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Relationship Between Retention Index in Dual-Phase ¹⁸F-FDG PET, and Hexokinase-II and Glucose Transporter-1 Expression in Pancreatic Cancer

¹ Department of Nuclear Medicine and Diagnostic Imaging, Graduate School of Medicine, Kyoto University, Kyoto, Japan
² Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan

	ABSTRACT

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Recently, some studies have shown that delayed scanning with ¹⁸F-FDG PET may help to differentiate malignant from benign pancreatic lesions. However, no study has evaluated the relationship between temporal changes in ¹⁸F-FDG uptake and expression of hexokinase or glucose transporter. Methods: Twenty-one consecutive patients with pancreatic cancer were studied preoperatively by dual-phase ¹⁸F-FDG PET, performed 1 and 2 h after injection of ¹⁸F-FDG. The standardized uptake value (SUV) of the pancreatic cancer was determined, and the retention index (RI) (%) was calculated by subtracting the SUV at 1 h (SUV1) from the SUV at 2 h (SUV2) and dividing by SUV1. The percentages of cells strongly expressing hexokinase type-II (HK-II) and glucose transporter-1 (GLUT-1) were scored on a 5-point scale (1 = 0%–20%, 2 = 20%–40%, 3 = 40%–60%, 4 = 60%–80%, 5 = 80%–100%) by visual analysis of immunohistochemical staining of paraffin sections from the tumor specimens using anti-HK-II and anti-GLUT-1 antibody (HK-index and G-index, respectively). Results: SUV2 (mean ± SD, 5.7 ± 2.6) was higher than SUV1 (5.1 ± 2.1), with an RI of 8.5 ± 11.0. Four cases of cancer, in which SUV2 showed a decline from SUV1, showed a low HK-index (1.8 ± 1.1), whereas 4 cases with an RI of 20 and 13 cases with an intermediate RI (0–20) showed significantly higher HK-indices (4.3 ± 0.7 and 3.1 ± 1.5, respectively; P < 0.05). RI showed a positive correlation with HK-index, with an R² of 0.27 (P < 0.05), but no significant correlation with the G-index. SUV1 showed no relationship with the HK-index but showed a weak positive correlation with the G-index, with an R² of 0.05 (P = 0.055). Conclusion: These preliminary findings suggest that the RI obtained from dual-phase ¹⁸F-FDG PET can predict HK-II expression and that the SUV (at 1 h) has a positive correlation with GLUT-1 expression but not with HK-II expression.

Key Words: pancreatic cancer • ¹⁸F-FDG PET • hexokinase • glucose transporter

	INTRODUCTION

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Imaging with ¹⁸F-FDG PET has been used as a powerful evaluation modality in oncologic nuclear medicine (1–6), not only for detecting tumors but also for monitoring therapy (7,8), for staging (9–10), and for grading (11). Emission scans are usually obtained 1 h after ¹⁸F-FDG administration in oncologic ¹⁸F-FDG PET. Recently, several studies showed that delayed scanning (90 min after ¹⁸F-FDG administration) with ¹⁸F-FDG PET may help to differentiate between malignant and benign lesions (12–15). In these studies, ¹⁸F-FDG accumulation constantly increased up to 3–4 h in many cases, whereas in a few cases it fell 1 h after ¹⁸F-FDG administration. These temporal changes in ¹⁸F-FDG uptake in the tumor may arise from the balance of expression of glucose transporters and glycolytic enzymes in tumor cells. However, no study has evaluated the expression of these transporters and enzymes in relation to the ¹⁸F-FDG uptake kinetics. Hexokinase-II (HK-II) and glucose transporter-1 (GLUT-1) are known as major subtypes of each family for many cancer cells (16–19). This retrospective study investigated the usefulness of dual-phase ¹⁸F-FDG PET scanning (1 and 2 h) as a noninvasive preoperative tool to evaluate HK-II and GLUT-1 expression in pancreatic cancer.

	MATERIALS AND METHODS

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Patients
The study group comprised 21 consecutive patients with pancreatic cancer (13 men, 8 women; age range, 40–82 y; mean age, 60.8 ± 8.9 y) of 27 patients with malignant disease reported previously (15). Surgical resection or needle biopsy during laparotomy confirmed the histologic diagnosis. (Five patients without an appropriate surgical specimen for immunohistochemical evaluation were excluded from this study.) The diseases included 17 cases of invasive ductal adenocarcinoma, 3 cases of pancreatic mucinous cystadenocarcinoma, and 1 case of intraductal papillary carcinoma. Before being enrolled in this study, each patient gave written informed consent, as required by the Kyoto University Human Study Committee.

PET Study
¹⁸F was produced by a ²⁰Ne (d, ) ¹⁸F nuclear reaction, and ¹⁸F-FDG was synthesized by the acetyl hyprofluorite method (20). PET was performed using a whole-body PET camera (PCT3600W; Hitachi Medico, Tokyo, Japan) that had 8 rings, which provided 15 tomographic sections at 7-mm intervals. The intrinsic resolution was 4.6 mm in full width at half maximum at the center, and the axial resolution was 7 mm at half maximum. The effective resolution after reconstruction was approximately 10 mm. The patients fasted for at least 5 h before the ¹⁸F-FDG injection. The exact position of the pancreatic lesion was confirmed and marked on the skin using sonography before PET examination. The patients were placed supine on the center of the PET table. During the entire imaging procedure, they kept their arms over their head in the same position, aided by a headrest and a holding bar. This patient position was determined and marked with 8 corresponding points in a cross line with a pen using a laser beam alignment system, as the center of the tumor was located in the center of the imaging field. The patient was then fixed in place with a holding belt across the abdomen. Each patient underwent transmission scanning for attenuation correction for 11 min. After the transmission scan was obtained, approximately 370 MBq (10 mCi) ¹⁸F-FDG were administered intravenously, and serial static scanning was performed for 12 min at 2 time points, 1 h (54–72 min) and 2 h later (114–135 min). At the time of emission scanning, the subject was repositioned on the PET table. The marking and the laser beam system were used to ensure that the patient was placed in precisely the same position as in the transmission scan. Serum levels of glucose were monitored immediately before the ¹⁸F-FDG injection. Initially, PET images were compared with the corresponding CT images, which permitted accurate identification of the tumor relative to anatomic landmarks, for example, the upper and lower part of the kidney, the shape of the liver, and the gallbladder bed. ¹⁸F-FDG accumulation was analyzed semiquantitatively by calculating the standardized uptake value (SUV) in the regions of interest placed over the suspected lesions on 1- and 2-h images (SUV [at 1 h] and SUV [at 2 h]) after injection of ¹⁸F-FDG (15).

The region of interest placed over the tumor was 10 x 10 mm (independent of tumor size) and was placed in tumor areas that showed the highest ¹⁸F-FDG activity. We defined the retention index (RI) (%) as follows: RI = 100 x (SUV [at 2 h] - SUV [at 1 h])/SUV (at 1 h).

Histologic Examination
All patients underwent surgical resection or needle biopsy during laparotomy. Three or more paraffin sections per patient were processed for anti-GLUT-1 or anti-HK-II immunostaining or routine hematoxylin staining. The polyclonal rabbit anti–glucose transporter antibody reactive with human GLUT-1 (brain/erythrocyte type) was purchased from DAKO (Carpinteria, CA). It was raised against 12-amino-acid synthetic peptide corresponding to the carboxyl terminus of human GLUT-1 (21). It undergoes immunoreaction with a 50-kDa glucose transporter species in human erythrocytes and in a variety of human cancer cells. It was diluted 1:200 with 0.05 mol/L Tris-HCl buffer containing a carrier protein and 0.015 mol/L sodium azide (DAKO). The polyclonal rabbit antihexokinase antibody reactive with rat HK-type II isozyme (HK-II) was purchased from Chemicon International, Inc. (Temecula, CA). It was raised against synthetic peptide corresponding to the carboxyl terminus of rat HK-II (22). It undergoes immunoreaction with a 10-kDa hexokinase species in a variety of human cancer cells. It was diluted 1:500 with 0.05 mol/L Tris-HCl buffer containing a carrier protein and 0.015 mol/L sodium azide.

Paraffin was removed from sections of each tumor using xylene and ethanol. Before immunohistochemical procedures, unmasking treatments were performed on all sections. Sections for anti-GLUT-1 immunostaining were incubated with Target Retrieval Solution (DAKO), using the water bath method at 95°C–99°C for 20 min. The other sections, including those for anti-HK-II immunostaining, were unmasked by the microwave method (strong range) using a distilled water bath for 15 min (5 min for each of 3 times).

After 20 min for cooling, the sections were washed with phosphate-buffered saline (PBS) (DAKO), containing 20 mmol/L sodium phosphate and 150 mmol/L NaCl (pH 7.0), for 15 min (5 min for each of 3 times). Then, the endogenous peroxidase activities were blocked for 10 min at 25°C with 0.3% hydrogen peroxide in distilled water and were washed with the PBS for 5 min. The nonspecific binding was blocked for 30 min at 25°C with blocking buffer (DAKO), which contained 10% normal bovine serum in PBS. In the next step, each section was incubated with the anti-GLUT-1 antibody or anti-HK-II antibody as a primary antibody for 1 h at 25°C. Parallel sections were incubated with healthy rabbit IgG (20 µg/mL) as negative controls. Then, all the sections were washed with PBS with 0.05% polyoxyethylene sorbitan monolaurate (Tween 20; Kanto Chemical Co., Tokyo, Japan) for 15 min (5 min for each of 3 times). In the following steps, each section was stained by the horseradish peroxidase (HRP)-labeled polymer method, using an Envision Kit/HRP 3,3'-diaminobenzidine tetrahydrochloride (DAB) (DAKO). For linking, the sections were incubated with the labeled polymer for 60 min at 25°C and washed with PBS with 0.05% Tween 20 for 15 min (5 min for each of 3 times). As a substrate-chromogen solution, DAB was used at 25°C for 10 min, diluted at 1 mg/mL with 0.05 mol/L Tris-HCl buffer, pH 7.5. All sections were then rinsed gently with distilled water and washed in flowing water for 5 min. In the final step, the sections were lightly counterstained with Gill’s hematoxylin and then dehydrated, the alcohol was removed, and a coverslip was positioned with mounting medium. Other chemicals not mentioned were of the highest purity available. All slides were examined by light microscopy.

Data Analysis
Immunohistochemical analysis for anti-GLUT-1 antibody and anti-HK-II antibody was independently performed 3 times by a well-experienced physician who was unaware of the SUVs. In each analysis, the percentages of strongly immunoreactive tumor cells in the total tumor cells were visually analyzed for each of 10 low-power fields (magnification, 10 x 10) or more (up to 30 fields), and the averaged percentage was calculated and scored on a 5-point scale (1 = 0%–20%, 2 = 20%–40%, 3 = 40%–60%, 4 = 60%–80%, 5 = 80%–100%) for each counting trial. Then, the 3 scores from all 3 counting trials were averaged again to give the GLUT-1 expression index (G-index) or HK-II expression index (HK-index).

One section from each tumor, processed with a nonspecific IgG as a negative control, was visually analyzed twice for tumor cellularity by a well-experienced physician who was unaware of the SUVs. In each analysis, tumor cellularity was scored on a 5-point scale (1 = low, 2 = low to moderate, 3 = moderate, 4 = moderate to high, 5 = high) by visual analysis for each of 10 low- power fields or more (up to 30 fields), and the averaged score was then calculated and scored on a 5-point scale. Two of each score from each counting trial were averaged again to give the tumor cell cellularity index (C-index). The data were statistically analyzed by nonparametric analysis using the Mann-Whitney test and the Spearman rank correlation.

	RESULTS

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Clinical and PET Findings
No patients had hyperglycemia. Table 1 summarizes the clinical and PET findings and the routine histologic diagnoses for the 21 patients. Ten patients underwent tumor resection. The others underwent a partial resection or open biopsy for advanced pancreatic cancer, with gastrojejunostomy or other anastomoses, or intraoperative radiation therapy, or both. The SUV increased 2 h after injection in 17 of 21 lesions but decreased in 4 lesions. The SUV at 2 h (mean ± SD, 5.7 ± 2.6) tended to be higher than the SUV at 1 h (5.1 ± 2.1), with an RI of 8.5 ± 11.0. There was no significant relationship between histologic diagnosis, differentiation, stage of disease, operative procedure, and each of the ¹⁸F-FDG PET quantitative findings. Figure 1 shows the relationship between SUV (at 1 h) and the RI obtained from dual-phase ¹⁸F-FDG PET. They correlated positively: Tumors with higher SUVs had higher RIs (P < 0.05). No patient had an RI of 30%, and no patient with a negative RI had an SUV (at 1 h) of 4.0.

View larger version (13K): [in this window] [in a new window]   FIGURE 1. Results of SUV at 1 h and RI of dual-phase 18F-FDG PET. Positive correlation existed between SUV at 1 h and RI (P < 0.05). Four patients with negative RI showed low SUVs at 1 h.

View larger version (15K): [in this window] [in a new window]   FIGURE 2. Results of immunohistochemical staining using anti-GLUT-1 and anti-HK-II. They correlated closely (P < 0.005).

View larger version (20K): [in this window] [in a new window]   FIGURE 3. Results of comparative analysis between quantitative values of dual-phase 18F-FDG PET and immunohistochemical staining. SUV at 1 h showed a weak positive correlation with GLUT-1 glucose transporter expression (P = 0.055), whereas no significant relationship was found between SUV at 1 h and HK-II hexokinase expression. However, RI had no significant relationship with GLUT-1 glucose transporter expression, whereas RI and HK-II hexokinase expression had significant positive relationship (P < 0.05).

View larger version (156K): [in this window] [in a new window]   FIGURE 4. Invasive ductal adenocarcinoma (arrows) in pancreatic head of patient 1. 18F-FDG PET images obtained at 1 h, when tumor SUV was 2.82 (A), and at 2 h, when tumor SUV was 2.48 (B), with RI of -12.1%. Immunohistochemical staining of GLUT-1 (C) and of HK-II (D) shows no significant strong expression of GLUT-1 or HK-II. Percentages of strong expressed cells of both proteins were scored as <20%. (x400; bar = 20 µm)

View larger version (166K): [in this window] [in a new window]   FIGURE 5. Invasive ductal adenocarcinoma (arrows) in pancreatic head of patient 17. 18F-FDG PET images obtained at 1 h, when tumor SUV was 6.0 (A), and at 2 h, when tumor SUV was 7.75 (B), with RI of 29.2%. Immunohistochemical staining of GLUT-1 (C) and of HK-II (D) shows overexpression of GLUT-1 and HK-II. Expression of GLUT-1 is observed mainly in membrane, whereas that of HK-II is observed mainly in cytoplasm. Percentages of strong expressed cells of GLUT-1 were scored as 50%–80%, and those of HK-II were scored as >80%. (x400; bar = 20 µm)

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

In this retrospective study, we evaluated 2 factors that were suggested to be responsible for the ¹⁸F-FDG accumulation mechanism in tumor tissue: the expression of HK-II and the expression of GLUT-1. Among the family of hexokinases and glucose transporters, HK-II and GLUT-1 were selected because each is known as a major subtype of each family for various cancer cells and for various cancer tissues (16–19). A close correlation exists between GLUT-1 and HK-II expression (Fig. 2). Tumor cells or transformed cells are known to have enhanced anaerobic glycolysis as a whole, which requires both glucose transporter overexpression and enhanced hexokinase activity, although the relative importance (as the rate-limiting step) of these 2 factors is still controversial (31–34). The present findings indicated that expression of both GLUT-1 and HK-II increased as the enhanced anaerobic glycolysis rose, whereas there appeared to be an imbalance between them in some cases (Table 2). The findings also suggested that the RI calculated by dual-phase ¹⁸F-FDG PET could predict HK-II expression and might be an indicator of the phosphorylation rate. In the late phase after ¹⁸F-FDG injection, only a low concentration of ¹⁸F-FDG remains in the blood or in the interstitial space. Glucose transporters are facilitative diffusion carriers locating across the plasma membrane that accelerate the transport of glucose down its concentration gradient by facilitative diffusion, a form of passive transport, between cytosol of tumor cells and blood or the interstitial space (35). If ¹⁸F-FDG uptake of tumor cells is still increasing during the late phase, the concentration of ¹⁸F-FDG in the cytosol of tumor cells should be much lower than that in the blood system or interstitial space, and free ¹⁸F-FDG in the cytosol should be phosphorylated to ¹⁸F-FDG-6-phosphate rapidly inside the tumor cells by hexokinase. Therefore, the concept that overexpression of hexokinase is associated with a high RI has considerable validity. On the other hand, four patients with negative retention indices all had low SUV values. Two of these patients had low GLUT-1 and low HK-II, whereas a third had high GLUT-1 and low HK-II and a fourth had low GLUT-1 and high HK-II. Further study would be needed for evaluation of the glycolytic mechanism in cases of low ¹⁸F-FDG uptake, including background activity of surrounding tissues. In this study, a close correlation was also found between the SUV at 1 h and GLUT-1 expression. These findings are compatible with our previous findings for pancreatic tumors despite the difference in histologic analyzing methods (19,36). However, the SUV at 1 h did not correlate with HK-II expression. Therefore, SUV at 1 h may be considered an indicator of GLUT-1 expression grade but not an indicator of HK-II. Thus, the present findings suggest that dual-phase ¹⁸F-FDG PET can predict 2 important factors in cellular glycolysis of cancers: GLUT-1 glucose transporter expression and HK-II hexokinase expression. Furthermore, our results have important implications for the evaluation of repeated ¹⁸F-FDG PET studies during follow-up after treatment. For example, if the first study were performed 1 h after injection of ¹⁸F-FDG and the follow-up scan were acquired at 2 h, the comparison between pre- and posttherapeutic PET would be unreliable and misleading.

In this retrospective study, we could not analyze HK-II expression or RI as a prognostic factor because the follow-up period after initial treatment was inadequate. However, some studies have suggested the usefulness of HK activity or the fractional rate constant k3 in the 3-compartment model as a prognostic factor in a variety of cancers (3,37–38). Further follow-up observations are needed in these types of cancer patients.

In the previous study, there were 4 patients with false-positive benign lesions in the differential diagnosis using dual-phase ¹⁸F-FDG PET (15). These included 1 patient with acute pancreatitis in whom endoscopic retrograde cholangiopancreatography was performed 3 d before the PET study, 1 patient with acute cholangitis in whom a nasogastric biliary drainage tube had been inserted in the common bile duct, and 2 patients with autoimmune pancreatitis. Evaluation of the histopathologic background of the increasing ¹⁸F-FDG uptake during the late phase should be required for these 3 types of inflammatory lesion.

	CONCLUSION

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We propose the use of a dual-phase ¹⁸F-FDG PET static scan in evaluating HK-II and GLUT-1 expression. An additional acquisition at 2 h after injection is beneficial for differentiating between malignant and benign lesions in the pancreas. Also, the additional acquisition obviates a dynamic ¹⁸F-FDG PET scan with arterial lines.

	ACKNOWLEDGMENTS

 
The authors thank Toru Fujita, Keiichi Matsumoto, Haruhiro Kitano, and Dr. Takahiro Mukai for their excellent technical assistance and Eric Daniel Mrozek for his editorial assistance.

	FOOTNOTES

 
Received Apr. 9, 2001; revision accepted Aug. 20, 2001.

For correspondence or reprints contact: Tatsuya Higashi, MD, PhD, c/o Tsuneo Saga, Department of Nuclear Medicine, Kyoto University Hospital, 54 Shogoin-kawahara-cho, Sakyo-Ku, Kyoto, 606-8507 Japan.

E-mail: higashi{at}kuhp.kyoto-u.ac.jp

	REFERENCES

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1. Strauss LG, Clorius JH, Schlag P, et al. Recurrence of colorectal tumors: PET evaluation. Radiology. 1989;170:329–332.[Abstract/Free Full Text]
2. Strauss LG, Conti PS. The applications of PET in clinical oncology. J Nucl Med. 1991;32:623–648.[Abstract/Free Full Text]
3. Wahl RL, Cody RL, Hutchins GD. Primary and metastatic breast carcinoma: initial clinical evaluation with PET with the radiolabeled glucose analog 2-[¹⁸F]-fluoro-2-deoxy-D-glucose. Radiology. 1991;179:765–770.[Abstract/Free Full Text]
4. Hawkins RA, Hoh C, Dahlbom M, et al. PET cancer evaluations with FDG. J Nucl Med. 1991;32:1555–1558.[Free Full Text]
5. Hoh CK, Hawkins RA, Glaspy JA, et al. Cancer detection with whole-body PET using 2-[¹⁸F]fluoro-2-deoxy-D-glucose. J Comput Assist Tomogr. 1993;17:582–589.[Medline]
6. Inokuma T, Tamaki N, Torizuka T, et al. Evaluation of pancreatic tumors with positron emission tomography and F-18 fluorodeoxyglucose: comparison with CT and US. Radiology. 1995;195:345–352.[Abstract/Free Full Text]
7. Vitola JV, Delbeke D, Meranze SG, Mazer MJ, Pinson CW. Positron emission tomography with F-18-fluorodeoxyglucose to evaluate the results of hepatic chemoembolization. Cancer 1996;78:2216–2222.[Medline]
8. Findlay M, Young H, Cunningham D, et al. Noninvasive monitoring of tumor metabolism using fluorodeoxyglucose and positron emission tomography in colorectal cancer liver metastases: correlation with tumor response to fluorouracil. J Clin Oncol. 1996;14:700–708.[Abstract/Free Full Text]
9. Vansteenkiste JF, Stroobants SG, De Leyn PR, et al. Lymph node staging in non-small-cell lung cancer with FDG PET scan: a prospective study on 690 lymph node stations from 68 patients. J Clin Oncol. 1998;16:2142–2149.[Abstract]
10. Kole AC, Plukker JT, Nieweg OE, Vaalburg W. Positron emission tomography for staging of oesophageal and gastroesophageal malignancy. Br J Cancer. 1998;78:521–527.[Medline]
11. Adler LP, Blair HF, Makley JT, et al. Noninvasive grading of musculoskeletal tumors using PET. J Nucl Med. 1991;32:1508–1512.[Abstract/Free Full Text]
12. Lodge MA, Lucas JD, Marsden PK, Cronin BF, O’Doherty MJ, Smith MA. A PET study of ¹⁸FDG uptake in soft tissue masses. Eur J Nucl Med. 1999;26:22–30.[Medline]
13. Boerner AR, Weckesser M, Herzog H, et al. Optimal scan time for fluorine-18 fluorodeoxyglucose positron emission tomography in breast cancer. Eur J Nucl Med. 1999;26:226–230.[Medline]
14. Hustinx R, Smith RJ, Benard F, et al. Dual time point fluorine-18 fluorodeoxyglucose positron emission tomography: a potential method to differentiate malignancy from inflammation and normal tissue in the head and neck. Eur J Nucl Med. 1999;26:1345–1348.[Medline]
15. Nakamoto Y, Higashi T, Sakahara H, et al. Delayed FDG PET scan for differentiation between malignant and benign lesions in the pancreas. Cancer 2000;89:2547–2554.[Medline]
16. Golshani-Hebroni SG, Bessmann SP. Hexokinase binding to mitochondria: a basis for proliferative energy metabolism. J Bioenerg Biomembr 1997;29:331–338.[Medline]
17. Board M, Humm S, Newsholme EA. Maximum activities of key enzymes of glycolysis, glutaminolysis, pentose phosphate pathway and tricarboxylic acid cycle in normal, neoplastic and suppressed cells. Biochem J. 1990;265:503–509.[Medline]
18. Clavo AC, Brown RS, Wahl RL. Fluorodeoxyglucose uptake in human cancer cell lines is increased by hypoxia. J Nucl Med. 1995;36:1625–1632.[Abstract/Free Full Text]
19. Higashi T, Tamaki N, Honda T, et al. Expression of glucose transporters in human pancreatic tumors compared with increased FDG accumulation in PET study. J Nucl Med. 1997;38:1337–1344.[Abstract/Free Full Text]
20. Tamaki N, Yonekura Y, Yamashita K, et al. Relation of left ventricular perfusion and wall motion with metabolic activity in persistent defects on thallium-201 tomography in healed myocardial infarction. Am J Cardiol. 1988;62:202–208.[Medline]
21. Younes M, Brown RW, Mody DR, Fernandez L, Laucirica R. GLUT1 expression in human breast carcinoma: correlation with known prognostic markers. Anticancer Res. 1995;15:2895–2898.[Medline]
22. Tsai HJ, Wilson JE. Functional organization of mammalian hexokinases: both N- and C-terminal halves of the rat type II isozyme possess catalytic sites. Arch Biochem Biophys 1996;329:17–23.[Medline]
23. Wahl RL, Zasadny K, Helvie M, Hutchins GD, Weber B, Cody R. Metabolic monitoring of breast cancer chemohormonotherapy using positron emission tomography: initial evaluation. J Clin Oncol. 1993;11:2101–2111.[Abstract/Free Full Text]
24. Torizuka T, Tamaki N, Inokuma T, et al. In vivo assessment of glucose metabolism in hepatocellular carcinoma with FDG PET. J Nucl Med. 1995;36:1811–1817.[Abstract/Free Full Text]
25. Zasadny KR, Wahl RL. Standardized uptake values of normal tissues at PET with 2-[fluorine-18]-fluoro-2-deoxy-D-glucose: variations with body weight and a method for correction. Radiology. 1993;189:847–850.[Abstract/Free Full Text]
26. Strauss LG. Fluorine-18 deoxyglucose and false-positive results: a major problem in the diagnostics of oncological patients. Eur J Nucl Med. 1996;23:1409–1415.[Medline]
27. Shreve PD. Focal fluorine-18 fluorodeoxyglucose accumulation in inflammatory pancreatic disease. Eur J Nucl Med. 1998;25:259–264.[Medline]
28. Zimny M, Buell U, Diederichs CG, Reske SN. False-positive FDG PET in patients with pancreatic masses: an issue of proper patient selection [letter]? Eur J Nucl Med. 1998;25:1352–1352.[Medline]
29. Torizuka T, Zasadny KR, Recker B, Wahl RL. Untreated primary lung and breast cancers: correlation between F-18 FDG kinetic rate constants and findings of in vitro studies. Radiology 1998;207:767–774.[Abstract/Free Full Text]
30. Gupta N, Gill H, Graeber G, Bishop H, Hurst J, Stephens T. Dynamic positron emission tomography with F-18 fluorodeoxyglucose imaging in differentiation of benign from malignant lung/mediastinal lesions. Chest. 1998;114:1105–1111.[Abstract/Free Full Text]
31. Smith TA. FDG uptake, tumour characteristics and response to therapy: a review. Nucl Med Commun. 1998;19:97–105.[Medline]
32. Pauwels EK, Ribeiro MJ, Stoot JH, McCready VR, Bourguignon M, Maziere B. FDG accumulation and tumor biology. Nucl Med Biol. 1998;25:317–322.[Medline]
33. Waki A, Kato H, Yano R, et al. The importance of glucose transport activity as the rate-limiting step of 2-deoxyglucose uptake in tumor cells in vitro. Nucl Med Biol. 1998;25:593–597.[Medline]
34. Aloj L, Caraco C, Jagonda E, Eckelman WC, Neumann RD. Glut-1 and hexokinase expression: relationship with 2-fluoro-2-deoxy-D-glucose uptake in A431 and T47D cells in culture. Cancer Res. 1999;59:4709–4714.[Abstract/Free Full Text]
35. Smith TA. Facilitative glucose transporter expression in human cancer tissue. Br J Biomed Sci. 1999;56:285–292.[Medline]
36. Higashi T, Tamaki N, Torizuka T, et al. FDG uptake, GLUT-1 glucose transporter and cellularity in human pancreatic tumors. J Nucl Med. 1998;39:1727–1735.[Abstract/Free Full Text]
37. Fukunaga T, Okazaki S, Koide Y, Isono K, Imazeki K. Evaluation of esophageal cancers using fluorine-18-fluorodeoxyglucose PET. J Nucl Med. 1998;39:1002–1007.[Abstract/Free Full Text]
38. Paggi MG, Fanciulli M, Del Carlo C, Citro G, Carapella CM, Floridi A. The membrane-bound hexokinase as a potential marker for malignancy in human glioma. J Neurosurg Sci. 1990;34:209–213.[Medline]

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				J. D. Lee, W. I. Yang, Y. N. Park, K. S. Kim, J. S. Choi, M. Yun, D. Ko, T.-S. Kim, A. E.H. Cho, H. M. Kim, et al. Different Glucose Uptake and Glycolytic Mechanisms Between Hepatocellular Carcinoma and Intrahepatic Mass-Forming Cholangiocarcinoma with Increased 18F-FDG Uptake J. Nucl. Med., October 1, 2005; 46(10): 1753 - 1759. [Abstract] [Full Text] [PDF]

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				L. Hooft, A. A. M. van der Veldt, P. J. van Diest, O. S. Hoekstra, J. Berkhof, G. J. J. Teule, and C. F. M. Molthoff [18F]Fluorodeoxyglucose Uptake in Recurrent Thyroid Cancer Is Related to Hexokinase I Expression in the Primary Tumor J. Clin. Endocrinol. Metab., January 1, 2005; 90(1): 328 - 334. [Abstract] [Full Text] [PDF]

				A.-J. Lemke, S. M. Niehues, N. Hosten, H. Amthauer, M. Boehmig, C. Stroszczynski, T. Rohlfing, S. Rosewicz, and R. Felix Retrospective Digital Image Fusion of Multidetector CT and 18F-FDG PET: Clinical Value in Pancreatic Lesions--A Prospective Study with 104 Patients J. Nucl. Med., August 1, 2004; 45(8): 1279 - 1286. [Abstract] [Full Text] [PDF]

				T.-C. Yen, L.-C. See, C.-H. Lai, C. W. Yah-Huei, K.-K. Ng, S.-Y. Ma, W.-J. Lin, J.-T. Chen, W.-J. Chen, C.-R. Lai, et al. 18F-FDG Uptake in Squamous Cell Carcinoma of the Cervix Is Correlated with Glucose Transporter 1 Expression J. Nucl. Med., January 1, 2004; 45(1): 22 - 29. [Abstract] [Full Text] [PDF]

				S.-Y. Ma, L.-C. See, C.-H. Lai, H.-H. Chou, C.-S. Tsai, K.-K. Ng, S. Hsueh, W.-J. Lin, J.-T. Chen, and T.-C. Yen Delayed 18F-FDG PET for Detection of Paraaortic Lymph Node Metastases in Cervical Cancer Patients J. Nucl. Med., November 1, 2003; 44(11): 1775 - 1783. [Abstract] [Full Text] [PDF]

				T.-C. Yen, K.-K. Ng, S.-Y. Ma, H.-H. Chou, C.-S. Tsai, S. Hsueh, T.-C. Chang, J.-H. Hong, L.-C. See, W.-J. Lin, et al. Value of Dual-Phase 2-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography in Cervical Cancer J. Clin. Oncol., October 1, 2003; 21(19): 3651 - 3658. [Abstract] [Full Text] [PDF]

				B B Chin and R L Wahl 18F-Fluoro-2-deoxyglucose positron emission tomography in the evaluation of gastrointestinal malignancies Gut, June 1, 2003; 52(90004): iv23 - 29. [Abstract] [Full Text] [PDF]

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