A New Method for Detecting Urinary Bladder Cancer by Using FDG PET/CT

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1 Technology in Cancer Research and Treatment ISSN Volume 13, Number 4, August 2014 Adenine Press (2014) A New Method for Detecting Urinary Bladder Cancer by Using FDG PET/CT DOI: /tcrt To evaluate the accuracy of a new fluorine-18-2-fluoro-2-deoxy-d-glucose ( 18 F-FDG) positron emission tomography (PET)/computed tomography (CT) method when applying an increased upper limit of the image threshold (IULIT) to detect bladder cancer. All patients with an unknown history of bladder tumors were retrospectively included for analysis. Applying an IULIT in PET showed a hypermetabolic focus. 18 F-FDG accumulation in the bladder that was higher or lower than the urinary level of 18 F-FDG was considered an abnormal focus. In 12 of the 28,767 patients with bladder cancer, applying an IULIT in PET allowed the visualization of the contrast between lesion and urinary activity. The proposed method could increase the accuracy of detection of bladder cancer. Key words: 18 F-FDG; Positron emission tomography; Computed tomography; Bladder cancer. Introduction The bladder is the most frequent site of urinary tract cancer, which is the fourth most common cancer in men and the ninth most common cancer in women in the United States (1). More than 95% of primary bladder cancers are of epithelial origin, most commonly transitional-cell (urothelial) carcinoma (2). Fortunately, most bladder cancers are diagnosed early, before spreading beyond the bladder. Eight-five percent of bladder cancer cases are localized in the bladder. The incidence of bladder cancer tends to increase considerably with age; approximately two-thirds of cases occur in people aged 65 years and older (3). Fluorine-18-2-fluoro-2-deoxy-d-glucose ( 18 F-FDG) positron emission tomography (PET) is used to detect a wide variety of tumor foci. However, high levels of 18 F-FDG activity in urine can mask abnormal activity in the urinary bladder. To overcome this limitation, some authors have advocated retrograde irrigation of the urinary bladder during PET data acquisition (4, 5) or delayed imaging after forced diuresis coupled with parenteral hydration (6), which are methods that enhance urinary flux and allow rapid evacuation of the urinary bladder. These methods are useful for detecting suspected lesions of the bladder; however, bladder catheterization and continuous irrigation are too invasive for routine use. When 18 F-FDG is injected intravenously in humans, non-metabolized 18 F-FDG is eliminated by glomerular filtration without complete reabsorption into the bladder. Heightened 18 F-FDG accumulation in the bladder and similarly increased Abbreviation: CT: Computed Tomography; 18 F-FDG: Fluorine-18-2-fluoro-2-deoxy-d-glucose; IULIT: Increased Upper Limit of the Image Threshold; MIP: Maximum Intensity Projection; PET: Positron Emission Tomography; ROI: Region of Interest; SUV: Standard Uptake Value. Yen-Kung Chen, M.D., Ph.D. 1,4 Chung-Hsin Yeh, M.D. 2,4 Chen-Tau Su, M.D. 3 Chih-Cheng Tsui, M.Sc. 1 Ru-Hwa Cheng, M.Sc. 1 Guang-Uei Hung, M.D. 5 Chia-Hung Kao, M.D. 6,7 * 1 Department of Nuclear Medicine and PET Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 2 Division of Urology, Department of Surgery, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 3 Department of Medical Imaging, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan 4 School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan 5 Department of Nuclear Medicine, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan 6 Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan 7 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan *Corresponding author: Chia-Hung Kao, M.D. Phone: Fax: d10040@mail.cmuh.org.tw 369

2 370 Chen et al. 18 F-FDG uptake in malignant lesions may be misinterpreted. We hypothesized that using 18 F-FDG PET/computed tomography (CT) with an increased upper limit of the image threshold (IULIT) could improve the detection of abnormal bladder 18 F-FDG foci. The purpose of this study was to evaluate the diagnostic accuracy of 18 F-FDG PET/CT when applying an IULIT for detecting urinary bladder cancer. Materials and Methods Participants This study followed the guidelines issued by the institutional review board (ethics committee) ethics committee on human studies of the hospital and the Helsinki Declaration. In this retrospective study conducted from February 2001 to January 2010, the inclusion criteria required that participants without a history of bladder cancer underwent FDG PET or PET/CT scans as part of their clinical care or screening program. In total, 28,973 consecutive patients (mean age, years [standard deviation]; age range, 2 to 96 years) consisting of 14,631 men (mean age, years; age range, 2 to 95 years) and 14,342 women (mean age, years; age range, 5 to 96 years) participated. The sample comprised 6224 patients with a history of cancer (mean age, years; age range, 2 to 96 years), who were undergoing 18 F-FDG PET or PET/CT scans as part of their clinical care, and 22,543 participants without a history of cancer (mean age, years; age range, 23 to 94 years), who were receiving 18 F-FDG PET or PET/CT scans as part of a screening program. Among the 6224 patients with a history of cancer, 2 patients underwent 18 F-FDG PET/CT and showed an unexpected presence of secondary primary tumors of bladder cancer. Of the 22,543 participants without a history of cancer, 8 underwent cystoscopy and histology and were diagnosed with bladder cancer after 18 F-FDG PET or PET/CT scanning. Patients were excluded if they were lost to follow-up before 1 year; this constituted 512 of the 6224 patients with a history of cancer and 987 of the 22,543 participants without a history of cancer. In total, 1499 patients were excluded, whereas 28,767 patients met the study criteria. Imaging Protocol Initial 18 F-FDG PET images were obtained using either a PET scanner (ECAT EXACT HR1, Siemens, Knoxville, TN) or an integrated PET/CT scanner (Discovery LS, General Electric Medical Systems, Waukesha, WI). Patients were required to fast for at least 8 hours before the initial PET scanning, and blood-glucose measurements were obtained from all patients before 18 F-FDG administration. A cut-off value of less than 8 mmol/l indicated that the examination could be performed. As many sequential images as necessary were taken to include the entire head, thorax, abdomen, and pelvis in the initial PET or PET/CT scans. For the PET scanner, transmission images were obtained for 2 minutes per bed position to correct for photon attenuation, using a germanium-68 line source. For PET/CT scanning, the PET attenuation correction factors were calculated based on the CT images. CT was performed using a four-detector-row spiral CT scanner (LightSpeed, General Electric Medical Systems, Waukesha, WI). Images were acquired in 5 to 7 bed positions, using the following parameters: 140 kv, 40 ma, 0.8 seconds per CT rotation, a pitch of 6, a table speed of 22.5 mm/s, coverage of to mm, and an acquisition time of 31.9 to 37 seconds. CT was performed before emission acquisition. CT data were resized from a matrix to a matrix to match the PET data and enable fusion of the images, and CT transmission maps were generated. The full width at half maximum of PET/CT was 4.8 mm. The emission scan occurred 50 to 70 minutes after intravenous administration of 370 MBq (10 mci) of 18 F-FDG. Patients were asked to void, and were then positioned on the scanner table. Emission images were acquired at 5 minutes per bed position. Image datasets were iteratively reconstructed using the ordered subset expectation maximization method. Images were displayed for visual interpretation in three orthogonal projections and whole-body maximum intensity projection (MIP) images. Delayed images were obtained using PET or an integrated PET/CT scanner. Image acquisition and processing for delayed PET or PET/CT scans were performed in the same manner as the PET or PET/CT scans, except that the range of image acquisition was limited to the region of interest (ROI) identified in the initial scan. A workstation (Xeleris, Elegems, Haifa, Israel) was used for image display and analysis. Image Interpretation Images were interpreted by 2 experienced nuclear medicine physicians, by consensus. When a consensus could not be reached, the opinion of the senior nuclear medicine physician was accepted. They were aware of the patients clinical history, which was provided by the referring physician, but they were unaware of the results of other imaging examinations, if these had been performed. First, the initial attenuation corrected PET images were reviewed using MIP images of the transaxial, coronal, and sagittal planes. Visual analysis was used and foci with abnormal 18 F-FDG uptake were recorded. In uremia patients without urine or oliguria, the intensity of the 18 F-FDG uptake in the bladder region was compared with the intensity of the liver uptake, and graded subjectively on a 4-point scale: 11 indicated that the bladder 18 F-FDG uptake was less than the liver uptake; 21 indicated that the bladder 18 F-FDG uptake was as intense as the liver uptake; 31 indicated a moderately intense bladder 18 F-FDG uptake, which was slightly higher than the liver uptake; and 41 indicated an intense bladder 18 F-FDG uptake, which was markedly higher than the liver uptake. In patients with a high level of urinary

3 A New Method of FDG PET/CT to Detect Urinary Bladder Cancer 371 radioactivity, PET with an IULIT was performed, and the abnormal foci were graded as having less than, equal to, or higher activity than the urinary 18 F-FDG activity. Hypermetabolic foci having higher or lower 18 F-FDG intensity than the urinary level of 18 F-FDG accumulation in the bladder were considered to be abnormal foci. CT images showing soft-tissue lesions, which were isometabolic relative to the urinary activity, required additional analyses using delayed PET/CT scanning following the administration of diuretics and oral hydration. The uptake within lesions was quantified by determining the mean activity within a circular ROI of a minimum of pixels placed within the area of maximal activity. The standard uptake value (SUV) was calculated as follows: Mean ROI activity in mci/ml SUV Injected dose in mci/weight of patient in kg. Data and Statistical Analyses Data were expressed as the mean the standard deviation or number (percentage) of patients in each group. Data analysis was based on data generated from the initial 18 F-FDG PET and delayed PET/CT interpretations. Cystoscopic findings and pathologic results served as the reference standard for all lesions. A clinical follow-up period of at least 1 year served as the reference standard for patients not undergoing cystoscopy or biopsy. The clinical follow-up period ranged from 1 to 9.9 years, with a mean of 4.7 years. Patterns of abnormal bladder foci in the initial PET images were analyzed based on the bladder distribution and reference standard. Abnormal bladder foci on the initial PET or PET/CT and delayed PET/ CT images were also categorized into grades. The accuracy of PET and PET/CT image interpretation was assessed using the reference standard. Considering negative results to be physiological and equivocal results to be physiological and benign, we classified the initial PET or PET/CT and delayed PET/CT findings as true positive, true negative, false positive, or false negative. Because only abnormal 18 F-FDG foci of the bladder were analyzed, and patients without cystoscopic evaluation did not undergo an adequate follow-up, sensitivity and specificity were not calculated; instead, accuracy was presented for the proportion of correctly classified foci on a per-patient basis. A P value of 0.05 was considered to indicate statistical significance. Results In 10 of the 28,767 patients, areas of abnormal tracer uptake (urothelial carcinoma) in the bladder were noted during PET or PET/CT examination (Table I). Two patients (Patient Nos. 2 and 12) showed negative results at the initial diagnosis, but proved to have urothelial carcinoma of the bladder after follow-up and histological interpretation. Based on the background of urinary accumulation of 18 F-FDG activity, patients were divided into groups of uremia patients and high- background urinary radioactivity patients. An IULIT for PET was applied to patients with a high level of urinary radioactivity, in which the patterns and grade of bladder foci in the high-activity bladder were divided into focal increased activity, central decreased activity, peripheral decreased activity, and isometabolic activity. Only the initial images of 2 of the 12 patients (Nos. 1 and 3) were recorded using PET scans. The delayed view of Patient No. 1 was recorded using the same PET, and the delayed view of Patient No. 3 was recorded using PET/CT scan. Table I Patient characteristics in relation to the PET/CT (PET) findings. Patient No. Age Sex PET finding CT finding Lesion size (cm) Initial image (SUV) Delay image (SUV) Lesion UB Lesion UB 1 70 M RUR increased N/A M RUR increased N/A N/A 3 43 M RUR decreased F RUR decreased M RUR decreased N/A N/A 6 52 M RUR decreased N/A N/A 7 85 F Equal M Equal F N/A N/A M F N/A N/A M N/A = Non-applicable; RUR = Relatively to urinary radioactivity; 2 5 Negative; 1 5 Positive.

4 372 Chen et al. focal intense activity (SUV 5 5.4) was located easily in the bladder (SUV 5 2.9). For another patient, who had a chronic cough and intermittent hematuria, a PET/CT scan was used to design the initial image status in the medium-upper threshold, which caused masking of the lesion by urinary radioactivity, resulting in a false negative identification of the bladder lesion (Figure 1A). One month later, the patient was diagnosed with urothelial carcinoma of the bladder. When images were reviewed retrospectively, focal-intense 18 F-FDG activity in the anterior portion of the bladder (Figure 1B and 1D) was detected using an IULIT, which corresponded to the soft-tissue lesion observed on the CT image (Figure 1C). Figure 1: An 80-year-old male with a chronic cough and intermittent hematuria underwent 18 F-FDG PET/CT for cancer screening. (A) A MIP PET image showed complete masking of the primary tumor by urinary activity. (B, D) A focal lesion ( cm), hiding in the anterior portion of the bladder and showing higher activity (SUV ) than urinary activity (SUV 5 9.4), was observed after using an IULIT. The arrow indicates a focal with relatively increased 18 F-FDG uptake in the bladder on the MIP (B) and axial (D) view of the PET images, corresponding to the focal-wall thickening observed in the CT image (C). Histopathological study indicated an invasive high-grade urothelial carcinoma. The bladder foci of Patient Nos. 1 and 2 showed relatively increased 18 F-FDG activity in the urinary tract after increasing the upper limit of the image threshold. For one patient, a PET scan was used to design the initial image status in the upper limit of the image threshold. A lesion with relatively After using the IULIT, the bladder foci showed decreased 18 F-FDG activity relative to the urinary activity in the central (Patient Nos. 3 and 4) and peripheral (Patient Nos. 5 and 6) regions of the bladder (Figures 2 and 3). Hybrid PET/CT scans confirmed the presence of the soft-tissue lesions observed in the CT images. When using a PET image without a combined CT image, a false negative may be diagnosed on a lesion in the peripheral region of the bladder. When a suspicious bladder lesion having an 18 F-FDG uptake lower than the urinary activity was observed, the delayed view after diuretic and oral hydration were administered may have caused a reverse contrast of the lesion toward the urinary background ratio (such as in Patient No. 4). Patient No. 3 received only oral hydration without diuretic administration before the delayed images were captured. Patients occasionally showed a soft-tissue lesion of the bladder, detected on CT images with an 18 F-FDG activity equal to the urinary activity (Patient Nos. 7 and 8 were Figure 2: A 43-year-old male underwent 18 F-FDG PET/CT for cancer screening. He had hematuria in the 3 months preceding the screening, and was asymptomatic at the time of screening. A lesion with lower activity (SUV 5 5.1) than the urinary activity (SUV ) was observed when using an IULIT. The arrow indicates a focal with relatively decreased 18 F-FDG uptake in the bladder on MIP (A), coronal (B), transaxial (C), and sagittal (D) views of the PET images, corresponding to the soft-tissue density mass ( cm) in the central region of the bladder observed on the CT image (E). Histopathological study showed papillary and high-grade urothelial carcinoma. Focal tumor necrosis was noted.

5 A New Method of FDG PET/CT to Detect Urinary Bladder Cancer 373 Figure 3: A 52-year-old male with hematuria underwent 18 F-FDG PET CT for cancer screening. A transaxial image captured when an IULIT was applied showed a focal lesion with lower activity (SUV ) than the urinary activity (SUV ) in the anterior portion of the bladder on PET (B) and PET/CT fusion (C) images. The arrow indicates a focal with decreased 18 F-FDG uptake in the bladder on an axial (B) view of the PET image, corresponding to the soft-tissue density lesion ( cm) in the left anterior portion of the bladder observed on the CT image (A). A complete masking of the primary tumor by urinary activity (D) was observed when an increased upper limit of the PET image was not used. Histopathological study showed papillary and high-grade urothelial carcinoma. Figure 4: An 85-year-old female patient with lung adenocarcinoma underwent 18 F-FDG PET/CT for cancer staging. A hypermetabolic nodular lesion in the posterior portion of the lower-right lung showed compatible lung cancer (not shown). When an IULIT was applied, transaxial CT and PET images were captured with the patient in a supine position (from left to right) before furosemide was administered (A), CT showed a suspicious lesion in the posterior wall of the bladder (white arrow), and the PET was equivocal. Delayed pelvic PET/ CT images captured when the patient was in a prone position (B) after receiving intravenous furosemide administration and oral hydration showed a hypermetabolic lesion in the posterior wall of the bladder (black arrow). Histopathological study indicated papillary high-grade urothelial carcinoma ( cm). asymptomatic). The delayed view after a diuretic with 20 mg of furosemide was injected intravenously and oral hydration with 800 ml of water was administered demonstrated the presence of a lesion with high 18 F-FDG activity (Figure 4). A change in position from supine to prone may exclude the possibility of a false 18 F-FDG deposit in the posterior portion of the bladder. Positive findings were obtained in 2 patients, with a more intense accumulation of FDG in the inferiorposterior portion of the bladder compared with the upper portion of the bladder. Cystoscope examinations yielded negative results. Uremia patients with hematuria (Patient Nos. 9 and 11) and malignancy changes in urine cytology (Patient No. 10) underwent an 18 F-FDG PET/CT examination. Urinary 18 F-FDG activity was not observed in the initial images of uremia patients (Patient Nos. 9, 10, and 11), but the 18 F-FDG uptake in the genitourinary tract may suggest abnormal findings (Figure 5). CT images that confirm these findings require further examination. Bladder cancer was not detected in the CT images of 2 of the 3 uremia patients. Patient No. 10 had oliguria and presented little urinary activity in the delayed image. Figure 5: A 62-year-old female patient with uremia and painless hematuria underwent 18 F-FDG PET/CT for cancer screening. Transaxial (B) and MIP (D) views of the PET images showed a focal hypermetabolic lesion (arrow) in the left side of the bladder. Histopathological study indicated papillary high-grade urothelial carcinoma ( cm).

6 374 Chen et al. Patient No. 12 was an asymptomatic man who underwent 18 F-FDG PET/CT for cancer screening. Ten months later, bladder urothelial carcinoma was diagnosed, and the patient received TUR-BT and chemotherapy. This was an 18 F-FDG PET/CT false negative case. When applying an IULIT for 18 F-FDG PET or PET/CT and a delayed PET/CT combined with diuretics for detecting bladder cancer, the sensitivity and specificity were 91.17% (95% confidence interval (CI): 59.8% to 99.6%) and 99.99% (95% CI: 99.97% to 100%), respectively. The positive predictive value and negative predictive value were 84.6% (95% CI: 53.66% to 97.29%) and 99.99% (95% CI: 99.98% to 100%), respectively. Discussion When the kidneys are functioning normally, approximately 16% of the administered 18 F-FDG is eliminated in urine after 60 minutes, and 50% is eliminated after 135 minutes (7, 8). We performed PET/CT scans on 30 asymptomatic health checkup examinees (20 men and 10 women) 1 hour after the patients received an infusion of 18 F-FDG and 500 ml of normal saline intravenously. The mean SUV levels of the liver and bladder of these examinees were (1.6 to 2.5) and (8 to 33), respectively. The wide range and high mean of the bladder SUV level were affected by the 18 F-FDG injection dose, dehydration, hydration, and renal function of the patients. Some authors believe that a high level of radioactivity in the bladder may complicate lesion assessments. 18 F-FDG PET/CT has excellent sensitivity and specificity for metastatic bladder cancer detection, and provides additional diagnostic information that enhances clinical management compared with CT/MRI alone (9). Patients with end-stage renal disease present oliguria or anuria, which causes low bladder 18 F-FDG activity. Lesions of the bladder with increased 18 F-FDG uptake can be detected easily because of a marked contrast with the peripheral region. Most uremic patients show rare excretory urinary radioactivity; therefore, when focal 18 F-FDG activity in the bladder is observed, further examination is necessary for the diagnosis of a highly possible bladder malignancy (10). Early investigations of bladder neoplasm imaging using 18 F-FDG PET were disappointing. Image reconstruction with filtered back projection produced steak artifacts around the bladder. Iterative reconstruction using the ordered subset expectation maximization method provided a high image quality. Furthermore, for retrograde irrigation of the bladder to remove 18 F-FDG radioactivity, saline irrigate and a Foley catheter were used during 18 F-FDG PET data acquisition (4). This technique has the benefit of allowing the evaluation of tumors of the bladder; however, it is an invasive procedure. Thereafter, PET combined with CT or hybrid PET/CT revealed the structure of the lesions, as well as anatomical information, providing additional diagnostic and prognostic accuracy (11). CT scans were used for correcting the attenuation of PET images. Patients were asked to void, and were positioned on the scanner table, complicating urinary bladder lesion assessments using CT images only. Another method involved recording delayed 18 F-FDG PET/CT images after administering a diuretic coupled with parenteral hydration (6, 12). This technique was noninvasive and could improve the detection of locally recurrent or residual bladder tumors; however, furosemide must be injected at least 2 hours after radiotracer injection, and many delayed images must be taken (6). In addition, early dynamic FDG PET images can demonstrate the presence of bladder lesions that are obscured by urine activity on routine images taken 1 hour after a radiotracer is injected (13). The upper limit of the image threshold in the projection view was presented in counts per pixel, according to the intravenous dose of 18 F-FDG, body weight, acquisition time, and reconstruction method. In addition, the upper limit of the image threshold in volume view (transaxial, coronal, and sagittal) can be presented in counts per pixel or gigameters per milliliter units. In lesions with high radioactivity backgrounds, such as those in the bladder and brain, using a high upper limit of the image threshold may allow differentiation of high-activity lesions from the highly active background region. If the upper limit of the image threshold is set too low, the difference between the lesion and the background may not be visualized, because the lesion intensity is above the threshold. In the present study, 18 F-FDG PET with an IULIT allowed the visualization of the higher or lower contrasts of lesions relative to urinary radioactivity. Delayed PET/CT images taken after administering a diuretic coupled with parenteral hydration were used to identify small existing isometabolisms or suspicious lesions of the bladder. Furthermore, hybrid PET/CT, which enabled detecting abnormal metabolism, could indicate lesion size, shape, and location. Delayed imaging and intravenous administration of furosemide were used to identify soft-tissue lesions with a high level of SUV. Papillary tumors represent the majority of urothelial carcinomas, which grow narrow, finger-like projections (14). In addition to papillary tumors, bladder cancer can develop in the form of a flat, red (erythematous) patch on the mucosal surface, requiring additional delayed PET/CT images to be recorded after administering a diuretic coupled with parenteral hydration and/or cystoscopy. With the help of an IULIT, 18 F-FDG PET enabled the visualization of focal FDG accumulation in the dependent area of the bladder, possibly because of 18 F-FDG deposition. Physiological changes usually cause symmetrical focal 18 F-FDG accumulation in the posterior-inferior area of the bladder. Requesting patients to change position from supine to prone may resolve the pitfalls of image interpretation (15). Focal

7 A New Method of FDG PET/CT to Detect Urinary Bladder Cancer 375 false negatives and increase accuracy when detecting bladder cancer. Delayed images captured after administering diuretics and oral hydration to the patients reduced the number of equivocal (isometabolism) and false positive findings in patients with a dependent site of 18 F-FDG deposition in the bladder. In initial 18 F-FDG PET or PET/CT images, an IULIT could be applied to screen lesions, regardless of whether they are located in the bladder. Delayed images captured after administering diuretics and oral hydration may improve the confidence of decisions made regarding cystoscopy. Therefore, we suggest using an initial image captured with an IULIT for evaluating bladder 18 F-FDG uptake. Funding Figure 6: A 79-year-old male received low-anterior resection for rectal adenocarcinoma 6 months before receiving screening. He was suspected to have a residual rectal tumor and underwent further examination using an 18 F-FDG PET/CT scan. When an IULIT was applied, transaxial CT and PET images were captured when the patient was in a supine position (from left to right) (A), CT showed a diverticulum in the posterior wall of the bladder (short arrow), and PET showed intense focal 18 F-FDG deposits in the inferior portion of the bladder (long arrow) and bladder diverticulum (short arrow). Delayed pelvic PET/CT images captured with the patient in a prone position (B) showed a flat intense 18 F-FDG deposit in the anterior wall of the bladder (long arrow). During a 5-year follow-up, the patient was not found to have a bladder lesion, except in the diverticulum. 18 F-FDG retention in the extravesical area of the bladder may be due to the diverticulum of the bladder (16). CT images or delayed PET/CT after patients received hydration and had a full bladder may aid in the diagnosis. When focal-intense 18 F-FDG deposits occur in the dependent area of the bladder diverticulum, a change in the position of the patient from supine to prone is necessary. If focal 18 F-FDG is deposited in the dependent area, rather than in the bladder lesion, a position change causes a focal 18 F-FDG move and persistent deposits in the dependent area (Figure 6). This study had a number of limitations. Several comparisons of the various permutations and combinations were not considered, including a single delayed scan, a delayed scan after diuretic and oral hydration, only delayed scans, and dualphase scans, all with diuretic administration. These comparisons should be included in future studies. An additional limitation was the inherent possibility of missing potentially non- 18 F-FDG avid, small-sized, and flat-bladder lesions. Using an IULIT for 18 F-FDG PET clearly improved the visualization of the contrast between lesion activity and urinary activity. Therefore, applying an IULIT may reduce The study was supported by grants from the study hospital (DMR and DMR ) in Taiwan, Department of Health Clinical Trial and Research Center and for Excellence (DOH102-TD-B ) in Taiwan, Department of Health Cancer Research Center for Excellence (DOH102-TD-C ), and International Research-Intensive Centers of Excellence (I-RiCE) in Taiwan (NSC I ). Conflicts of Interest The authors have no potential conflicts of interest to disclose. References 1. Jemal, A., Siegel, R., Ward, E., Hao, Y., Xu, J., Thun, M. J. Cancer Statistics, CA Cancer J Clin 59, (2009). DOI: / caac Cotran, R. S., Kumar, V., Collins, T. The lower urinary tract. In: Cotran, R. S., Kumar, V., Collins, T. (Eds.), Pathologic Basis of Disease. 6th Edition Philadelphia, PA: Saunders, (1999). DOI: /rg Cohen, S. M., Johansson, S. L. Epidemiology and etiology of bladder cancer. Urol Clin North Am 19, (1992). PMID: Kosuda, S., Kison, P. V., Greenough, R., Grossman, H. B., Wahl, R. L. Preliminary assessment of fluorine-18 fluorodeoxyglucose positron emission tomography in patients with bladder cancer. Eur J Nucl Med 24, (1997). PMID: Koyama, K., Okamura, T., Kawabe, J., Ozawa, N., Torii, K., Umesaki, N., Miyama, M., Ochi, H., Yamada, R. Evaluation of 18 F-FDG PET with bladder irrigation in patients with uterine and ovarian tumors. J Nucl Med 44, (2003). PMID: Anjos, D. A., Etchebehere, E. C., Ramos, C. D., Santos, A. O., Albertotti, C., Camargo, E. E. 18 F-FDG PET/CT delayed images after diuretic for restaging invasive bladder cancer. J Nucl Med 48, (2007). PMID: Gallagher, B. M., Fowler, J. S., Gutterson, N. I., MacGregor, R. R., Wan, C. N., Wolf, A. P. Metabolic trapping as a principle of radiopharmaceutical design: some factors responsible for the biodistribution of [ 18 F] 2-deoxy-2-fluoro-D-glucose. J Nucl Med 19, (1978). PMID: Woosley, R. L., Kim, Y. S., Hung, K. C. Renal tubular transport of 2-deoxy-d-glucose in dogs and rats. J Pharmacol Exp Ther 173, (1970). PMID: Apolo, A. B., Riches, J., Schöder, H., Akin, O., Trout, A., Milowsky, M. I., Bajorin, D. F. Clinical value of fluorine-18

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