Liver Physiology and Pathophysiology Investigated by PET/CT
The work of the Liver PET Group at Aarhus University Hospital focuses on the development of physiologically based PET/CT methods for studying the liver. The aim is to improve our understanding of liver physiology and pathophysiology and optimise human PET/CT studies. Clinical implementation of physiologically based PET/CT will improve the diagnosis and treatment of patients with liver diseases.
In conceptual interaction with the results of animal experiments and clinical studies on healthy human subjects and patients with liver diseases we are developing new mathematical-physiological models for PET studies of liver blood perfusion, metabolism and excretory function. Our work takes greatest possible account of the liver's special anatomy and physiology/pathophysiology. The location of the liver between the gastrointestinal circulation and the systemic circulation is the basis for its filter function, including detoxification of harmful substances absorbed from the gut. In our modelling work we therefore take into account the liver's dual blood supply, liver microcirculation, hepatocellular metabolism and biliary excretion. We integrate the power of data acquisition by contemporary PET and PET/CT in the development of our physiological approach to liver PET.
New methods are tested, challenged and validated in animal PET studies in conjunction with appropriate laboratory tests. Non-invasive methods are validated against fully invasive studies in animals. After obtaining the approval of the Danish Medical Ethics Committee we test the novel non-invasive methods in experimental studies in human subjects. Whenever possible, the same equipment and scan procedures are used in both the animal studies and the human studies. Finally we implement these methods in routine clinical work with patients with liver diseases, including primary and secondary liver cancer.
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The Liver PET Group's projects encompass four areas
- The liver's blood supply and exchange of substances with the blood
- Hepatic metabolism and excretory function
- Hepatic encephalopathy
- Cancer
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1. The liver's blood supply and exchange of substances with the blood
The liver plays a vital role in the metabolism of endogenous and exogenous substances. It's location between the gastrointestinal tract and the systemic circulation means that food and other consumed substances have to pass through the liver before reaching the systemic circulation. The liver receives blood from the gut via the portal vein (approx. 75%) and from the hepatic artery (approx. 25%) (Fig. 1). The blood from these two vessels mixes proportionally to the flow ratio at the entrance to the liver sinusoids - small fenestrated blood vessels through which the majority of substances can pass directly from the blood to the hepatocytes (Fig. 2). The sinusoidal membrane of the hepatocytes is lined with innumerable microvilli that project into the space of Dissé between the hepatocytes and the endothelial cells lining the sinusoids. The structure of the liver is thus optimal for the exchange of substances with the blood. From the sinusoids the blood flows into the liver veins and is subsequently returned to the systemic circulation.
In Dynamic Positron Emission Tomography (PET) and PET/CT, biological processes are recorded externally in three dimensions following administration of radiolabelled tracers by intravenous injection or inhalation. Compared to other functional imaging techniques such as SPECT, contemporary PET has a better spatial and temporal resolution. Moreover, specific PET tracers can be synthesized for studies of specific metabolic processes by radiolabelling naturally occurring substances (e.g. 11C-glucose and 13N-ammonia) and analogues hereof (e.g. 18F-deoxy-2-glucose, FDG and 18F-decay-2-galactose, FDGal), pharmaceuticals or ligands for biliary excretory transporters. During and following tracer administration the time course of the concentration of radioactivity in the tissue is recorded by the PET tomograph and the time course of the concentration of radioactivity in the inflowing blood is measured in successive blood samples. The resulting data are then analysed using a kinetic model for turnover of the tracer used (Fig. 3).
We work with PET tracers labelled with 15O, 13N, 11C, 18F or 68Ga. The three former isotopes must be produced on-site as their radioactive half-life is only 2—20 minutes. At the same time, though, the short half-lives make it possible to perform sequential studies in the same subject within the space of a few hours. A tracer labelled with 18F (radioactive half-life 109 minutes) is preferred in studies of slow metabolic processes. The use of combined PET/CT further provides the anatomical location (CT) of the biological processes (PET) in merged images.
Dual blood supply. Following an intravenous injection of tracer, the time-dependent concentration profile of the tracer in arterial CHA and portal venous blood CPV differs markedly (Fig. 4). Assuming that the blood from the two vessels mixes completely at the entry to reaching the liver sinusoids, the flow-weighted dual-input concentration CDual can be calculated as:
where F is flow and C is the concentration of radioactivity in the portal vein (PV) and hepatic artery (HA), respectively.
In man the portal vein is inaccessible to blood sampling. In the case of substances that are not metabolized in the gut, tracer input via the portal vein can be ignored if only net uptake is to be measured. We find, for example, that this is the case for the sugar FDG. However, if a considerable proportion of the substance is metabolized in the gut or if one wants to calculate more specific rate constants and parameters for uptake and turnover of the substance (Fig. 3), it is necessary to know the total tracer input to the liver (CDual). In return, though, this enables differential measurement of the liver blood perfusion, transport of the tracer across the cell membrane and its turnover in the cell and/or excretion via the bile. We are therefore developing PET/CT methods to obtain the dual input data without the need for blood sampling, and to apply these methods in human studies.
Liver microcirculation. Analysis of dynamic PET studies is usually performed using "standard" compartmental models (Fig. 5, left). In these models the tracer and any degradation products are considered in separate compartments. The substances are exchanged between compartments as a function of time following injection of the tracer. The model parameters are rate constants describing this exchange. It is assumed that the concentration of the substance is always uniform throughout each compartment at a given time point and, as a consequence, that the blood concentration is the same throughout the sinusoid from the inlet to the outlet. From a practical point of view these models are often useful, but they clearly deviate from normal liver physiology. As illustrated on the right side of Fig. 5, the blood flows through the sinusoids from the inlet to the outlet. When a PET tracer passes through the sinusoids, spatial and temporal concentration gradients develop. We have developed a microcirculation model that takes these factors into account for determining liver tissue blood perfusion by dynamic 15O-carbon monoxide PET in pig experiments. This is not possible with the traditional compartmental model.
Publications from our group
Sørensen M, Keiding S, Positron emission tomography of the liver. In Textbook of Hepatology: From Basic Science to Clinical Practice, 3. ed. (eds. Rodés J, Benhamou JP, Blei A, Reichen J and Rizzetto M), Blackwell, 2007, pp. 561—566.
Keiding S, Sørensen M. Hepatic removal kinetics: importance for quantitative measurements of liver function. In Textbook of Hepatology: From Basic Science to Clinical Practice, 3. ed. (eds. Rodés J, Benhamou JP, Blei A, Reichen J and Rizzetto M), Blackwell, 2007, pp. 468—478.
Keiding S, Munk OL, Vilstrup H, Nielsen DT, Roelsgaard K, Bass L. Hepatic microcirculation assessed by PET of first-pass ammonia metabolism in porcine liver. Liver Int 2005; 25: 171—176.
Keiding S, Solvig J, Grønbæk H, Vilstrup H. Combined liver vein and spleen pulp pressure measurements in patients with portal or splenic vein thrombosis. Scand J Gastroent 2004; 39: 594—599.
Munk OL. Hepatic metabolism of glucose analogues measured by dynamic positron emission tomography and interpreted by compartment models - with special reference to the hepatic dual-input function. (PhD-thesis 2004, Aarhus University) Dan Med Bull 2004; 51: 446.
Munk OL, Bass L, Feng H, Keiding S. Determination of regional flow using intravascular PET tracers: microvascular theory and experimental validation for pig livers. J Nucl Med 2003; 44: 1862—1870.
Munk OL, Keiding S, Bass L. Capillaries within compartments: microvascular interpretation of dynamic positron emission tomography data. J Theor Biol 2003; 225: 127—141.
Munk OL, Keiding S, Bass L. Impulse-response function of splanchnic circulation with model-independent constraints: theory and experimental validation. Am J Physiol Gastrointest Liver Physiol 2003; 285: G671—G680.
Keiding S, Vilstrup H. Intrahepatic heterogeneity of hepatic venous pressure gradient in human cirrhosis. Scand J Gastroeterol 2002; 37: 960—964.
Weiss M, Roelsgaard K, Bender D, Keiding S. Determinants of [13N]ammonia kinetics in hepatic PET experiments: a minimal recirculatory model. Eur J Nucl Med 2002; 29: 1648—1656.
Munk OL, Bass L, Roelsgaard K, Bender D, Hansen SB, Keiding S. Liver kinetics of glucose analogs measured in pigs by PET: Importance of dual-input blood sampling. J Nucl Med 2001; 42: 795—801.
Ott P, Clemmesen O, Keiding S. Interpretation of simultanous measurements of hepatic extraction fractions of indocyanine green and sorbitol: Evidence of hepatic shunts and capillarization? Dig Dis Sci 2000; 45: 359—365.
Keiding S, Munk OL, Schiøtt KM, Hansen SB. Dynamic 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography of liver tumors without blood sampling. Eur J Nucl Med 2000; 27: 407—412.
Keiding S, Engsted E, Ott P. Sorbitol as a test substance for measurement of liver plasma flow in humans. Hepatology 1998; 28: 50—56.
Ott P, Bass L, Keiding S. Hepatic ICG removal in the pig depends on plasma protein and hematocrit: Evidence of sinusoidal binding disequilibrium and unstirred water layer effects. Hepatology 1997; 26: 679—690.
Keiding S, Ott P, Bass L. Enhancement of unbound clearance of ICG by plasma protein, demonstrated in human subjects and interpreted without assumption of facilitating structures. J Hepatol 1993; 19: 327—344.
Ott P, Keiding S, Bass L. Intrinsic hepatic clearance of indocyanine green in the pig: Dependence on plasma protein concentration. Eur J Clin Invest 1992; 22: 347—357.
Keiding S, Skak C. Methodological limitations of the use of intrinsic hepatic clearance of ICG as a measure of liver cell function. Eur J Clin Invest 1988; 18: 507—511.
Bass L, Keiding S. Physiologically based models and strategic experiments in hepatic pharmacology. Biochem Pharmacol 1988; 37: 1425—1431.
Keiding S. Galactose clearance and liver blood flow. Gastroenterol 1988; 94: 477—481.
Winkler K, Bass L, Keiding S, Tygstrup N. The physiologic basis of clearance measurements in hepatology. Scand J Gastroenterol 1979; 14: 439—448.
Winkler K, Keiding S, Tønnesen K, Tygstrup N. The effect of physiological temperature changes on the galactose elimination capacity of the isolated perfused pig liver. Clin Physiol 1986; 6: 381—387.
Keiding S, Chiarantini E. Effect of sinusoidal perfusion on galactose elimination kinetics in perfused rat liver. J Pharm Exp Ther 1978; 205: 465—470.
Bass L, Keiding S, Winkler K, Tygstrup N. Enzymatic elimination of substrates flowing through the intact liver. J theor Biol 1976; 61: 393—409.
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2. Hepatic metabolism and excretory function
We are developing PET and PET/CT methods for non-invasive regional measurement of a number of specific liver functions, including excretory function. New tracers are being developed as required by the biological questions (Fig. 6). Such methods will be very useful in the diagnosis and treatment of patients with liver diseases, for example to assess whether a patient with liver cancer can tolerate removal of the part of the liver whose removal is necessary to cure the patient.
Publications from our group
Jepsen P, Vilstrup H, Ott P, Keiding S, Andersen PK, Tygstrup N. The galactose elimination capacity and mortality in 781 Danish patients with newly-diagnosed liver cirrhosis: a cohort study. BMJ Gastroenterol 2009; 9: 50.
Dam G, Sørensen M, Munk OL, Keiding S. Hepatic ethanol elimination kinetics in patients with cirrhosis. Scand J Gastroent 2009; 44: 867—871.
Munk OL, Keiding S, Bass L. A method to estimate catheter dispersion and to calculate dispersion-free blood time-activity curves. Medical Physics 2008; 35: 3471—3481.
Sørensen M, Munk OL, Mortensen FV, Olsen AK, Bender D, Bass L, and Keiding S. Hepatic uptake and metabolism of galactose can be quantified in vivo by 2-[18F]fluoro-2-deoxygalactose positron emission tomography. Am J Physiol Gastrointest Liver Physiol 2008; 295: G27—G36.
Bender D, Munk OL, Feng H, Keiding S. Metabolites of 18F-FDG and 3-O-11C-methylglucose in pig liver. J Nucl Med 2001; 42: 1673—1678.
Weiss M, Roelsgaard K, Bender D, Keiding S. Determinants of [13N]ammonia kinetics in hepatic PET experiments: a minimal recirculatory model. Eur J Nucl Med 2002; 29: 1648—1656.
Keiding S, Munk OL, Roelsgaard K, Bender D, Bass L. Positron emission tomography of hepatic first-pass metabolism of ammonia in pig. Eur J Nucl Med 2001; 28: 1770—1775.
Roelsgaard K, Bøtker HE, Stødkilde-Jørgensen H, Andreasen F, Jensen SL, Keiding S. Effects of brain death and glucose infusion on hepatic glycogen and blood hormones in the pig. Hepatology 1996; 24: 871—875.
Ott P, Bass L, Keiding S. The kinetics of continuously infused indocyanine green in the pig. J Pharmacokinetics Biopharm 1996; 24: 19—44.
Kjær M, Keiding S, Engfred K, Rasmussen K, Sonne B, Kirkegaard P, Galbo H. Glucose homeostasis during exercise in humans with a liver or kidney transplant. Am J Phys 1995; 268: E636—644.
Keiding S, Johansen S, Tygstrup N. Galactose removal kinetics during hypoxia in perfused pig liver: Reduction of Vmax, but not of intrinsic clearance Vmax/Km. Eur J Clin Invest 1990; 20: 305—309.
Keiding S, Johansen S, Winkler K. Hepatic galactose elimination kinetics in the intact pig liver. Scand J clin Lab Invest 1982; 42: 253—259.
Keiding S, Chiarantini E. Effect of sinusoidal perfusion on galactose elimination kinetics in perfused rat liver. J Pharm Exp Ther 1978; 205: 465—470.
Keiding S, Johansen S, Midtbøll I, Rabøl A, Christiansen L. Ethanol elimination kinetics in pig liver and human liver. Am J Physiol 1979; 237: E316—324.
Keiding S, Johansen S, Winkler K, Tønnesen K, Tygstrup N. Michaelis-Menten kinetics of galactose elimination by the isolated perfused pig liver. Am J Physiol 1976; 320: 1302—1313.
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3. Hepatic encephalopathy
Cirrhosis causes loss of functional liver mass and intra- and extrahepatic shunting of blood from the portal circulation to the systemic circulation, thereby compromising the liver's filter function. Ammonia that has escaped detoxification in the diseased liver is assumed to play a key role in the pathogenesis of the toxic brain syndrome hepatic encephalopathy (HE). We are studying possible impairment of brain metabolism by ammonia (Fig. 7) in a series of conceptually interrelated studies ranging from experiments with cultured mouse brain cells (neurons and astroctyes) to PET studies of rats with experimental cirrhosis of the liver and of liver patients with HE. The aim of this research is to enhance our understanding of the biochemical disturbances in HE and the causal mechanisms, and thereby help improve the foundation for rational treatment of patients with HE.
Publications from our group
Leke R, Bak LK, Anker M, Melø TM, Sørensen M, Keiding S, Vilstrup H, Ott P, Portela LV, Sonnewald U, Schousboe A, Waagepetersen H S. Detoxification of ammonia in mouse cortical GABAergic cell cultures increases neuronal oxidative metabolism and reveals an emerging role for release of glucose-derived alanine. Neurotox Res 2010 In press
Gjedde A, Keiding S, Vilstrup H, Iversen P. No oxygen delivery limitation in hepatic encephalopathy. Metab Brain Dis 2010; 25: 57—63.
Keiding S, Sørensen M, Munk OL, Bender D. Human13N-ammonia PET studies: The importance of measuring 13N-ammonia metabolites in blood. Metab Brain Dis 2010; 25: 49—56.
Berding G, Banati RB, Buchert R, Chierichetti F, Grover VPB, Kato A, Keiding S, Taylor-Robinson SD. Recommendations for imaging and tracer studies in hepatic encephalopathy. Liver Int 2009; 29: 621—628.
Iversen P, Sørensen M, Bak LK, Waagepetersen HS, Vafaee MS, Borghammer P, Mouridsen K, Jensen SB, Vilstrup H, Schousboe A, Ott P, Gjedde A, Keiding S. Low cerebral oxygen consumption and blood flow in patients with cirrhosis and an acute episode of hepatic encephalopathy. Gastroenterology 2009; 136: 863—871.
Bass L, Keiding S, Munk OL. Benefits and risks of transforming data from dynamic positron emission tomography, with an application to hepatic encephalopathy. J Theor Biol 2009; 256: 632—636.
Bak L, Iversen P, Sørensen M, Keiding S, Vilstrup H, Ott P, Gjedde A, Waagepetersen HS, Schousboe A. Metabolic fate of isoleucine in a rat model of hepatic encephalopathy and in cultured neural cells exposed to ammonia. Metab Brain Dis 2009; 24: 135—145.
Sørensen M, Munk OL, Keiding S. Backflux of ammonia from brain to blood in human subjects with and without hepatic encephalopathy. Metab Brain Dis 2009; 24: 237—242.
Johansen ML, Bak LK, Schousboe A, Iversen P, Sørensen M. Keiding S, Vilstrup H, Gjedde A, Ott P, Waagepetersen HS. The metabolic role of isoleucine in detoxification of ammonia in cultered mouse neurons and atrocytes. Neurochem Int 2007; 50: 1042—1051.
Sørensen M, Vilstrup H, Keiding S, Ott P. Hepatisk encefalopati. Ugeskr Læger 2007; 169: 1106.
Sørensen M, Keiding S. New findings on cerebral ammonia uptake in HE using functional 13N-ammonia PET. Metabolic Brain Disease 2007; 22: 277—284.
Schousboe A, Waagepetersen HS, Bak LK, Johansen ML, Keiding S, Vilstrup H, Iversen P, Sørensen M. Når skrumpelever får hjernen til at slå fra. Lægemiddelforskning 2006, Institute of Pharmacology and Pharmacotherapy, University of Copenhagen.
Sørensen M, Keiding S. Reply to Letter-to-the Editor by Lockwood A and Wack DS. Permeability surface products for brain ammonia metabolism. Hepatology 2006; 44: 1053—1054.
Sørensen M, Keiding S. Ammonia metabolism in cirrhosis. In Hepatic Encephalopathy and Nitrogen Metabolism (eds. Häussinger D, Kircheis G, Schliess F), Springer 2006: pp. 406—419.
Keiding S, Sørensen M, Bender D, Munk OL, Ott P, Vilstrup H. Brain metabolism of 13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by PET. Hepatology 2006; 43: 42—50.
Iversen P, Hansen DAa, Bender D, Rodell A, OL, Cumming P, Keiding S. Peripheral benzodiazepine receptors in the brain of patients with cirrhosis and manifest hepatic encephalopathy. Eur J Nucl Med Mol Imaging 2006; 33: 810—816.
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4. Cancer
Primary liver cancer. In a recent study we performed dynamic PET of the liver in 24 patients on the waiting list for liver transplantation due to cirrhosis caused by the liver disease primary sclerosing cholangitis. This disease entails a high risk of the development of biliary duct cancer inside the liver. While CT and ultrasound were unable to detect signs of cancer, PET revealed signs of cancer in three patients that was subsequently confirmed by histology of the removed liver. PET was thus significantly better than CT at detecting very small liver tumours in this group of patients.
Hepatocellular carcinoma can be very difficult or impossible to visualize with CT, ultrasound and FDG PET. This is due to the great similarity with the surrounding tissue as regards both structure and metabolism. We are therefore attempting to exploit differences in the metabolism of malignant and normal liver cells to find a PET tracer suitable for detecting this form of cancer so early as to improve the possibility for curative treatment.
Secondary cancer of the liver. PET is used to diagnose and monitor the treatment of patients with metastases in the liver as well as patients with primary liver cancer. In one in five patients with metastases from colorectal cancer we find that PET improves the treatment strategy.
Fig. 8 illustrates how merging PET (upper) and CT (centre) images into a single image (lower) provides useful information about the precise location of liver metastases from a primary colorectal cancer. We use this information in the planning and monitoring of treatment by surgical resection or other local treatment.
Publications from our group
Fischer B, Lassen U, Mortensen J, Larsen S, Loft A, Bertelsen A, Ravn J, Clementsen P, Høgholm A, Larsen K, Rasmussen T, Keiding S, Gerke O, Skov B, Steffensen I, Hansen H, Vilmann P, Jacobsen G, Backer V, Maltbaek N, Pedersen J, Madsen H, Nielsen H, Højgaard L. Preoperative staging of lung cancer with combined PET-CT. N Engl J Med 2009; 361: 32—39.
Memon AA, Jakobsen A, Dagnaes-Hansen F, Sørensen BS, Keiding S, Nexø E. Positron emission tomography (PET) imaging with [11C] labeled erlotinib. A micro-PET study on mice with lung tumor xenografts. Cancer Res 2009; 69: 873—878.
Busk M, Jakobsen S, Keiding S, van der Kogel AJ, Bussink J, Overgaard J. Imaging hypoxia in xenografted and murine tumors with 18F-Fluoroazomycin arabinoside: A comparative study involving microPET, autoradiography, pO2-polarography, and fluorescence microscopy. Int J Radiat Oncol Biol Phys 2008; 70: 1202—1212.
Johansen J, Buus S, Loft A, Keiding S, Overgaard M, Hansen HS, Grau C, Bundgaard T, Kirkegaard J, Overgaard J. Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study. Head Neck 2008; 30: 471—478.
Sørensen M, Mortensen FV, Høyer M, Vilstrup H, Keiding S. Positronemissionstomografi har klinisk betydning ved planlægning af behandling af kolorektale levermetastaser - sekundærpublikation. Ugeskr Læger 2008; 170: 1364—1366.
Sørensen M, Mortensen FV, Høyer M, Vilstrup H, Keiding S and The Liver Tumour Board at Aarhus University Hospital. FDG-PET improves management of patients with colorectal liver metastases allocated for local treatment: a consecutive prospective study. Scand J Surgery, 2007; 96: 209—213.
Hutchings M, Loft A, Hansen M, Pedersen LM, Berthelsen AK, Keiding S, D'Amore F, Boesen AM, Roemer L, Specht L. Position emission tomography with or without computed tomography in the primary staging of Hodgkin's lymphoma. Haematologica 2006; 9: 482—489.
Hutchings M, Loft A, Hansen M, Pedersen LM, Buhl T, Jurlander J, Buus S, Keiding S, D'Amore F, Boesen AM, Berthelsen AK, Specht L. FDG-PET after two cycles of chemotherapy predicts treatment failure and progression-free survival in Hodgkin lymphoma. Blood 2006; 107: 52—59.
Buus S, Grau C, Munk OL, Rodell A, Jensen K, Mouridsen K, Keiding S. Individual radiation response of parotid glands investigated by dynamic 11C-methionine PET. Radiother Oncl 2006; 78: 262—269.
Prytz H, Keiding S, Björnsson E, Broomé U, Almer S, Castedal M, Munk OL and The Swedish Internal Medicine Liver Club (SILK). Dynamic FDG PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation. Hepatology 2006; 44: 1572—1580.
Sørensen M, Horsman MR, Cumming P, Munk OL, Keiding S. Effect of intratumoral heterogeneity in oxygenation status on FMISO PET, autoradiography, and electrode pO2 measurements in murine tumors. Int J Radiat Oncol Biol Phys 2005; 62: 854—861.
Buus S, Grau C, Munk OL, Bender D, Jensen K, Keiding S. 11C-methionine PET, a novel method for measuring regional salivary gland function after radiotheraphy of head and neck cancer. Radiother Oncol 2004; 73: 289—296.
Grönroos T, Bentzen L, Marjamäki P, Murata R, Horsman MR, Keiding S, Eskola O, Haaparanta M, Minn H, Solin O. Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma. Eur J Nucl Med Mol Imaging 2004; 31: 513—520.
Bentzen L, Keiding S, Nordsmark M, Falborg L, Hansen SB, Keller J, Nielsen OS, Overgaard J. Tumour oxygenation assessed by 18F-fluoromisonidazole PET and polarographic needle electrodes in human soft tissue tumours. Radiother Oncol 2003; 67: 339—344.
Bentzen L, Keiding S, Horsman M, Falborg L, Hansen SB, Overgaard J. Assessment of hypoxia in experimental tumors by [18F]Fluoromisonidazole PET examination and pO2 electrode measurements. Influence of tumour volume and carbogen breathing. Acta Oncol 2002; 41: 304—312.
Kaarstad K, Bender D, Bentzen L, Munk OL, Keiding S. Metabolic Fate of 18F-FDG in mice bearing either SCCVII squamous cell carcinoma or C3H mammary carcinoma. J Nucl Med 2002; 43: 940—947.
Bentzen L, Keiding S, Horsman MR, Falborg L, Hansen SB, Overgaard J. Feasibility of detecting hypoxia in experimental mouse tumours with 18F-fluorinated tracers and positron emission tomography. A study evaluating [18F]Fluoromisonidazole and [18F]Fluoro-2-deoxy-D-glucose. Acta Oncol 2000; 39: 629—637.
Keiding S, Schiøtt KM, Vilstrup H, Gjedde A. Positron-emissionstomografi af levertumorer. Ugeskr Læger 1999; 161: 6163—6165. [Danish]
Keiding S, Hansen SB, Rasmussen HH, Gee A, Kruse A, Roelsgaard K, Tage-Jensen U, Dahlerup JF. Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography. Hepatology 1998; 28: 700—706.
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Pieter Paul Rubens, 1612, Philadelphia Museum of Art
Prometheus Bound
The ancient Greeks knew that the liver possessed an unusual ability to regenerate in response to damage. According to Greek mythology, when the Olympian god Zeus hid fire from mortals, the Titan deity Prometheus stole it from Zeus and retuned it to the mortals. This enraged Zeus, who then had Prometheus taken to the Caucasus Mountains and bound naked to a rock. Every morning an eagle came and pecked away at Prometheus' liver - here depicted by Rubens. Each night, though, Prometheus' liver regenerated.
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