplan-Meier statistics. RESULTS: (18)F-FLT uptake in tumors was rapid, peaking at 5-10 min after injection and remaining stable up to 75 min. Hence, a 30-min scan beginning at 5 min after injection was sufficient for imaging. (18)F-FLT visualized all high-grade (grade III or IV) tumors. Grade II tumor did not show appreciable (18)F-FLT uptake and neither did the stable lesions. The absolute uptake of (18)F-FLT was low (maximum-pixel SUV [SUV(max)], 1.33) but image contrast was better than with (18)F-FDG (T/N ratio, 3.85 vs. 1.49). (18)F-FDG PET studies were negative in 5 patients with recurrent high-grade glioma who subsequently suffered tumor progression within 1-3 mo. (18)F-FLT SUV(max) correlated more strongly with Ki-67 index (r = 0.84; P < 0.0001) than (18)F-FDG SUV(max) (r = 0.51; P = 0.07). (18)F-FLT uptake also had more significant predictive power with respect to tumor progression and survival (P = 0.0005 and P = 0.001, respectively). CONCLUSION: Thirty-minute (18)F-FLT PET 5 min after injection was more sensitive than (18)F-FDG to image recurrent high-grade tumors, correlated better with Ki-67 values, and was a more powerful predictor of tumor progression and survival. Thus, (18)F-FLT appears to be a promising tracer as a surrogate marker of proliferation in high-grade gliomas.     

Usefulness of fasting 18F-FDG PET in identification of cardiac sarcoidosis.

Cardiac PET using (18)F-FDG under fasting conditions (fasting (18)F-FDG PET) is a promising technique for identification of cardiac sarcoidosis and assessment of disease activity. The aim of this study was to investigate the usefulness of fasting (18)F-FDG PET in detecting inflammatory lesions of cardiac sarcoidosis from a pathophysiologic standpoint. METHODS: Twenty-two patients with systemic sarcoidosis were classified into 2 groups of 11 each according to the presence or absence of sarcoid heart disease. Cardiac sarcoidosis was diagnosed according to the Japanese Ministry of Health and Welfare guidelines for diagnosing cardiac sarcoidosis with the exception of scintigraphic criteria. Nuclear cardiac imaging with fasting (18)F-FDG PET, (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) SPECT, and (67)Ga scintigraphy were performed in all patients. PET and SPECT images were divided into 13 myocardial segments and the standardized uptake value (SUV) of (18)F-FDG was calculated and defect scores (DS) for (99m)Tc-MIBI uptake were assessed for each segment. The total SUV (T-SUV) and total DS (TDS) were calculated as the sum of measurements for all 13 segments, and the diagnostic accuracy of fasting (18)F-FDG PET was compared with that of the other nuclear imaging modalities. In addition, pathophysiologic relationships between inflammatory activity and myocardial damage were examined by segmental comparative study using the SUV and DS. RESULTS: In patients with cardiac sarcoidosis, fasting (18)F-FDG PET revealed a higher frequency of abnormal myocardial segments than (99m)Tc-MIBI SPECT (mean number of abnormal segments per patient: 6.6 +/- 3.0 vs. 3.0 +/- 3.2 [mean +/- SD], P < 0.05). The sensitivity of fasting (18)F-FDG PET in detecting cardiac sarcoidosis was 100%, significantly higher than that of (99m)Tc-MIBI SPECT (63.6%) or (67)Ga scintigraphy (36.3%). The accuracy of fasting (18)F-FDG PET was significantly higher than (67)Ga scintigraphy. The T-SUV demonstrated a good linear correlation with serum angiotensin-converting enzyme levels (r = 0.83, P < 0.01), and the TDS showed a significant negative correlation with the left ventricular ejection fraction (r = -0.82, P < 0.01). In abnormal myocardial segments on the nuclear scan, the SUV showed a significant negative correlation with the DS (r = -0.63, P < 0.0001). CONCLUSION: This study suggests that fasting (18)F-FDG PET can detect the early stage of cardiac sarcoidosis, in which fewer perfusion abnormalities and high inflammatory activity are noted, before advanced myocardial impairment.     

A preliminary study of anti-1-amino-3-18F-fluorocyclobutyl-1-carboxylic acid for the detection of prostate cancer.

We evaluated the feasibility of anti-1-amino-3-(18)F-fluorocyclobutyl-1-carboxylic acid (anti-(18)F-FACBC) in diagnosing prostate cancer (PCa), using a rat orthotopic prostate cancer transplantation (OPCT) model. Furthermore, using in vivo experiments, we examined the potential of anti-(18)F-FACBC for differentiating between PCa and inflammation and between PCa and benign prostatic hyperplasia (BPH). METHODS: The OPCT model was developed by transplanting DU145, a human PCa cell line, into the ventral prostate of athymic F344 rats. To develop a dual PCa and inflammation (DPCI) model, MAT-Ly-Lu-B2--a rat PCa cell line--was transplanted subcutaneously into male Copenhagen rats. Streptozotocin was injected into the hind footpad of these rats for inducing popliteal lymphadenitis. For inducing the BPH, normal F344 rats were castrated and injected subcutaneously with testosterone propionate. In biodistribution studies, the rats were injected with anti-(18)F-FACBC or (18)F-FDG and sacrificed at 15 or 60 min after injection. We performed dynamic small-animal PET of the abdominal portion of the OPCT rats for 60 min after the injection of anti-(18)F-FACBC or (18)F-FDG. RESULTS: The biodistribution in the OPCT rats at 60 min after injection showed that the uptake of anti-(18)F-FACBC and (18)F-FDG into the PCa tissue was 1.58 +/- 0.40 %ID/cm(3) (percentage injected dose per cm(3)) and 1.48 +/- 0.90 %ID/cm(3), respectively (P > 0.05). The accumulation of anti-(18)F-FACBC in the urinary bladder at 60 min after injection was 3.09 +/- 1.43 %ID/cm(3), whereas that of (18)F-FDG was 69.31 +/- 16.55 %ID/cm(3) (P < 0.05). Consequently, small-animal imaging with anti-(18)F-FACBC facilitated the visualization of the PCa tissue of the OPCT rats with higher contrast than (18)F-FDG. Furthermore, in comparison with (18)F-FDG, apparently higher ratios of PCa to inflammation and PCa to BPH accumulation of anti-(18)F-FACBC were demonstrated in the animal models. CONCLUSION: FACBC PET is believed to be useful not only for the visualization of human PCa but also for differentiating between PCa and inflammation and between PCa and BHP.     

Chemokine receptor-4 targeted PET/CT with 68 Ga-Pentixafor in assessment of newly diagnosed multiple myeloma: comparison to 18 F-FDG PET/CT

18F-FDG PET/CT has some limitations in the evaluation of multiple myeloma (MM). Since chemokine receptor-4 is overexpressed in MM, we perform a prospective cohort study to compare the performance of 68Ga-Pentixafor and 18F-FDG PET/CT in newly diagnosed MM. Thirty patients with newly diagnosed MM were recruited. All patients underwent 68Ga-Pentixafor and18F-FDG PET/CT within 1 week after enrollment. A positive PET/CT was defined as the presence of focal PET-positive lesions in bone marrow or diffuse bone marrow patterns (uptake > liver). Bone marrow uptake values in 68Ga-Pentixafor and18F-FDG PET/CT (total bone marrow glycolysis [TBmGFDG], total bone marrow uptake with 68Ga-Pentixafor [TBmUCXCR4], total bone marrow volume [TBmV], SUVmean, and SUVmax) were obtained by drawing total bone marrow volume of interest on PET/CT. The positive rates of the PET/CT scans were statistically compared, and the correlation between quantitative bone marrow uptake values and clinical characteristics, laboratory findings, and staging was analyzed. 68Ga-Pentixafor PET/CT had a higher positive rate than 18F-FDG PET/CT in recruited patients (93.3 vs. 53.3%, p = 0.0005). In quantitative analysis, bone marrow uptake values in 68Ga-Pentixafor (TBmUCXCR4, SUVmax, and SUVmean) were positively correlated with end organ damage, staging, and laboratory biomarkers related to tumor burden including serum β2-microglobulin, serum free light chain, and 24-h urine light chain (p < 0.05). In 18F-FDG PET/CT, only the SUVmean of total bone marrow was positively correlated with serum free light chain and 24-h urine light chain (p < 0.05). 68Ga-Pentixafor PET/CT is promising in assessment of newly diagnosed MM. NCT 03436342