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Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

X-ray computed tomography (CT) has been used for diagnoses of human pancreatic cancer. Although micro-CT is a useful approach to evaluate macromorphology of organs/tissue also in animal models, reports on pancreatic tumors are limited. In this study, the utility of micro-CT was assessed in characterizing chemically induced pancreatic tumors in Syrian hamsters. Hamsters treated with or without N-nitrosobis(2-oxopropyl)amine (BOP) were injected with the antispasmodic agent, scopolamine butylbromide, and contrast agents, 5 or 10 mL/kg body weight of iopamidol or Fenestra VC at 18–38 weeks, then examined by micro-CT scanning with a respiratory gating system. Both peristaltic and respiratory movements were substantially suppressed by the combination of scopolamine butylbromide treatment and the respiratory gating system, resulting in improvements of image qualities. Iopamidol clearly visualized the pancreatic parenchyma and contrasted the margins among the pancreas and other abdominal organs/tissue. Meanwhile Fenestra VC predominantly contrasted abdominal vascular systems, but the margins among pancreas and other organs/tissue remained obscure. Six pancreatic tumors of 4–13 mm in diameter were detected in four of 15 animals, but not the five tumors of 1–4 mm in diameter. The inner tumor images were heterogeneously or uniformly visualized by iopamidol and Fenestra VC. Overall, iopamidol could clearly contrast between pancreatic parenchyma and the tumors as compared with Fenestra VC. All tumors confirmed were histopathologically diagnosed as pancreatic ductal adenocarcinomas. Thus, micro-CT could be useful to evaluate the carcinogenic processes and preventive methods of pancreatic cancer in hamsters and to assess the novel contrast agents for detection of small pancreatic cancer in humans. (Cancer Sci 2010)

Pancreatic cancer is the fifth cause of cancer death in Japan and ranks high in mortality among developed countries.(1,2) Because of the difficulty in detecting pancreatic cancer in early operable stages, and because of the lack of any curative treatment approaches other than complete surgical removal, 5-year relative survival rate is <6%.(3,4) Therefore, for improvement of outcome, future strategies for early diagnosis of pancreatic cancer should aim at diagnosing most pancreatic cancers before they grow 20 mm in size.(5,6)

X-ray computed tomography (CT) has been widely used in detection and evaluation of pancreatic tumor progression and metastasis during clinical treatment. Recently, the CT devices have been markedly improved in their volume coverage speed, longitudinal resolution, and quality of three-dimensional reformations. In addition, dynamic CT scanning has been developed, in which CT-images of pancreas can be obtained for a short time with breath holding. This method reveals some adequate contrasts between pancreatic parenchyma and neoplastic lesions.(7) However, detectability of small pancreatic cancer, especially those <10 mm in size, has not yet been satisfactory.(8–10) Further amelioration of contrasting technologies that differentiate between tumors and pancreatic parenchyma is desirable to detect small pancreatic cancer.

Micro-CT is a useful tool for monitoring tumor development in living animal models, for example utility has been reported for detection of metastatic foci of xenograft rodent models(11,12) and periodic measurement of sizes in lung tumors and their growth overtime in a chemically induced carcinogenesis model.(13) In addition, respiratory gating systems appreciably resolve the thoracic movements in lung imaging.(11,13) However, the utility of micro-CT has been limited to several organs/tissue harboring distant X-ray adsorption ranges from surrounding tissue. The X-ray adsorption range is too close among abdominal organs/tissue to observe fine structures, and not only respiratory but also intestinal peristaltic movement interferes with CT imaging. Because of these limitations, pancreatic morphology and tumor imaging have not yet been reported in experimental animals.

In the present study, hamster pancreas and chemically induced pancreatic tumors were macromorphologically investigated by micro-CT with two characteristic contrast agents, iopamidol, which is a nonionic water-soluble iodine contrast agent typically used for clinical evaluations, and Fenestra VC, which is a polyiodinated lipid emulsion with blood pool properties developed for small animals.(14) The results obtained in the present study should provide basic information for CT-imaging of the pancreas and pancreatic tumor macromorphology and location in hamsters.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Animals.  A total of 19 female Syrian golden hamsters at 5 weeks of age were purchased from Japan SLC (Shizuoka, Japan). They were housed two or three to a plastic cage with woodchip bedding in an air-conditioned animal room maintained at 24 ± 2°C and 60 ± 5% relative humidity with a 12:12-h light–dark cycle. Basal diet (CE-2; CLEA Japan, Tokyo, Japan) and water were available ad libitum throughout the experiment.

Anatomical features of hamster pancreas.  For anatomical references of the pancreatic location and morphology, hamsters were dissected and pancreata were excised from abdominal cavity. A representative macroscopic feature of hamster pancreas is shown in Figure 1. In hamsters, the pancreas is a soft and flat organ and consists of four compartmentalized sections of the head portion and gastric, splenic, and duodenal lobes. There were no clear borderlines among the four sections, and three lobes including gastric, splenic, and duodenal are extended from the head (Fig. 1a). The duodenal lobe is smaller than the other two lobes, and the length of this lobe is about 10 mm in an animal with 180–200 g bodyweight (BW). Gastric and splenic lobes are 20–25 mm long. The tails of both gastric and splenic lobes are bridged by adipose tissue, which is called “fat ring.”Figure 1(b) shows the location of the pancreas in hamsters at laparotomy. The gastric and splenic lobes of pancreas are beside the gastric wall at the ventral and dorsal sides, respectively, (Fig. 1b,c) partially adhering to the colon (Fig. 1c, red dotted circles). The spleen is adjacent to the splenic lobe (Fig. 1a,c). The head and duodenal lobe were observed under the duodenum (Fig. 1b).

image

Figure 1.  Anatomical features of hamster pancreas and abdomen. (a) Pancreas excised from a hamster abdomen. (b) A hamster intra-abdomen at laparotomy and (c) behind the stomach. Red dotted circles indicate a part of gastric or splenic lobes adhered to colon. Co, colon; Du, duodenum; FR, fat ring; L, liver; Pd, pancreas duodenal lobe; Pg, pancreas gastric lobe; Ph, pancreas head; Ps, pancreas splenic lobe; Sg, glandular stomach; Sp, spleen.

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Pancreatic tumor induction.  After an acclimation period of 1 week, 15 hamsters were subcutaneously injected with N-nitrosobis(2-oxopropyl)amine (BOP; Nacalai Tesque, Kyoto, Japan) in saline at 10 mg/kg BW four times every other day. The other four hamsters without BOP were underwent the following treatments for micro-CT imaging of normal pancreatic morphology. The experiments were conducted according to the Guidelines for Animal Experiments from the Committee for Ethics of Animal Experimentation at the National Cancer Center.

Micro-CT scan procedure.  After fasting for 24 h, all hamsters with or without BOP treatment at ages from 18 to 38 weeks were anesthetized with Isoflurane (ISOFLU; Dainippon Sumitomo Pharmaceutical, Osaka, Japan) and the anesthesia was maintained with a mixture of Isoflurane and room air delivered during the micro-CT scanning.

Each hamster was placed on its back on an animal bed for micro-CT scanning. 5 mL/kg BW of iopamidol (Iopamiron 370; N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2S)-2-hydroxypropanoylamino]-2,4,6-triiodoisophthalamide; Bayer Shering Pharma, Osaka, Japan) (Fig. 2a), which is a nonionic iodine contrast agent for urinary tract and vascular imaging, or 10 mL/kg BW of Fenestra VC (1,3-bis-[7-(3-amino-2,4,6-triiodophenyl)heptanoyl]-2-oleoyl-glycerol; ART Advanced Research Technologies, Saint-Laurent, QC, Canada) (Fig. 2b), which is an iodinated lipids contrast agent with blood pool properties for animal imaging, were injected into cervical vein. The dose of each contrast agent was determined on the basis of the manufacturer’s recommendation with modifications to obtain optimal contrasts among organs/tissue for hamster abdominal imaging. The dose of iopamidol is about three times higher than that in human cases. An intraperitoneal injection of 5 mg/kg BW of scopolamine butylbromide (Buscopan; (1S,2S,4R,5R,7s)-9-butyl-7-[(2S)-3-hydroxy-2-phenylpropanoyloxy]-9-methyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide; Boehringer Ingelheim, Ingelheim, Germany), which is an antispasmodic agent diluted with saline, was then given to suppress intestinal peristaltic movement, and a sensor for detecting respiration was placed on the chin to avoid the shift of organ positions. In order to observe the precise morphology of each hamster pancreas, following the first micro-CT scanning for each animal, hamsters were injected with either of the contrast agents again after a washout period of the contrast agents for 24 h, and immediately sacrificed by cervical dislocation, and again, examined by micro-CT at 30 min after sacrifice.

image

Figure 2.  Chemical structures of iopamidol (N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2S)-2-hydroxy-propanoylamino]-2,4,6-triiodoisophthalamide) (a) and Fenestra VC (1,3-bis-[7-(3-amino-2,4,6-triiodo-phenyl)heptanoyl]-2-oleoyl-glycerol) (b).

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The X-ray scanning time point was set at 1200 millisecond (ms) after expiration. For scanning, a cone-beam micro-CT scanner (eXplore Locus; GE Healthcare, London, UK) was used. The scan parameters that are consistent for gated in vivo scan acquisitions include 80 kV peak, 450 μA, 400 ms per frame, 0.5 degrees at the angle of increment, and 720 views. The measured in-air radiation at the isocenter was 240 mGy. Scanning times with and without the respiratory gating system were about 40 and 15 min, respectively. Three-dimensional images obtained from axial, sagittal, and coronal micro-CT images were reconstructed at 45 μm voxel using MicroView (GE Healthcare).

Histopathological examination.  After X-ray scanning, the hamsters were autopsied. Pancreas was removed and fixed in 10% buffered formalin, and then they were embedded in paraffin, sectioned, and stained with hematoxylin–eosin (H&E) for histopathological evaluation. Pancreatic lesions were diagnosed according to the criteria described earlier.(15)

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

Micro-CT imaging of hamster pancreas with iopamidol.  A hamster abdomen was scanned by micro-CT without contrast agents. As a result, only a few major organs such as the liver, stomach, and kidneys were observed. However, pancreas and other abdominal organs/tissue were not detected by micro-CT images (data not shown). Therefore, the contrast agent, iopamidol, was administered to a hamster in order to visualize pancreatic images before micro-CT scanning. The liver, stomach, kidneys, spleen, colon, and duodenum were clearly visualized (Fig. 3). Some undigested food and/or wood chip residues were left in the stomach, despite fasting for 24 h. Gastric and splenic lobes of pancreas were also observed (Fig. 3b–i) by iopamidol treatment. Both gastric and splenic lobes of pancreas were located on the ventral and dorsal side, respectively, of gastric wall (Fig. 3b,c) and spleen was adjacent to the splenic lobe (Fig. 3c). The head and duodenal lobe of pancreas were located under the duodenum (Fig. 3e) and colon was adjacent to the duodenal, gastric, and splenic lobes (Fig. 3e,f,h,i). Each sagittal view in Figure 3 also visualized gastric and splenic lobes on the ventral and dorsal sides of stomach (Fig. 3g–i). To summarize the configuration of pancreatic sections on micro-CT images, the head beside the pylorus was medial, and the gastric and splenic lobes lay directly anterior and posterior to the antrum of stomach, respectively, and the duodenal lobe of the pancreas was inferior to the duodenum. In Figure 3(c,f), artifacts appear as radial white lines in the renal medulla and cortex, and renal papilla and ureter were intensely contrasted by iopamidol concentration.

image

Figure 3.  The micro-computed tomography (CT) images of hamster abdomen with iopamidol. A hamster administrated with scopolamine butylbromide and iopamidol was examined by micro-CT with respiratory gating system. Each image represents axial (a–c), colonal (d–f), and sagittal (g–i) views around the pancreas. An arrow indicates iopamidol excretion into the urinary tract (f). Co, colon; Du, duodenum; Kl, left kidney; Kr, right kidney; L, liver; Pd, pancreas duodenal lobe; Pg, pancreas gastric lobe; Ph, pancreas head; Ps, pancreas splenic lobe; Pyl, Pylorus of stomach; Sg, glandular stomach; Sp, spleen.

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Micro-CT scanning required at least several minutes. In addition to both respiratory and peristaltic movements, excretion of contrast agents during micro-CT scanning is thought to cause the contrast degradations in each organs/tissue. In order to detect the precise location and structure of pancreas by micro-CT, hamsters were treated with iopamidol again and immediately sacrificed to stop both respiratory and peristaltic movement and excretion of iopamidol, and then hamsters were examined by micro-CT scanning. Distinct contrasts in parenchyma among organs/tissue and the sharp edge of the liver, stomach, kidneys, esophagus, duodenum, and all pancreatic sections were clearly visualized in a sacrificed animal (Fig. 4) and compared with the images of a living animal shown in Figure 3. As well as the anatomical information in Figure 1, the head and duodenal lobe of the pancreas were located under the pylorus and duodenum, respectively, (Fig. 4e) and the gastric and splenic lobes were located beside the gastric wall (Fig. 4b–d,f–i) and they were also adjacent to the colon (Fig. 4e,f). In addition to main abdominal vascular systems of the inferior vena cava (IVC) and aorta (Ao), part of the blood vessels in the pancreatic parenchyma was also visualized (Fig. 4d, arrowheads). Radial artifacts in the renal medulla and cortex and iopamidol concentration into renal papilla and ureter were not observed.

image

Figure 4.  The micro-computed tomography (CT) images of hamster abdomen with iopamidol after sacrifice. A hamster administrated with iopamidol was immediately sacrificed and was examined by micro-CT. Each image represents axial (a–c), colonal (d–f), and sagittal (g–i) views around pancreas. Arrowheads indicate the blood vessel in the pancreatic parenchyma (d). Co, colon; Du, duodenum; Es, esophagus; Kl, left kidney; Kr, right kidney; L, liver; Pg, pancreas gastric lobe; Ph, pancreas head; Ps, pancreas splenic lobe; Pyl, pylorus of stomach; Sg, glandular stomach.

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Micro-CT imaging of hamster pancreas with Fenestra VC. Figure 5 shows the Fenestra VC-visualized micro-CT images in hamster abdomen. Administration of Fenestra VC clearly contrasted abdominal vascular systems, such as portal vein (PV), IVC, and Ao (Fig. 5a–c,f,g). The gastric and splenic lobes of the pancreas were visualized on the same positions as those visualized by iopamidol in Figure 3. However, the border and the parenchyma of the organs/tissue were not clearly differentiated in comparison to the images made visible with iopamidol. Figure 6 shows a sacrificed hamster abdominal image contrasted with Fenestra VC. The edges of each abdominal organ, such as the liver, stomach, kidneys, and blood vessels, were improved to some extent as compared with the images in a living animal (Fig. 6). The contrasts among organs/tissue parenchyma did not seem to change. Fenestra VC was likely retained in blood vessels during micro-CT imaging for 40 min.

image

Figure 5.  The micro-computed tomography (CT) images of hamster abdomen with Fenestra VC. A hamster administrated with Buscopan and Fenestra VC was examined by micro-CT with the respiratory gating system. Images depict axial (a–c), colonal (d–f), and sagittal (g–i) views around pancreas. Ao, aorta; Co, colon; IVC, inferior vena cava; Kl, left kidney; Kr, right kidney; L, liver; Pg, pancreas gastric lobe; Ps, pancreas splenic lobe; PV, portal vein; Sg, glandular stomach; Sp, spleen.

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image

Figure 6.  The micro-computed tomography (CT) images of hamster abdomen with Fenestra VC after sacrifice. A hamster administrated with Fenestra VC was immediately sacrificed and was examined by micro-CT. Images depict axial (a–c), colonal (d–f), and sagittal (g–i) views around pancreas. Ao, aorta; Co, colon; IVC, inferior vena cava; Kl, left kidney; Kr, right kidney; L, liver; Pg, pancreas gastric lobe; Ps, pancreas splenic lobe; PV, portal vein; Sg, glandular stomach; Sp, spleen.

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Micro-CT imaging of hamster pancreatic tumors.  A total of 15 BOP-treated hamsters were examined by micro-CT. Groups of eight and seven hamsters were administered with iopamidol and Fenestra VC, respectively. A total of six pancreatic tumors of 4–13 mm in diameter were visualized with iopamidol or Fenestra VC in four of 15 animals from 18 to 38 weeks old. Micro-CT scanning with iopamidol visualized four tumors of 4, 6, 7, and 10 mm in diameter in two animals. The tumors of 4 and 6 mm in diameter numbered 1 and 2 (#1 and #2) developed in one animal shown in Figure 7(a,b). A poorly defined heterogeneously visualized mass-like image of 4 mm in diameter, which was confirmed to be a tumor #1 in an autopsy finding (dotted black circle of Fig. 7a), was observed in the body of the gastric lobe (Fig. 7e). Tumor #2 showed a hypoattenuating mass image of 6 mm in diameter with a clear margin compared with surrounding pancreatic parenchyma in the pancreatic body of the splenic lobe (Fig. 7b,e). The other tumors of 7 and 10 mm in diameter developed in another animal and also were visible as heterogeneous masses in the gastric and splenic lobes, respectively (data not shown). All these four tumors were diagnosed as pancreatic ductal adenocarcinomas. Tumors #1 and #2 were moderately differentiated tubular adenocarcinomas (Fig. 7h,i). The other two tumors were moderately differentiated tubular adenocarcinoma and poorly differentiated adenocarcinoma with abundant stromal formation (data not shown). In addition to the above-mentioned four tumors detected by micro-CT with iopamidol, two moderately differentiated small adenocarcinomas of 1 and 0.5 mm in diameter each were histopathologically confirmed in the head of the pancreas of another animal, while these ones were not detected by micro-CT imaging with iopamidol.

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Figure 7.  Representative images of hamster pancreatic tumors. Micro-computed tomography (CT) images visualized with iopamidol and Fenestra VC are shown in (a–d) respectively. Tumors in dotted circles in (a–d) are numbered 1–4 (tumors #1–4), respectively. Macroscopic and microscopic features stained with H&E from tumors #1–4 are shown in (e–g) and (h–k), respectively. (e–g) Scale bar = 10 mm. (h–k) Scale bar = 500 μm. Kl, left kidney; L, liver; Pg, pancreas gastric lobe; Ph, pancreas head; Ps, pancreas splenic lobe; Sg, glandular stomach; Sp, spleen.

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Micro-CT scanning with Fenestra VC revealed two tumors of 13 and 10 mm in diameter (tumors #3 and #4) in two animals each (Fig. 7c,d). Both tumors #3 and #4 were observed in the tails of splenic lobes. Both tumor contrasts were slightly attenuated as compared with pancreatic parenchyma and the images of inner tumors were uniformly made visible with Fenestra VC. At autopsy, two tumors were found in similar positions (Fig. 7f,g) and histopathologically diagnosed as pancreatic ductal adenocarcinomas (Fig. 7j,k). Tumor #3 was cystadenocarcinoma (Fig. 7j) and tumor #4 was poorly differentiated adenocarcinoma with abundant stromal formation (Fig. 7k). In addition to these two tumors, three adenocarcinomas of 4, 1, and 1 mm in diameter were histopathologically confirmed in the gastric lobes of pancreas in other hamsters, while these ones were not detected by micro-CT imaging with Fenestra VC. These three adenocarcinomas were poorly differentiated adenocarcinomas with stromal formation (data not shown).

In addition to pancreatic ductal carcinogenic changes, moderate fatty infiltrations were also histopathologically observed in pancreatic parenchyma of all the BOP-treated hamsters. However, no significant contrast changes in pancreatic parenchyma were found by micro-CT imaging among hamsters with and without BOP (Figs 3,5,7a–d).

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

In the present study, pancreatic morphology and chemically induced pancreatic tumors in Syrian hamsters were shown to be detectable by micro-CT. The Syrian hamster model with BOP has been widely applied as an animal model for the study of human pancreatic ductal carcinogenesis and data showing morphological details of both the early and advanced lesions have been reported.(15–17)

In order to substantially suppress the respiratory and the peristaltic movements during CT scanning, the antispasmodic agent, scopolamine butylbromide, was administered in combination with the respiratory gating system. The respiratory gating system improved and reduced motion artifacts caused by respiratory movements on the present scanning parameter. The images of abdomen without scopolamine butylbromide treatment were not clearly visible, especially at the edge of organs/tissue, as compared with the images using scopolamine butylbromide (data not shown). The 5 mg/kg BW dose of scopolamine butylbromide is about 15 times higher than that in human cases. No toxicological data of scopolamine butylbromide in hamsters is available, but lethal dose 50% (LD50) of scopolamine butylbromide in an intravenous administration study in mice was estimated to 20 mg/kg BW (manufacturer’s in-house data), which is four times higher than the present dose. Therefore, it is likely that a single or short-term repeated intraperitoneal administration of scopolamine butylbromide at the present dose might be safe for administration. Although causes of the difference in adequate doses between hamsters and humans are unclear, application of both scopolamine butylbromide and the respiratory gating system is considered to be a useful method for abdominal imaging in animal models.

In the present study, two different types of abdominal organs/tissue and the pancreatic tumor images, which reflected the characteristics of iopamidol and Fenestra VC, were obtained by micro-CT scanning. In living animals, iopamidol clearly enhanced the visibility of major abdominal organs/tissue parenchyma, and simultaneously the kidneys and urinary tract were prominently contrasted and the radial white linear artifacts were seen in the regions. However, the contrasts among organs/tissue were thought to be attenuated by renal excretion during micro-CT scanning. In a sacrificed animal, the parenchyma and the edge of pancreas and other organs/tissue were clearly visible and Ao and IVC were also visualized as compared with living animals. The artifacts by iopamidol which appeared in living animals were not observed in the sacrificed animals. Assessments of such contrast agents, which are excreted rapidly, by using sacrificed animals may also be useful in addition to using living animals. On the other hand, Fenestra VC predominantly increased the visibility of major abdominal vascular systems and was likely retained during micro-CT scanning for 40 min. Ford et al.(18) reported that contrasts in blood vessels and several abdominal organs in mice were retained for 24 h after injection of Fenestra VC. The present study also supported the benefits of Fenestra VC to vascular systems imaging when scanning for longer periods of time.

Most pancreatic tumor imaging with contrast agents such as nonionic iodine materials including iopamidol typically appeared as a hypoattenuating mass relative to the pancreatic parenchyma in humans.(19) The same is true with the case of BOP-treated hamsters. However the contrast between tumors and parenchyma in hamster pancreas was slightly inferior to that in humans, despite the higher dose of iopamidol than the manufacturer’s recommendations for humans. It is implied that the difference in effects of nonionic contrast agents on humans and hamsters is the rapid clearance of iopamidol during image scanning, resulting in attenuation of the contrast of pancreatic parenchyma. From the viewpoint of toxicological effects of such contrast agents, repeated intravenous administrations of iopamidol for 5 weeks in rats at a dose of 2 g/kg BW iodine equivalent, which is almost similar to the present dose (1.85 g/kg BW iodine equivalent), did not show remarkable influences on body weights, food intakes, and hematological parameters (manufacturer’s in-house data). Therefore, it is likely that the present doses of each agent under the Isoflurane anesthesia with the use of respiratory gating systems might be safe in single or short-term repeated administration studies. However, the influence of repeated treatment with iopamidol on general toxicities and pancreatic carcinogenesis in hamsters is still unclear. Further detailed analyses are be required to elucidate these points. Baron reported that differences of at least 10–15 CT value (HU; Hounsfield unit) are required for visual detection of the tumor.(20) In other words, higher contrasts between tumor and parenchyma images by micro-CT are required for differentiating histomorphological changes in the tumors as compared with pancreatic parenchyma. In the present study, all the tumors observed by micro-CT were histopathologically diagnosed as pancreatic ductal carcinomas, which are also the frequently observed pancreatic carcinoma type in humans.

Micro-CT with contrast agents enhanced the imaging of BOP-induced pancreatic tumors over 4 mm in diameter. However, carcinoma-localized intralobules were not fully detected by micro-CT. The reason for this might also be due to insufficient contrast between the pancreatic tumor and parenchyma. Recently, Hainfeld et al.(21) reported that gold nanoparticles with higher X-ray absorptive power than iodine-based agents may be useful as a novel X-ray contrast agent. Further studies using powerful X-ray absorptive agents may shed light on the limitations of imaging with smaller sized pancreatic tumors. For evaluations of novel contrast agents, X-ray micro-CT imaging systems with BOP-induced pancreatic carcinogenesis models could be adequate.

In the present study, we focused on the imaging of both pancreatic morphology and BOP-induced pancreatic tumors at one time point using two types of contrast agents. Time-dependent imaging of pancreatic tumors might also be useful for evaluations of the tumor development and preventives for pancreatic carcinogenesis. Overall, iopamidol could clearly contrast between pancreatic parenchyma and the tumors as compared with Fenestra VC.

In conclusion, our results provided evidence that respiratory-gated micro-CT scanning of hamsters has potential as a method for evaluating changes in the growth of pancreatic tumors. These studies on scanning and pancreatic carcinogenesis model systems may also be useful for evaluation of newly developing contrast agents for pancreatic tumors. Development of novel contrast agents in combination with the improvement of devices may lead to detection of smaller pancreatic tumors and precancerous lesions.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References

This work was supported by Grants-in-Aid for Cancer Research, for the Third-Term Comprehensive 10-Year Strategy for Cancer Control, from the Ministry of Health, Labour and Welfare of Japan.

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. References
  • 1
    Matsuda T, Marugame T, Kamo K, Katanoda K, Ajiki W, Sobue T. Cancer incidence and incidence rates in Japan in 2002: based on data from 11 population-based cancer registries. Jpn J Clin Oncol 2008; 38: 6418.
  • 2
    Michaud DS. Epidemiology of pancreatic cancer. Minerva Chir 2004; 59: 99111.
  • 3
    Tsukuma H, Ajiki W, Ioka A, Oshima A. Survival of cancer patients diagnosed between 1993 and 1996: a collaborative study of population-based cancer registries in Japan. Jpn J Clin Oncol 2006; 36: 6027.
  • 4
    De Braud F, Cascinu S, Gatta G. Cancer of pancreas. Crit Rev Oncol Hematol 2004; 50: 14755.
  • 5
    Agarwal B, Correa AM, Ho L. Survival in pancreatic carcinoma based on tumor size. Pancreas 2008; 36: e1520.
  • 6
    Pongprasobchai S, Pannala R, Smyrk TC et al. Long-term survival and prognostic indicators in small (<or=2 cm) pancreatic cancer. Pancreatology 2008; 8: 58792.
  • 7
    Freeny PC, Marks WM, Ryan JA, Traverso LW. Pancreatic ductal adenocarcinoma: diagnosis and staging with dynamic CT. Radiology 1988; 166: 12533.
  • 8
    Legmann P, Vignaux O, Dousset B et al. Pancreatic tumors: comparison of dual-phase helical CT and endoscopic sonography. AJR Am J Roentgenol 1998; 170: 131522.
  • 9
    Prokesch RW, Schima W, Chow LC, Jeffrey RB. Multidetector CT of pancreatic adenocarcinoma: diagnostic advances and therapeutic relevance. Eur Radiol 2003; 13: 214754.
  • 10
    Bronstein YL, Loyer EM, Kaur H et al. Detection of small pancreatic tumors with multiphasic helical CT. AJR Am J Roentgenol 2004; 182: 61923.
  • 11
    Cavanaugh D, Johnson E, Price RE, Kurie J, Travis EL, Cody DD. In vivo respiratory-gated micro-CT imaging in small-animal oncology models. Mol Imaging 2004; 3: 5562.
  • 12
    Li XF, Zanzonico P, Ling CC, O’Donoghue J. Visualization of experimental lung and bone metastases in live nude mice by X-ray micro-computed tomography. Technol Cancer Res Treat 2006; 5: 14755.
  • 13
    Hori Y, Takasuka N, Mutoh M et al. Periodic analysis of urethane-induced pulmonary tumors in living A/J mice by respiration-gated X-ray microcomputed tomography. Cancer Sci 2008; 99: 17747.
  • 14
    Bakan DA, Weichert JP, Longino MA et al. Polyiodinated triglyceride lipid emulsions for use as hepatoselective contrast agents in CT: effects of physicochemical properties on biodistribution and imaging profiles. Invest Radiol 2000; 35: 15869.
  • 15
    Konishi Y, Mizumoto K, Kitazawa S, Tsujiuchi T, Tsutsumi M, Kamano T. Early ductal lesions of pancreatic carcinogenesis in animals and humans. Int J Pancreatol 1990; 7: 839.
  • 16
    Pour P, Althoff J, Kruger FW, Mohr U. A potent pancreatic carcinogen in Syrian hamsters: N-nitrosobis(2-oxopropyl)amine. J Natl Cancer Inst 1977; 58: 144953.
  • 17
    Mizumoto K, Tsutsumi M, Denda A, Konishi Y. Rapid production of pancreatic carcinoma by initiation with N-nitroso-bis(2-oxopropyl)amine and repeated augmentation pressure in hamsters. J Natl Cancer Inst 1988; 80: 15647.
  • 18
    Ford NL, Graham KC, Groom AC, Macdonald IC, Chambers AF, Holdsworth DW. Time-course characterization of the computed tomography contrast enhancement of an iodinated blood-pool contrast agent in mice using a volumetric flat-panel equipped computed tomography scanner. Invest Radiol 2006; 41: 38490.
  • 19
    Prokesch RW, Chow LC, Beaulieu CF, Bammer R, Jeffrey RB Jr. Isoattenuating pancreatic adenocarcinoma at multi-detector row CT: secondary signs. Radiology 2002; 224: 7648.
  • 20
    Baron RL. Understanding and optimizing use of contrast material for CT of the liver. AJR Am J Roentgenol 1994; 163: 32331.
  • 21
    Hainfeld JF, Slatkin DN, Focella TM, Smilowitz HM. Gold nanoparticles: a new X-ray contrast agent. Br J Radiol 2006; 79: 24853.